TY - JOUR
AU - Devi, C Subathra
AB - Abstract Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease associated with weakening of bones and joint pain. It primarily involves autoimmunity, matrix destruction, osteoclastogenesis, inflammation, and angiogenesis. Numerous cellular and humoral components of the immune system are involved in the etiology of diseases; however, the cardinal part is played by the inter-cellular signaling messengers called cytokines. Interleukins is a vaguely defined sub-class of cytokines that are abundantly found in the RA patients. The multifariousness and diversity in the function of the interleukins make them very likely to be associated with the pathogenesis in multiple ways. Nonetheless, the variety in opinions of researchers globally has led to contentious inferences. Ergo, in this review we have amalgamated the views of researchers from the past two decades till date to provide a comprehensive report about the role of interleukins in rheumatoid arthritis. Autoimmunity, Cytokines, Interleukins, Rheumatoid arthritis Introduction Rheumatoid arthritis (RA) is an autoimmune disorder characterized by synovial swelling and joint inflammation. RA affects the wrist and small joints of the hand, including the knuckles and the middle joints of the fingers [1]. RA epidemiology in India is about 0.75% [2]. This is considerably lower in contrast to the global prevalence of 1% according to a recent report [3]. A unique feature of RA is its obscure etiology, however, the mechanisms involved in the disease are fairly well known and here we begin to discuss them. Autoantibodies, antibodies against self-proteins, are an integral part of the disease and reflect its autoimmune nature. B cells, maturing inside structures similar to germinal centers within the synovium, are a prominent source of these autoantibodies [4–6]. Out of the several autoantibodies found in RA synovium, rheumatoid factor (RF) and anti–citrullinated protein antibodies (ACPA) are two important biomarkers that significantly correlate with the disease condition [7–10]. Tissue destruction in the synovium is another important feature of RA. The rheumatoid arthritis synovial fibroblasts (RASFs) vociferously destroy the matrix by producing matrix metalloproteinases, enzymes capable of degrading matrix proteins. Recent reports have suggested that the egregious nature of RASFs might be due to epigenetic control [11,12]. Excessive osteoclastogenesis, which commonly leads to bone erosion, is the arthritis counterpart of the disease. Osteoclastogenesis is the formation and development of new osteoclasts, which belong to the hematopoietic lineage in contrast to osteoblasts which have a mesenchymal origin. Normally, the osteoclasts aid in bone remodeling and maintaining the plasma calcium homeostasis [13]. However in RA, bones often become brittle due to excess loss of bone calcium as osteoclastogenesis is protracted. The primary culprit in osteoclastogenesis is known to be receptor activator of NF-κβ ligand (RANKL), a vital mediator of osteoclastogenesis which induces the differentiation of pre-osteoclasts to osteoclasts. Its mode of action requires binding to its cognate receptor RANK present on the membrane of Osteoclasts [14,15]. Nonetheless, RANKL independent pathways are also known [16,17]. Pannus, a tumor-like structure, is a key characteristic of RA. It involves the congregation of numerous immune cells to the synovium often leading to high-bone erosion [18,19]. Adhesion molecules have been found to be responsible for pannus formation [20,21]. Such a phenomenon may not be feasible normally due to the high oxygen requirement, but in RA, angiogenesis follows to support the survival and proliferation of these cells [22,23] (Table 1). Table 1. Overall role of interleukins in rheumatoid arthritis. Interleukins Reason IL-1 Anti-IL-1 mAbs significantly reduced inflammation in RA patients [24]. IL-2 Has potential to restore Treg cells and curb autoimmunity, but may aggravate the disease in some ways [25,26]. IL-4 Administration of antibody-fused-IL-4 showed mollification in arthritis mice [27]. IL-6 Anti-IL-6 mAb reduced RA progression [28]. IL-7 Anti-osteoclastogenic in vitro but osteoclastogenic in vivo [29,30]. IL-8 Can up inflammation by mobilizing neutrophils [31]. IL-10 Reported to suppress inflammatory cytokines [32]. IL-11 Found to appease inflammation but can sustain osteoclast-mediated bone resorption [33,34]. IL-12 Anti-IL-12 mAbs showed synergy with anti-TNFα in treating collagen-induced arthritis (CIA) in murine model [35]. IL-13 Can stimulate MMP production but IL-13 gene therapy has been found to reduce cytokine-mediated inflammation [36,37]. IL-15 Found to inhibit self-tolerance [38]. IL-17 Anti-IL-17 mAb [39] and microRNA [40] mediated IL-17 antagonism showed relief in RA patients. IL-18 Blockade of endogenous IL-18 stymied bone destruction [41]. IL-19 Anti-IL-19 mAbs reduced inflammation and bone destruction in murine model of CIA [42]. IL-20 Anti-IL-20 mAbs were found effective in RA patients [43]. IL-21 IL-21 Fc receptor administration led to decrease in inflammatory cytokine in murine RA models [44]. IL-22 May exacerbate disease condition by increasing inflammation and osteoclastogenesis [45,46]. IL-23 IL-23 blockade led to reduced inflammation [47]. IL-24 Anti-angiogenic but may support recruitment of neutrophils to synovium [48,49]. IL-26 Culprit in upregulating autoimmunity and inflammation. IL-27 A prominent anti-inflammatory cytokine [50]. IL-29 IL-29 was found to trigger RASFs to produce IL-6, IL-8, and MMP-3 in the synovium of RA patients [51]. IL-33 Etanercept plummeted IL-33 serum levels leading to reduction in RA severity [52]. IL-34 IL-34 serum levels significantly correlated with the level of inflammatory cytokines and MMPs [53]. IL-35 IL-35 gene therapy led to an increase in TH17 cell count [54]. IL-37 Downregulates TH17 cytokines [55]. Interleukins Reason IL-1 Anti-IL-1 mAbs significantly reduced inflammation in RA patients [24]. IL-2 Has potential to restore Treg cells and curb autoimmunity, but may aggravate the disease in some ways [25,26]. IL-4 Administration of antibody-fused-IL-4 showed mollification in arthritis mice [27]. IL-6 Anti-IL-6 mAb reduced RA progression [28]. IL-7 Anti-osteoclastogenic in vitro but osteoclastogenic in vivo [29,30]. IL-8 Can up inflammation by mobilizing neutrophils [31]. IL-10 Reported to suppress inflammatory cytokines [32]. IL-11 Found to appease inflammation but can sustain osteoclast-mediated bone resorption [33,34]. IL-12 Anti-IL-12 mAbs showed synergy with anti-TNFα in treating collagen-induced arthritis (CIA) in murine model [35]. IL-13 Can stimulate MMP production but IL-13 gene therapy has been found to reduce cytokine-mediated inflammation [36,37]. IL-15 Found to inhibit self-tolerance [38]. IL-17 Anti-IL-17 mAb [39] and microRNA [40] mediated IL-17 antagonism showed relief in RA patients. IL-18 Blockade of endogenous IL-18 stymied bone destruction [41]. IL-19 Anti-IL-19 mAbs reduced inflammation and bone destruction in murine model of CIA [42]. IL-20 Anti-IL-20 mAbs were found effective in RA patients [43]. IL-21 IL-21 Fc receptor administration led to decrease in inflammatory cytokine in murine RA models [44]. IL-22 May exacerbate disease condition by increasing inflammation and osteoclastogenesis [45,46]. IL-23 IL-23 blockade led to reduced inflammation [47]. IL-24 Anti-angiogenic but may support recruitment of neutrophils to synovium [48,49]. IL-26 Culprit in upregulating autoimmunity and inflammation. IL-27 A prominent anti-inflammatory cytokine [50]. IL-29 IL-29 was found to trigger RASFs to produce IL-6, IL-8, and MMP-3 in the synovium of RA patients [51]. IL-33 Etanercept plummeted IL-33 serum levels leading to reduction in RA severity [52]. IL-34 IL-34 serum levels significantly correlated with the level of inflammatory cytokines and MMPs [53]. IL-35 IL-35 gene therapy led to an increase in TH17 cell count [54]. IL-37 Downregulates TH17 cytokines [55]. The table states the generally accepted notions about various interleukins either being therapeutic agents, therapeutic targets, or showing an intermediate disposition. Bold values: Blockade for amelioration; Italic values: Potential as a therapy; Roman values: controverisal. Open in new tab Table 1. Overall role of interleukins in rheumatoid arthritis. Interleukins Reason IL-1 Anti-IL-1 mAbs significantly reduced inflammation in RA patients [24]. IL-2 Has potential to restore Treg cells and curb autoimmunity, but may aggravate the disease in some ways [25,26]. IL-4 Administration of antibody-fused-IL-4 showed mollification in arthritis mice [27]. IL-6 Anti-IL-6 mAb reduced RA progression [28]. IL-7 Anti-osteoclastogenic in vitro but osteoclastogenic in vivo [29,30]. IL-8 Can up inflammation by mobilizing neutrophils [31]. IL-10 Reported to suppress inflammatory cytokines [32]. IL-11 Found to appease inflammation but can sustain osteoclast-mediated bone resorption [33,34]. IL-12 Anti-IL-12 mAbs showed synergy with anti-TNFα in treating collagen-induced arthritis (CIA) in murine model [35]. IL-13 Can stimulate MMP production but IL-13 gene therapy has been found to reduce cytokine-mediated inflammation [36,37]. IL-15 Found to inhibit self-tolerance [38]. IL-17 Anti-IL-17 mAb [39] and microRNA [40] mediated IL-17 antagonism showed relief in RA patients. IL-18 Blockade of endogenous IL-18 stymied bone destruction [41]. IL-19 Anti-IL-19 mAbs reduced inflammation and bone destruction in murine model of CIA [42]. IL-20 Anti-IL-20 mAbs were found effective in RA patients [43]. IL-21 IL-21 Fc receptor administration led to decrease in inflammatory cytokine in murine RA models [44]. IL-22 May exacerbate disease condition by increasing inflammation and osteoclastogenesis [45,46]. IL-23 IL-23 blockade led to reduced inflammation [47]. IL-24 Anti-angiogenic but may support recruitment of neutrophils to synovium [48,49]. IL-26 Culprit in upregulating autoimmunity and inflammation. IL-27 A prominent anti-inflammatory cytokine [50]. IL-29 IL-29 was found to trigger RASFs to produce IL-6, IL-8, and MMP-3 in the synovium of RA patients [51]. IL-33 Etanercept plummeted IL-33 serum levels leading to reduction in RA severity [52]. IL-34 IL-34 serum levels significantly correlated with the level of inflammatory cytokines and MMPs [53]. IL-35 IL-35 gene therapy led to an increase in TH17 cell count [54]. IL-37 Downregulates TH17 cytokines [55]. Interleukins Reason IL-1 Anti-IL-1 mAbs significantly reduced inflammation in RA patients [24]. IL-2 Has potential to restore Treg cells and curb autoimmunity, but may aggravate the disease in some ways [25,26]. IL-4 Administration of antibody-fused-IL-4 showed mollification in arthritis mice [27]. IL-6 Anti-IL-6 mAb reduced RA progression [28]. IL-7 Anti-osteoclastogenic in vitro but osteoclastogenic in vivo [29,30]. IL-8 Can up inflammation by mobilizing neutrophils [31]. IL-10 Reported to suppress inflammatory cytokines [32]. IL-11 Found to appease inflammation but can sustain osteoclast-mediated bone resorption [33,34]. IL-12 Anti-IL-12 mAbs showed synergy with anti-TNFα in treating collagen-induced arthritis (CIA) in murine model [35]. IL-13 Can stimulate MMP production but IL-13 gene therapy has been found to reduce cytokine-mediated inflammation [36,37]. IL-15 Found to inhibit self-tolerance [38]. IL-17 Anti-IL-17 mAb [39] and microRNA [40] mediated IL-17 antagonism showed relief in RA patients. IL-18 Blockade of endogenous IL-18 stymied bone destruction [41]. IL-19 Anti-IL-19 mAbs reduced inflammation and bone destruction in murine model of CIA [42]. IL-20 Anti-IL-20 mAbs were found effective in RA patients [43]. IL-21 IL-21 Fc receptor administration led to decrease in inflammatory cytokine in murine RA models [44]. IL-22 May exacerbate disease condition by increasing inflammation and osteoclastogenesis [45,46]. IL-23 IL-23 blockade led to reduced inflammation [47]. IL-24 Anti-angiogenic but may support recruitment of neutrophils to synovium [48,49]. IL-26 Culprit in upregulating autoimmunity and inflammation. IL-27 A prominent anti-inflammatory cytokine [50]. IL-29 IL-29 was found to trigger RASFs to produce IL-6, IL-8, and MMP-3 in the synovium of RA patients [51]. IL-33 Etanercept plummeted IL-33 serum levels leading to reduction in RA severity [52]. IL-34 IL-34 serum levels significantly correlated with the level of inflammatory cytokines and MMPs [53]. IL-35 IL-35 gene therapy led to an increase in TH17 cell count [54]. IL-37 Downregulates TH17 cytokines [55]. The table states the generally accepted notions about various interleukins either being therapeutic agents, therapeutic targets, or showing an intermediate disposition. Bold values: Blockade for amelioration; Italic values: Potential as a therapy; Roman values: controverisal. Open in new tab All of these features make targeting the disease difficult due to the multiple variables involved. Even so, a common link exists among them: interleukins. This review provides an insight into the role of all the interleukins involved in the pathogenesis as well as the assuagement of RA. Interleukin 1 (IL-1) is an inflammatory cytokine. There are two distinct sub-types of IL-1, Interleukin 1α and 1β [56,57]. Lopalco et al. [58] referred to IL-1 as a “common denominator in autoimmune disorders” for its ubiquitous presence in a wide spectrum of autoimmune diseases. IL-1 primarily mediates inflammation by cyclooxygenase-2 (COX-2) upregulation through nuclear factor κβ (NF-κβ) transcription [59]. The abundance of COX-2 in synovium is perhaps one of the reasons behind the intense inflammation felt by RA patients. In an experiment, recombinant IL-1 with tumor necrosis factor α (TNFα) injected into rabbit knee showed a synergistic effect in causing leucocyte infiltration which shows IL-1’s prowess in coordination with other inflammation mediators [60]. IL-1 also exhibits upregulated cluster of differentiation 40L (CD40L) mediated cytokine stimulation of IL-12p70, an important factor for TH1 development [61,62]. Moreover, it can induce IL-6 and IL-8, which again have a discernible role in RA progression [63–65]. The chemotactic nature of this cytokine can be attributed to CAM mobilization and IL-1’s role in angiogenesis [66,67]. One mechanism of angiogenesis is through induction of vascular endothelial growth factor (VEGF) in cells [68]. For this reason, IL-1 inhibition therapy has been used to treat tumors and metastasis [69]. This pleiotropic cytokine also plays a significant role in RANKL mediated osteoclastogenesis and a common flavonoid kaempferol has shown to reduce this effect [70,71]. Normally, IL-1 activity is modulated by its natural inhibitor, IL-1 receptor antagonist (IL-1ra), but in case of RA an imbalance is seen [72]. The necessity to fix this imbalance led to the development of a recombinant IL-1ra, Anakinra [73]. Even so, more anti IL-1 antibodies are in development and have been compared for treatment since IL-1 still remains a prominent target for the treatment of RA [24]. Since IL-1 is also secreted by cells, especially macrophages, in response to damage-associated molecular patterns (DAMPs) and pattern-associated molecular patterns (PAMPs) by Toll-like receptors (TLRs), Rig-like receptors (RLRs), and NOD-like receptors (NLRs), IL-1 can be quite abundant during the state of inflammation [74]. We believe it is essential to highlight the primacy of this cytokine and there is a need to look more into these mechanisms, which could be a lot more involved in the pathogenesis than we currently know. Interleukin-2 (IL-2) functions by binding to its cognate hetero-trimer receptor consisting of CD25 (α chain), CD122 (β chain), and CD132 (common γ chain); or a heterodimer of CD122 and CD132 (since CD25 has been found to be dispensable for signal transduction) [75]. It is known to exhibit autocrine stimulation and activation in T helper cells in murine model and has severe implications in leukemia [76,77]. The autocrine stimulation results in an amplified T helper response during the disease condition. However, at the same time IL-2 is required for Treg development and also modulates T helper and T follicular differentiation. This leaves us in a dilemma whether IL-2 can be considered a therapeutic target. IL-2 may also play a part in matrix destruction in RA since murine IL-2 was found to induce the natural killer (NK) cells to produce MMPs [78]. Wood et al. [26] appended that a deficiency of IL-2 in the serum of RA patients relates to the disease condition while another group, Kitas et al. [79], in the same year reported that decrease in serum IL-2 level reflected RA activity. This unveils the doubled faced behavior of IL-2 in autoimmunity [80–84]. For its immunosuppressive function, recombinant IL-2 (proleukin) is one of the few cytokines that have been approved by FDA for therapeutic use. As far as angiogenesis is concerned, recombinant IL-2-induced NK cells were found to assist in angiogenesis in myocardial infarction but such a function in RA has not been demonstrated yet [85]. Current IL-2 inhibition therapies include basiliximab and daclizumab, which are anti-CD25 (anti IL-2 receptor α chain) antibodies [86]. Due to continuous research and shifting opinions, it was reported of late that IL-2 therapy in low dose may help rejuvenate the Treg count in RA patients; hence, putting IL-2 in the list of the potential therapeutic cytokines [25]. The clinical trials are underway [87]. Even so, the role of IL-2 in normal functioning of the adaptive immune system in vivo is quite unique and non-overlapping, unlike the role of some other cytokines. It not only indirectly controls inflammation but also maintains overall adaptive immunity by assisting in the proliferation of T helper cells. A deficiency or an excess blockade may render the patient susceptible to those pathogenic invasions which require T helper liaison for defense. Interleukin-3 (IL-3) is a growth factor that functions by binding to its receptor complex consisting of α and β subunits. It shares the common α and β chain receptor subunits with IL-5 and GM-CSF which serve similar purposes [88]. The primary function of this cytokine is to assist in the differentiation of hematopoietic stem cells (HSC) to myeloid progenitor cells but other cytokines with overlapping function also exist [89]. Brown et al. [90] suggested that IL-3 could assist IL-7 in differentiating HSCs to lymphoid progenitors. IL-3 mostly acts as a controlling element in RA since it inhibits TNFα induced bone resorption in inflammatory arthritis even in the presence of pro-inflammatory cytokines by preventing the activity of AP-1 and the translocation of c-Fos to the nucleus [91]. Gillespie et al. [92] in their study stated that IL-3 could inhibit RANK-mediated osteoclastogenesis. IL-3 has also been shown to stimulate IL-2-induced Treg production in collagen-induced arthritis (CIA). Hence, it also establishes the central role of Treg cells in controlling autoimmunity [93]. On the negative side, raised levels of IL-3 have been found during the earlier stages of RA which supposedly aid in producing terminally differentiated lymphoid cells. Anti-IL-3 mAbs are currently under clinical trials. Interleukin-4 (IL-4) is a pleiotropic cytokine. It acts by binding to its cognate receptor IL-4α and shares a receptor subunit with IL-13, which has somewhat overlapping functionality with IL-4 [94]. The major functions of IL-4 include IgE class switching and allergy. In addition, it also shows autocrine stimulation in inducing naïve T cells to TH2 cells, i.e. TH2 polarization [95]. This cytokine has some pronounced anti-inflammatory effects. It inhibits IL-1-induced matrix destruction [96]. In lipopolysaccharide (LPS)-induced monocytes, it directly modulates IL-1 transcription, stimulates the production of IL-1’s natural antagonist, IL-1Ra, and modulates other inflammatory cytokines, such as IL-6 and TNFα [97,98]. It enables alternative activation in macrophages and monocytes which brings out their anti-inflammatory role [99]. Through a cdkn2a-dependent mechanism, IL-4 induces CD8 + T cell population, which produces IL-10, a potent immunomodulatory cytokine. IL-4 also inhibits osteoclastogenesis in three ways. Firstly, it downregulates IL-11 in RA synovial cells, secondly, it aids in STAT-6 dependent inhibition of NF-κβ, which is an important element in RANK-mediated osteoclastogenesis, and thirdly, it acts directly on peroxisome proliferator-activated receptor γ1 [100–102]. High-IL-4 levels were found in RA patients and this upregulation was inferred as a control mechanism to alleviate the disease condition. Moreover, a recent study by Hammerle et al. [27] succeeded in curing murine arthritis with antibody-based IL-4 delivery. This certainly makes IL-4 a promising therapy. Interleukin-5 (IL-5) is a TH2 cytokine secreted by TH2 cells and mast cells. It functions by binding to its cognate receptor IL-5R. Its primary roles in immunity include activation of eosinophils, induction of B cell growth, and mucosal IgA secretion [103]. It can check inflammation and studies have confirmed that IL-5 can also reduce tumor metastasis in lungs [104,105]. IL-5 has shown to promote Treg cells to suppress autoimmunity, whatsoever, no direct link exists with RA since IL-5 is not much expressed in the synovium [106]. Interleukin-6 (IL-6) functions through the receptor complex consisting of IL-6Rα (CD126) and the signal transduction element gp130 (CD130). As a myokine, it has immunosuppressive effects and is released during strenuous muscle exercise [107]. As a cytokine, it is too substantial a factor to be overlooked in RA. High-IL-6 mRNA is found in the synovium of RA patients and Wada et al. [108] suggested that it is due to sudden epigenetic changes, i.e. anomalous histone acetylation. Also, it has been found that NF-κβ is an important regulator of IL-1β-induced IL-6 expression in RA-fibroblast-like synoviocytes (RA-FLS) [109]. IL-6 stimulates B cell growth in synovium and pannus formation through VEGF induction. This also establishes its role in angiogenesis [110–112]. Regarding osteoclastogenesis, Palmqvist et al. [113] found that IL-6, with its receptor, can induce RANK-mediated osteoclastogenesis while Yoshitake et al. [114] got some contradicting results. Unlike its myokine function, IL-6 as a cytokine can inhibit Treg induction and with TGFβ it promotes TH17 differentiation which has implications in autoimmunity [115,116]. Even fatigue in RA has a significant correlation with IL-6 serum levels [117]. This shows the deep connection IL-6 has with this disease. Current treatments include IL-6 antagonism through siltuximab and IL-6 receptor antagonism through tocilizumab. Another human anti-IL-6 antibody, sirukumab, has been found safe for use in patients [28,118,119]. Curcumin, an active component of Curcuma longa, can also modulate IL-6 gene expression [120]. Interleukin-7 (IL-7) is a type-1 cytokine produced by bone marrow stromal cells and functions by binding to its cognate receptor IL-7R, a heterodimer of α subunit (CD127) and common γ chain (CD132). It is essential for the differentiation of HSCs to terminally differentiate lymphoid cells as well as their development [121–123]. Contrary to its systemic role, IL-7 can modulate T cell function in vivo in RA patients [124]. High IL-7 has clear correlation with pronounced effect in osteoclastogenesis, monocyte homing, and angiogenesis [30,125]. However, IL-7 has shown to inhibit osteoclastogenesis in vitro in M-CSF and RANKL-induced bone marrow cultures [29]. While high IL-7 plays a pro-inflammatory role in RA by activating CD4 + T cells and macrophages, lymphocyte-depleting therapy in RA was followed by low-IL-7 expression leading to lymphopenia. Also, it is believed that low IL-7 can be the cause of RA relapse after remission [124,126,127]. We believe that treatment with exogenous IL-7 after lymphocyte-depleting therapy may prove helpful as it can rejuvenate the immune system. Interleukin-8 (CXCL8, IL-8) is a chemokine produced by macrophages, epithelial cells, and endothelial cell. It is also called neutrophil chemotactic factor. Chemokines are the alarm bells of the immune system that attract leucocytes to the site of injury. IL-8 functions by binding to chemokine receptors CXCR1 and CXCR2 present on neutrophils [128]. NF-κβ is important for the regulation of IL-1β- and IL-17-induced expression of IL-8 in RA-FLS [109,129]. Troughton et al. [31] in their research suggested that IL-8 helps in neutrophil priming and since neutrophils are one of the key agents responsible for synovium infiltration, IL-8 conspicuously aids in RA pathogenesis. These neutrophils release neutrophil extracellular traps (NETs) which have severe implications in autoantibody production, another hallmark of RA [31,130]. Not only that, IL-8 can itself activate NF-κβ through TRAF-6 dependent pathway which can lead to angiogenesis as well as osteoclastogenesis [131]. The chemokine signaling through CXCR1 present on osteoclasts and their progenitors is another reason for osteoclastogenesis mediated by this chemokine [132]. IL-8 has been found to prevent endothelial cell apoptosis and increase MMP production, which is the primary cause of tissue destruction in RA [133]. Anti-IL-8 autoantibodies can be found circulating in RA patients and are potential biomarkers of the disease condition [134]. Interleukin-9 (IL-9) functions through its cognate receptor IL-9R. It is majorly produced by TH9 cells and has shown to arrest cell growth in cancer [135,136]. IL-4 and TGFβ help in the proliferation of IL-9-producing TH9 population in both murine and human models. IL-21 has a similar effect in the regulation of TH9 cells with a complex network of cytokines closely associated [137–139]. Elyaman et al. [140] showed how IL-9 could play a protective role in autoimmunity by enhancing the function of FoxP3+ CD4+ Treg cells in vitro, but on the other hand it could also facilitate TH17 differentiation. Recent studies have talked about the possible role of IL-9 and TH9 cells in RA since high expression was seen in patients [141,142]. It has been found in some diseases that IL-9 is closely involved in angiogenesis through VEGF expression, hence it may have similar repercussions in RA as well [143,144]. However, till date little is known about this cytokine in the context of RA. Interleukin-10 (IL-10) also called cytokine synthesis inhibitory factor (CSIF), is a prodigious anti-inflammatory cytokine. It functions through its receptor IL-10R1 complex. It is produced by TH2 cells, Tc cells, monocytes, Treg cells, and mast cells [145–147]. IL-10 has been named CSIF taking in account its ability to reduce the synthesis of many cytokines including IL-1, IL-6, IL-8, IL-12 and TNFα in humans, and other [148–151]. This may be attributed to the inactivation of NF-κβ by IL-10 through DNA binding of the repressive homodimer p50/p50 [152]. IL-4 is the natural inhibitor of IL-10 [153]. IL-10 has a byzantine part in autoimmunity since it can facilitate plasma cell differentiation for the production of antibodies but also aids Treg cells in immune tolerance [154–156]. It can also suppress TH17 cells, which are primarily involved in RA progression, by binding to IL-10 receptor present on their surface [157,158]. IL-10 has somewhat inconclusive role in angiogenesis. Alexandrakis et al. [159] showed that IL-10 could induce angiogenesis in multiple myeloma. Dace et al. [160] and Wu et al. [161] had supportive findings where they embellished the mechanism of IL-10-induced angiogenesis in hypoxia; nonetheless, the work by Kohno et al. [162] was met with contradicting results in case of ovarian cancer. Talking about osteoclastogenesis, IL-10 can inhibit this phenomenon by reducing the expression of NFATc1, a momentous transcription factor that mediates osteoclast differentiation. IL-10 can also reduce the translocation of NFATc1 to the nucleus [163]. Moreover, inhibition of NF-κβ may be an important factor as well [164]. Early reports stated that high expression of IL-10 in RA may be a marker for the pathogenesis [165]. Furthermore, van Roon et al. [166] argued that IL-10 could aggravate inflammatory response to immune complex via upregulation of FcγR, a receptor present on some cells that binds the fc fragment of antibodies. But later, Keystone et al. [167] suggested IL-10 as possible therapy for RA. This was mainly because of the argument that the anti-inflammatory function of IL-10 supersedes its inflammatory counterpart. Recombinant IL-10 (rIL-10) has been subjected to clinical trials and has been found safe in humans. It appears to be effective to an extent [32]; however, this treatment alone cannot be considered a successful therapy and we recommend combination therapy with other cytokines. Interleukin-11 (IL-11) functions by binding to its receptor IL-11R composed of two chains, α-chain and gp130. It belongs to the IL-6 family since it signals through the gp130 signal transduction chain [168]. IL-11 was first identified to be functional in hematopoiesis but cytokines with redundant functions also exist [169–171]. It is an essential factor for platelet formation and bone remodeling [172,173]. IL-11 is known to be critical in inducing metastasis by activating NF-κβ and PI3K and regulating adhesion molecules (ICAM) in chondrosarcoma [174]. Autocrine stimulation of IL-11 has been found in hypoxia leading to tumor progression [175]. It should be noted that hypoxia is seen in RA pannus as well [176]. Girasole et al. [34] put forward that IL-11 could promote osteoclastogenesis and later the mechanism was explained to be independent of RANKL, by Kudo et al. [177]. What is more, IL-11 significantly sustains osteoclast progenitors in breast cancer [178,179]. On the other hand, endogenous IL-11 inhibition in RA patients led to increase in TNFα, MMP1, and MMP-3. Hence, IL-11 activity can be inversely related to matrix destruction. Recombinant human IL-11 (rIL-11) has shown anti-inflammatory properties [180]. It was found to be safe in clinical trials and was considered a therapy, but its osteoclastogenic activity leaves us in a dilemma if it could be a promising one [33]. Interleukin-12 (IL-12) is an important TH1 differentiation factor and acts through its heterodimeric receptor IL-12R consisting of two subunits, IL-12Rβ1 and IL-12Rβ2 [181]. IL-12 facilitated TH1 differentiation from naïve T cells through T-bet upregulation [182–184]. It also upregulates IFNγ and IL-10 in T cells [185,186]. IL-12 can inhibit TNFα-induced osteoclastogenesis through Fas–FasL and LPS-stimulated osteoclastogenesis in mice [187,188]. IL-12 is required for angiostatin-mediated angiogenesis inhibition and gene therapy using IL-12 gene has been tried as well. This highlights the anti-angiogenic prowess of IL-12 [189,190]. It even shows synergism with IL-18 in inhibiting osteoclastogenesis [191]. IL-12, with IFNγ, can convert TH17 cells into a peculiar cell type called TH1/TH17 which co-express RORγt and T-bet, the markers for type-17, and type-1 T cells, respectively. [192]. Nonetheless, despite the above facts, IL-12 and its IL-12 receptor are serious culprits in RA disease condition and exogenous IL-12 can lead to aggravation of RA [193]. Moreover, this cytokine has been found in high level in the synovial tissues of the patients [194–196]. Anti-TNF and Anti-IL-12 have shown to synergistically suppress the progression of murine CIA [35]. IL-12 antagonists have been in use to ameliorate RA. Interleukin-13 (IL-13) is a TH2 cytokine and shares similar sequence, structure, function, and a receptor subunit (IL-4α) with IL-4 [197,198]. IL-13 primarily deals with parasitic response. It is produced by TH2 cells and nuocytes, the type-2 innate lymphoid cells, exhibiting severe implications in asthma [199,200]. IL-13 has a blatant anti-inflammatory effect. It has been shown to suppress TNFα accumulation in guinea pig lungs [201]. IL-13 can prevent angiogenesis and IL-13 gene therapy has been done in rat model of RA to inhibit angiogenesis [202,203]. On the other side, IL-13 through its receptor IL-13Rα2 can further cancer metastasis and invasion as seen in the murine model of human ovarian cancer. It can also stimulate MMP production through AP-1 transcription factor activation [37]. These results may give us an insight into how IL-13 can be a contingent factor in fostering both cell recruitment and matrix destruction. But it is known that IL-13 is present in the synovium of RA patients and exogenous IL-13 can diminish the activity of inflammatory cytokines in the synovium [204]. In fact, Woods et al. [36] reported that IL-13 gene therapy was successful in plummeting inflammatory cytokines and PGE2 in the synovium of RA [36]. Even so, Marinou et al. [205] appended that polymorphism in IL-13 genes, and not a common variant of IL-13, might be responsible in RA. The pleiotropy of this cytokine has welcomed quite a lot of contradictory views. By and large, IL-13 is a beneficial cytokine that stymies overall inflammation in RA patients. Interleukin-14 (IL-14), also called Alpha-taxilin, is a B cell growth factor required for the growth of B and T cells and in their survival [206]. It has been found that lymphoma cancer cells conspicuously produce IL-14 but no relation with RA has been discussed so far [207]. However, anti-IL-14 mAb has been produced to look for any possible implications in autoimmune diseases [208]. Interleukin-15 (IL-15) is structurally similar to IL-2 and signals through the common γ chain (CD132) and the shared IL-2/IL-15β subunit (CD122) [209,210]. IL-15-induced IL-10 can increase the cytotoxic effect of NK cells through STAT3 signaling and is also required by CD8+ T cells to obtain functional NK receptors [211–213]. Not only that, IL-15 has also shown to induce IL-2α chain and a functional IL-2 receptor on memory-like NK cells [214]. In RA, IL-15 is highly expressed in RA patients and is known to mediate T cell dependent TNFα production but blocking TNFα has no effect on synovial expression of IL-15. Recruitment and activation of T cells, a phenomenon responsible for pannus formation in RA patients, is also mediated by IL-15 [215–217]. Besides that, IL-15 can promote the production of inflammatory cytokines, such as IL-17 and IFNγ [218–222]. Angiolillo et al. [223] found that IL-15 could promote angiogenesis in vivo. Badolato et al. [224] elucidated the role of IL-15 in inducing IL-8, an angiogenic chemokine in human monocytes but Lügering et al. [225] found rather contrasting results in human colonic cells. IL-15 may also have a hand in matrix destruction as well since it can also induce MMP-9 [226]. Furthermore, Tao et al. [227] proposed a correlation between the levels of MMP-7 and IL-15 in osteoarthritis. In the context of bone resorption, IL-15 can potentially cause apoptosis in osteoblasts and promote osteoclastogenesis through the PLD pathway [228–230]. IL-15 undoubtedly plays a pivotal role in RA. It is involved in the disease progression since IL-15 receptor-α is increasingly expressed in RA [231]. The cytokine-receptor system can lead to inflammation and autoimmunity [38]. Current therapies include IL-15 blockade with HuMax, an anti-IL-15 IgG1 antibody, for RA, and some other autoimmune diseases [232]. Interleukin-16 (IL-16) is a chemoattractant and modulator for T cells. It was formerly called lymphocyte chemoattractant factor (LCF) [233–235]. Blaschke et al. [236] found that there was a high expression of IL-16 in RA synovial fluid but no correlation with the disease activity could be established. Hence, IL-16 probably has an immunomodulatory role. Surprisingly it has been postulated that the CD8+ cells that intrude the synovium in RA may have an anti-inflammatory role partially due to their ability to release IL-16 and for this reason, IL-16 is a biomarker for early diagnosis of RA [237,238]. RA-synovial fibroblasts (RA-SF), B cells, and mast cells also produce this cytokine, perhaps, in response to the excess inflammation [239–241]. Lynch et al. [242] showed that IL-16 might preferentially attract TH1 cells through CD4+ binding which was enhanced in presence of CCR5, a chemokine. In fact, IL-17 can induce RA-FLS to produce IL-16 which may explain the high-IL-16 expression in the synovium [243]. Although IL-16 has no proven inflammatory role in the context of RA, it exhibits severe implications in case of other autoimmune diseases, such as multiple sclerosis [244]. Lately, Park et al. [245] have proven that IL-16 can bind to NF-κβ, AP-1, and Sp-1 motifs in vascular smooth muscle cells (VSMCs) to induce MMP-9 expression. This opens a way for a contingent role of IL-16 in matrix destruction in RA. Thus, it can be thought that IL-16 is a potential candidate for therapy in RA [237]. Interleukin-17 (IL-17A) is another infamous cytokine with respect to RA. It signals through its cognate receptor, IL-17RA. It has a major role against extracellular host pathogens; yet, it can also influence autoimmunity and tumor growth [246–248]. IL-17 has a ubiquitous role in RA and copious research work has been done on it. Normally, a TH17/Treg balance exists that prevents autoimmunity and immunosuppression, however, this balance is maintained by cytokines and they can disrupt it too [249]. TGFβ and IL-23, in presence of IL-6, can aid in TH17 differentiation and inhibit TH1 and TH2 differentiation [250]. Another cytokine TNF-like weak inducer of apoptosis (TWEAK) can also promote IL-17 upregulation [251]. IL-1, IL-18, and IL-23 can induce IL-17 production from γδ-T cells [252,253]. Conversely, mesenchymal stem cells (MSCs) have shown to inhibit the differentiation of IL-17-producing TH17 cells through IFNγ [254]. RORγt is the key transcription factor required for the differentiation of TH0 cells to TH17 cells, which idiosyncratically produce IL-17 [255]. Since high-TH17 differentiation signifies low-Treg count, these cells have a vicious role in autoimmunity which they mediate through IL-17 production [256,257]. The inflammatory role of IL-17 can also be attributed to its ability to induce other cytokines namely IL-6 and TNFα [248,258]. IL-17 has shown synergism with hypoxia in assisting RA synoviocyte migration by increasing MMP-2 and MMP-9 [259]. This brings out a clear role of IL-17 in matrix destruction. Moreover, IL-17 can mediate angiogenesis via the PI3K/AKT1 pathway [260]. Osteoclastogenesis and pannus formation are also mediated by IL-17 [261]. The mechanism in osteoclastogenesis is majorly RANKL induction, which leads to loss of RANKL/osteoprotegerin balance. Osteoprotegerin is a dummy receptor for RANKL which greatly controls osteoclastogenesis [262]. Another mechanism exists for osteoclastogenesis in the absence of osteoblasts which was found to be inhibited by anti-TNFα antibody. Hence, IL-17 can increase TNFα-mediated osteoclastogenesis [263]. This process is exacerbated in the presence of IL-32 [264]. Besides the above-mentioned roles, IL-17 gene polymorphism is also associated with RA with gene variants having juxtaposing effects in disease progression [265]. Clearly, targeting IL-17 and/or its receptor is necessary, even if not sufficient, to impede RA progression [266,267]. Multiple therapies exist that target IL-17. IL-23 blockade to prevent TH17 differentiation is one [268]. Röhn et al. [269] suggested vaccination against IL-17 as a new approach for treating RA. Secukinumab, an anti-IL-17A mAb, has shown relief in RA patients in cases when DMARDs and other therapies failed [39]. Anti-IL-17 therapy with anti-TNFα therapy has shown better results than anti-IL-17 alone [270]. MicroRNA therapy with miR-23b has shown IL-17 suppression in autoimmune inflammation [40]. IL-17 and its receptor are undoubtedly substantial therapeutic targets. Notwithstanding, we reckon that rather than suppressing IL-17 itself, it is wiser to regulate the cytokine signals like IL-6, IL-21, and IL-23 that appear upstream in the pathway and stimulate the TH17 cells to secrete IL-17. Interleukin-18 (IL-18), also called IFNγ inducing factor, binds to its receptor IL-18 for functioning. It is a member of IL-1 superfamily [271]. IL-18 mediates TH1 response.IL-18 has shown in vitro production of TNFα by CD14+ macrophages and promotes GM-CSF synthesis independently. In turn, TNFα and IL-1β can help in IL-18 upregulation. Since IL-18 primarily induces IFNγ, it is critical in TH1 development which adds to its inflammatory function and role in RA [272]. IL-12 can affect IL-18 expression in multiple ways. It upregulates IL-18 receptor expression on T and B cells and in this way it also synergistically skyrockets the expression of IFNγ. With IFNα, it can increase IL-18 receptor gene expression on NK cells and T lymphocytes [273,274]. IL-21 also positively influences the production of IFNγ in conjunction with IL-18 [220]. It is well established that IFNγ is a key cytokine in TH1 response hence the inflammatory property of IL-18 can be partially attributed to it. One element that can control IL-18 expression is IL-4 since IL-4 and STAT6 knockout T cells responded to IL-18 more readily due to higher IL-18Rα expression [275]. IL-18 has been known to induce autoantibodies in the marginal zone of the spleen; hence, it can cause autoimmune diseases [276]. IL-18 can also promote angiogenesis through Src and JNK kinase signaling and VEGF induction but some researchers have suggested a suppressive role in angiogenesis as well [277–282]. Chemokine production is embellished by IL-18 in human keratinocytes. It may have a similar action on the cells of the synovium, which exacerbates angiogenesis in RA [283]. IL-18 is significantly expressed in synovium of RA patients and can act as a leucocyte attractant [280]. Ji et al. [284] published about the implications of IL-18 gene polymorphism in RA. Meanwhile in the same year, Fariasa et al. [285] obtained results which were quite contradicting. IL-18 can bolster the production of osteoclastogenic factors in FLS; however despite that, it was experimentally proven by Horwood et al. [286] that IL-18 actually inhibits osteoclast formation [287]. Amalgamating all the above-mentioned factors, one thing is for sure, IL-18 orchestrates the pathogenesis of RA. For its high expression, IL-18 soluble receptor can be considered a biomarker for the disease condition [288]. Debets et al. [271] found that anti-IL-1 receptor accessory protein-like (IL-1RAcPL) can inhibit IL-18 function. Since caspase-1 is required for IL-18 processing, inhibiting it is another way to control IL-18 expression [289]. In fact, Plater-Zyberk et al. [41] suggested IL-18 blockade to be a beneficial therapy in RA. Since IL-18, in similar fashion to IL-1, is also secreted in response to DAMPS and PAMPS by cells through pattern recognition receptor (PRR) signaling [74], there is a need to look deeper into the participation of these receptors in RA. Interleukin-19 (IL-19) is a TH2 cytokine and a member of IL-10 family. It functions through the IL-20 receptor complex. IL-19 can upregulate some potent inflammatory cytokines, IL-6 and TNFα. This somewhat explains the role of IL-19 in autoimmune diseases [290–292]. IL-19 can promote angiogenesis in human endothelial cells and ischemic hind limbs. Mice injected with recombinant IL-19 were found to have higher VEGF-A expression. Macrophage polarization is another mechanism through which it mediates angiogenesis [293–295]. There is no vivid role of IL-19 in matrix destruction explained till date. Blockade of IL-19 in rats with CIA mollified the condition with decreased swelling in the limbs [42]. This may be due to the inhibition of angiogenesis followed by less lymphocyte recruitment. On this basis, we can hypothesize that IL-19 blockade may bring a similar relief in RA patients. Interleukin-20 (IL-20) signals through IL-20 receptor which consists of two subunits, α and β [292]. IL-20 has some overlapping roles with IL-19 including inflammation [296]. It is known to cause inflammatory skin diseases [297]. Heuzé et al. [297] have experimentally shown that IL-20 can have anti-inflammatory effects as well through COX-2 inhibition. The paradigm that IL-20 is anti-angiogenic can be juxtaposed with the work by Hsieh et al. [298] who have shown the direct and indirect ways in which IL-20 takes part in angiogenesis. IL-20 receptor was found to be severely overexpressed in RA [299]. Hsu et al. [300,301] in a series of work managed to show that anti-IL-20 mAbs were successful in plummeting not only osteoclast differentiation but also inflammation. IL-20 may also cause matrix destruction since it can upregulate MMP-9 and MMP-12 in case of breast cancer [302]. Recently, laser therapy to reduce IL-20 expression in RA patients has been introduced [303]. Treatment with anti-IL-20 mAb in RA patients was found to restore salubrity in the phase II trials [43]. Interleukin-21 (IL-21) is a class-I cytokine which functions through its receptor IL-21R and CD132. It has been found that the common γ chain (CD132) is indispensable for IL-21 signaling [304–306]. IL-21 modulates immunity in multiple ways, including the activation of NK cells and cytotoxic T cells [307–310]. Spolski et al. [311] called IL-21 “a double-edged sword” in their review for the both beneficial and detrimental effects IL-21 has on immunity. Autocrine stimulation of TH17 cells is one of the mechanisms through which IL-21 aggravates autoimmune disease, specifically RA. It also leads to a humungous secretion of IL-17 followed by fervent inflammation in RA [312–317]. Another reason is the development of T follicular cells which is mediated by IL-21 [318–321]. IL-6 can stimulate IL-21 production and its blockade has shown to reduce IL-21-mediated autoantibody production in RA [322,323]. IL-21 has a reputation for being an angiostatic cytokine since it prevents angiogenesis and tumor progression [324,325]. IL-21 furthers IL-17 secretion; therefore, it undoubtedly has a role in RANK-mediated osteoclastogenesis in RA human patients [326,327]. It can be assumed that IL-21 blockade is better therapy than IL-17 inhibition since IL-21 is its upstream mediator. In fact, there is a direct correlation between lowering in IL-21 serum level and the betterment of the RA condition [328]. Summing up, IL-21 can surely said to be a therapeutic target. Its blockade circumscribes the activity of T and B cells and has been found to reduce the pace of RA progression in animal models [44,329,330]. The need of the hour is a small chemical inhibitor against IL-21 which can slow down the autocrine stimulation of TH17 cells. Interleukin 22 (IL-22) is a TH17 cytokine that binds to its heterodimeric receptor complex made of IL-10R2 and IL-22Ra subunits [331]. The IL-22 receptor complex is expressed on tissues, not on immune cells, and IFNγ can upregulate the receptor expression. Therefore, it increases the innate immune response [332]. IL-22 showed angiogenesis in human umbilical cord endothelial cells (HUVEC) and its blockade reversed the effect, a similar effect in RA may possibly be hypothesized [333]. High IL-22 led to increased RANK mRNA in RA-SFs. We can conclude that IL-22 level correlates with the degree of osteoclastogenesis in RA patients [45]. In murine model of CIA, IL-22 was also found to increase autoantibody production apart from osteoclastogenesis [46]. They also regulate chemokine secretion and for the high level of IL-22 found in RA synovium, it is clear that this cytokine also has a role in the pathogenesis of this disease [334,335]. Anti-IL-22 antibodies have been trialed for psoriasis but not in RA. It is necessary to realize the IL-22 as a potential therapeutic target [336,337]. Interleukin 23 (IL-23) is a heterodimeric cytokine sharing a subunit with IL-12. It signals through its receptor composed of two subunits, IL-12β1 and IL-23R [338]. It has been reported that a novel protein p19 comes together with the IL-12p40 subunit to give rise to IL-23 [339]. For this reason, it also shares some functions with IL-12. It can also stimulate the TH1 cytokine IFNγ in T cells. STAT3 signaling in tumor niche can upregulate IL-23 production, which leads to more carcinogenesis [340,341]. Hamdy et al. [342] have linked IL-23 receptor gene polymorphisms with RA in Egyptian patients. The extensive role of IL-23 in autoimmunity can be attributed to its ability to induce the differentiation of TH0 cells to IL-17 producing inflammatory TH17 cells. Hence, blockade of IL-23 can attenuate TH17-mediated inflammation and autoimmunity [343–345]. IL-23 inhibits osteoclastogenesis in an indirect manner independent of RANKL [346]. In the context of angiogenesis, Przepiera-Będzak et al. [347] experimentally proved for several disorders, even though not for RA that IL-23 expression has no correlation with the presence of angiogenic cytokines. At the same time, IL-23 can lead to matrix destruction by MMP-9 expression [348]. Murphy et al. [349] reported their findings that IL-23 null mice could potentially rejuvenate in case of CIA. Ergo, antagonizing IL-23 has a therapeutic effect in autoimmune diseases, particularly RA [47,350]. Interleukin 24 (MDA-7, IL-24) is a TH2 cytokine belonging to IL-10 family of cytokines. It functions through its heterodimeric receptor, IL-20R1/IL-20R2, and IL-22R1/IL-20R2. This receptor is also shared by IL-19 and 20. This cytokine is usually secreted by TH2 cells and monocytes [292,351,352]. IL-24 is a pleiotropic cytokine with both beneficial and deterring roles in RA. A few studies have concluded that IL-24 can reduce growth and neovascularization in endothelial cells [353,354]. Nishikawa et al. [48] supported this finding by showing the suppression of angiogenesis after IL-24 gene therapy. However, high expression of IL-24 and its receptor in RA was correlated with the presence of chemokines CCL2/MCP-1 which recruited neutrophils. This is found to be one mechanism how IL-24 worsens the disease condition in RA [299]. The growth suppressive and anti-angiogenic properties of IL-24 surely make it a candidate for therapy in cancer. As far as RA is concerned, IL-24 blockade may be a viable option [291,49,355,356]. Interleukin 25 (IL-17E, IL-25) is again a TH2 cytokine possessing sequence similarity with IL-17. It binds to its receptor IL-17RB for functioning. IL-25 can stimulate the production of TH2 cytokines, IL-4,5, and 13 in vivo [357]. It activates eosinophils and signals them to produce IL-8, an angiogenic cytokine, and IL-6, an exuberant inflammatory cytokine, through the JNK, p38, and NF-κβ pathway [133,358,359]. IL-25 has serious implications in allergic asthma but nothing has been reported in the context of RA [360–362]. It can upregulate NF-κβ through TRAF-6 signaling, hence, there is a possible connection of this cytokine with RANK-mediated osteoclastogenesis [363]. Since eosinophils and its effector cytokines are involved in RA pathogenesis, we may speculate an indirect role of IL-25 in RA [364]. Interleukin 26 (AK155, IL-26) is a member of IL-10 family. It shares sequence similarity with IL-10 but has divergent functions [365]. It functions through its receptor complex comprising of IL-20R1 and IL-10R2. This receptor is mainly present of epithelial cells and is a desideratum for IL-20 signaling since blocking any of the subunit leads to loss of signaling [366]. IL-26 is highly expressed in T cells and its effector cells primarily are keratinocytes/epithelial cells. It can lead to IL-8 and IL-10 secretion through STAT1 and STAT3 signaling in epithelial cells [366,367]. In RA, serum level of IL-26 has been found to be skyrocketing. The major culprits identified are synoviolin+ FLS and CD68+  macrophage-like synoviocytes (CD68+ MLS) in joints. Besides this, IL-26 can also stimulate the secretion of IL-1β, IL-6, TNFα, and some chemokines. It is vexing to see that IL-1β can itself influence the production IL-26; this gives rise to an autocrine loop. The autoimmune role of IL-26 lies in its ability to induce RORγt+ TH17 cells and then these cells can produce more IL-26 [368–370]. It may also play a subtle role in bone resorption since it can upregulate TNFα. For now, we have a dearth of information about the role of IL-26 in angiogenesis and matrix destruction. Until further research, we can conclude that IL-26 blockade could be a prospective therapy. Interleukin 27 (IL-27) is a member of IL-12 family of cytokines. It is a TH1 cytokine and signals through the WSX-1 and gp130 subunit due to which it has been debated if it should be put in the IL-6 family of cytokines [371]. It functions through its cognate receptor IL-27R. IL-27 has been reported to suppress the production of TNFα, IL-1β, IL-2, IL-17, GM-CSF, and IL-22 while inducing IL-10 which shows the protective side of this cytokine [372–377]. Being a TH1 cytokine, it can induce IFNγ production [378]. IL-27 can control the responsiveness of CD4+ T cells to IL-12 signaling and the expression of T-bet, a TH1 polarization factor, via STAT1 signaling [379–381]. It can inhibit Treg development through STAT3 while some researches have shown that it can also promote its development [382,383]. Interestingly, IL-27 can downregulate the expression of RORγt and hence block TH17 differentiation [384]. IL-27 can profoundly suppress inflammation and autoimmunity [385]. Yoshimura et al. inferred from their work that the protective role of IL-27 is very much dependent on STAT3 signaling [386]. Its chemoattractant nature is found to be the primary cause of it being inflammatory [387,388]. Kamiya et al. [380] found that IL-27 could inhibit bone resorption. Later in 2011, they confirmed the mechanism, which was RANKL suppression in CD4+ T cells [346,389]. Other researches have embellished the anti-osteoclastogenic nature of this cytokine [390,391]. This cytokine has proven to be a worthy anti-tumor and anti-angiogenic factor in cancer [392–395]. Wong et al. [396] found higher plasma level of IL-27 in RA patients compared to healthy controls which could be correlated with the disease condition. They found that blocking IL-27 diminished the severity of the disease. This can be contrasted to the inference made by Moon et al. [385] who saw a therapeutic potential in this cytokine for its ability to regulate TH17 and Treg population. Moreover, Gong et al. [50] also referred to IL-27 as a therapy in RA owing its inflammation suppressing attributes. We believe the immense beneficial effects of this cytokine may give way to future therapies but as of now more research is needed in this avenue. Interleukin 28 & 29 (IL-28, IL-29) are related to IL-10 and IFN family of cytokines. They function through their receptor complex IL-10Rβ and IL-28Rα. They can respond to viral infection much like interferons hence they are also called type III IFNs (IFNλ) [397–400]. They have evident immunomodulatory effects. Dolganiuc et al. [401] concluded from their work on HCV that during infection IL-28 and IL-29 (IFNλ collectively) could induce dendritic cell (DC)-mediated FoxP3+ Treg cells. This lays the foundation that these cytokines can aid in immunosuppression. Even so in RA patients, IL-29 specifically has shown to induce IL-6 and IL-8 production via TLRs in RA-FLS [402,403]. Dysregulation of IL-29 and its receptor IL-28Rα has severe implications in RA [51]. This accounts for its inflammatory role of IFN-λ, specifically in RA. It can be concluded that blockade of IL-28/IL-29 may partially restore the well-being of the patients. Interleukin 30 (IL-30) is the p28 subunit of IL-27 hence signals through the same receptor. Similar to IL-27, it has anti-inflammatory and anti-oxidant properties [404]. About the regulation of IL-30, IL-6R has been found to mediate signaling of IL-30 through gp130 homodimer receptor [405]. Dibra et al. [406] came up with an interesting finding that the coordination between TLR9 signaling and CD3 signaling in T cells led to ardent increase in IL-30 production. Since IL-30 is an integral part of IL-27, it has the same role in inflammation, bone resorption, chemotaxis, and angiogenesis as its father cytokine. The functionality of IL-27 is critically dependent on IL-30. Interleukin 31 (IL-31) is a TH2 cytokine belonging to IL-6 family but it does not signal through the gp130 subunit. It functions by binding to its cognate receptor complex comprising of IL-31Ra and OSM-Rβ [407]. Bilsborough et al. [408] reported that the IL-31RA subunit is extremely momentous for regulate the cytokine activity. IL-31RA-negative mice showed excessive IL-6 and VEGF expression due to the pairing of OSM-Rβ with gp130. IL-31 is primarily involved in mediating inflammation and hematopoiesis [409–412]. IL-31 stimulates epidermal keratinocytes and bronchial epithelial cells showed high-chemokine expression [413,414]. Therefore, a possible role of this cytokine in angiogenesis can be speculated. A study by Ginaldi et al. [415] found that high-IL-31 serum level in osteoporosis, however, no correlation between intensity of bone erosion and IL-31 expression could be established. Hence, a contingent role of IL-31 in bone resorption can be predicted. IL-4 can increase IL-31-mediated TH2 response by upregulating IL-31 [416]. IL-31 itself can upregulate the expression of some inflammatory cytokines leading to disorders [417], which explains the high-IL-31 expression found in several inflammatory diseases, such as atopic dermatitis [418]. Intriguingly, gene polymorphism in IL-31 has been associated with anti-CCP antibodies in female RA patients [419]. Withal in the end, there is still little knowledge about IL-31 in the context of RA. Interleukin 32 (IL-32) is a relatively new member of the cytokine class. IL-32γ is the canonical and most abundant isoform of IL-32. It is one of the most substantial elements involved in orchestrating inflammation through other cytokines. IL-32 has been vividly found to manipulate other cytokines. It can induce macrophages to produce TNFα and then in presence of TNFα, it can exasperate inflammatory arthritis [420,421]. Very recently, IL-32 was found to positively influence the cytotoxic profile of NK DCs by stimulating them to release TNFα and IFNγ [422]. Additionally, IL-32 can limit the adhesion molecule-mobilizing effect of IL-1β and can upregulate the chemokines CCL17 and CCL18 [423,424]. IL-17, one of the primary culprits in RA, has common downstream signaling molecules with IL-32, DAPK-1, and p300; therefore, they have similar roles in inflammatory pathways [425]. Nonetheless, an isoform of IL-32, IL-32β, has contrasting function compared to the canonical IL-32. It can increase the expression of IL-10, a prominent anti-inflammatory cytokine, and lead to regulation of the immune system [426]. In the context of osteoclastogenesis, IL-32 treatment was found to diminish bone resorption despite the fact that it could facilitate osteoclast differentiation. The previous paradox could be explained by the fact that IL-32 was found to induce anti-osteoclastogenic cytokines like IL-4 and IFNγ. A research group contradicted that IL-32 could worsen osteoclastogenesis by cyclically inducing IL-17 in RA-FLS. Moreover, soluble RANKL-stimulated IL-32 production boisterously which was reported to affect bone resorption [264,427,428]. Clearly, a better understanding of this cytokine is needed before coming to any strong conclusion. The angiogeneic role of IL-32 also remains quite inconclusive. Meyer [429] explained that IL-32 could negatively regulate angiogenesis through VEGF downregulation but this explanation was contradicted by Nold-Petry et al. [430] who reported an integrin-αVβ3 mediated VEGF-independent mechanism of IL-32 mediated angiogenesis. Even though IL-32 expression has been correlated with RA progression, it is suggested to resolve the arcane complexities lying behind this cytokine’s functioning before targeting the cytokine [431]. Interleukin 33 (NF-HEV, IL-33) is a TH2 cytokine from the IL-1 family and signals through the cognate receptor complex made of IL-1RAcP, also present in IL-1 receptor complex, and ST2 [432–434]. It can affect downstream signaling molecules NF-κβ and MAP kinase and induce the production of TH2 cytokines IL-4, IL-5, and IL-13 by TH2 cells [435]. It shows some anti-inflammatory effects by inhibiting IFNγ and IL-17 hence acting as a TH2 polarizing cytokine [436]. In fact, IL-33 is a chemoattractant for TH2 cells and essential for the maturation of human mast cells and eosinophils [437–439]. Intriguingly, Carriere et al. [440] proposed the role of IL-33 as a transcription repressor. Oboki et al. [441] reported that IL-33 could stupendously affect innate immunity in the lungs and IL-33-negative mice showed a vitiated response to LPS. Moreover, IL-33 has been found to play an intense role in autoimmunity [442]. Saidi et al. [443] proposed that IL-33 has no role in bone remodeling even though it is expressed in osteoblasts. Then, Zaiss et al. [444] and Schulze et al. [445] added that IL-33 could protect bones from erosion. Their findings were further strengthened by Lima et al. [446]. However, Xiangyang et al. [447] later suggested that, high-IL-33 expression in RA patients was correlated with fervent bone resorption. Both antigen-induced and autoantibody-induced arthritis is induced by IL-33 [448,449]. Several studies have confirmed high IL-33 in RA patients [450,451]. This clearly shows that IL-33 is involved in RA disease progression. This cytokine is also involved in angiogenesis through ST2/TRAF6 and urokinase induction, but it has an anti-tumorigenic effect in color cancer [452–454]. Kamradt et al. [455] proved that IL-33 receptor blockade was more successful in slowing disease progression than the blockade of IL-33. Furthermore, it was interestingly found in a study that etanercept, a TNFα blocker, could decrease IL-33 levels in the serum [52]. IL-33 is definitely a biomarker as well as a therapeutic target [456]. Interleukin 34 (IL-34) shares the CSF-1 receptor with CSF-1 (M-CSF). Both of these ligands signal through the same tyrosine kinase, Fms, but their biological activities can be told apart [457]. IL-34 and M-CSF are known to regulate myeloid cells and promote survival of monocytes and growth of immunosuppressive macrophages. The latter function is opposed by IFNγ and GM-CSF [458–460]. Bézie et al. [461] added to the immunomodulatory role of IL-34 by stating its efficient role in inducing transplant tolerance in rats. Research has shown that in contrast to its immunoregulatory role, it can assist in bone resorption by stimulating osteoclast differentiation and can upregulate RANKL. Hence, we can conclude CSF-1 receptor blockade may prove to be helpful [462–465]. Recent studies have shown that IL-34 also has implication in angiogenesis and metastatic growth in osteosarcoma. The proposed mechanism is through VEGF overexpression which is even further potentiated by hypoxia [466,467]. Chemel et al. [468] found IL-34 to be a downstream activator of TNFα and IL-1 in RASFs. Anti-TNFα antibodies could control IL-34-mediated inflammation thus strengthening the finding [469]. Later on Zhang et al. [53] reported the high expression of IL-34 in exacerbated RA and its positive correlation with other inflammatory cytokines. This makes IL-34 a significant biomarker as well as a therapeutic target [470]. Interleukin 35 (IL-35) signals through the heterodimeric chains of IL-12Rβ and gp130 or either of their homodimers. Research suggests that IL-35 has an acute role in immunosuppression and can convert TH0 cells to IL-35 producing induced Treg cells [471,472]. IL-35 can also broaden the CD4+ CD25+ and IL-10 secreting-CD39+ Treg populations [473,474]. Similarly, in allergy IL-35 has been found to reverse IL-17-mediated inflammation [475]. This cytokine is undoubtedly cardinal for Treg function [476–478]. Wang et al. [479] showed that IL-35 could prevent TH1 and TH17 differentiation and could subdue autoimmunity in CNS through Breg induction. Ning-Wei et al. [480] have referred to IL-35 as an extremely promising target for treating inflammation and autoimmunity. Further, Choi et al. [481] stated that recombinant IL-35 could reduce autoimmunity to a great extent. Nonetheless, Thiolat et al. [54] in their IL-35 gene therapy experiment in RA mice showed results which were quite incongruous with the typical IL-35 behavior. The experiment was followed by aggravation of inflammation. It was reported that even though IL-35 induced the activation of Treg cells, the simultaneous increase in CD62L prevented them from exhibiting their immunoregulatory role. Perhaps, IL-35 is not an appropriate choice for treating RA. Interleukin 36 (IL-36) is a member of IL-1 family of cytokines and binds to its cognate receptor IL-36 receptor for signaling. Recent work has brought into light that the ubiquitin-binding Tollip protein is an essential component of IL-36 receptor signaling [482]. Dietrich et al. [483] proffered that IL-36 has no role in arthritis joint inflammation. Even so, it is involved in skill and chondrocyte inflammation and myeloid cell recruitment [483–485]. In psoriasis, IL-36 has been found to affect TH17 cytokines via DC-induced-IL-23 implicating its role in autoimmunity [486]. It can influence synovial fibroblasts to release inflammatory cytokines and upregulate MAPK and NF-κβ. The notion that IL-36 causes RA pathogenesis was flawed when a blockade of IL-36 was not found to mollify inflammation or bone resorption. Lamacchia et al. [487] buttressed the fact with their findings that IL-36R signaling has no contribution in RA progression whatsoever. This leads to the conclusion that IL-36 has little or no role in RA [488]. Interleukin 37 (Interleukin-1 family member 7, IL-37) signals through the heterodimer complex of IL-1R8 and IL-18Rα. It is a regulator of inflammation [489]. Transgenic mice with enhanced IL-37 expression were found to have low-circulating cytokine and low-DC activation. This paves way for the inhibitory role of IL-37 in the context of innate immunity [490]. The translocation of IL-37 to the nucleus is mediated by caspase-1 and the IL-1R8 receptor is essential for inhibiting inflammation [491,492]. IL-37 gene silencing led to a decrease in TGFβ and IL-10 secretion as well as FOXP3 and CTLA4 expression. Hence, IL-37 is momentous for the immunosuppressive properties of CD4+ CD25+ Treg cells [493]. In another study, IL-37 gene knockdown led to LPS-mediated upregulation of IL-1β, TNFα, and chemokines [494]. In RA, IL-37 has shown rejuvenating effects in patients owing to its ability to downregulate TH17 cytokines, which are critical for inducing autoimmunity in RA [55,495–498]. Studies have also indicated a positive correlation between IL-37 and RA progression. This is possibly due the excess expression of IL-37 in response to perpetual inflammation [499–501]. Its absolute role in angiogenesis is for now controversial since it has varying effects in disorders [502,503]. Interleukin 38 (IL-38) is the most recently discovered hence the least researched cytokine in the family. It can antagonize IL-36 receptor much like IL-36Ra [504,505]. Takenaka et al. [506] have proposed a protective role of IL-38 in autoantibody-induced arthritis [506]. IL-38 was recently found to be involved in apoptotic cell-dependent immune regulation which shows contingent role of this cytokine in autoimmunity [507]. No assertion about its involvement in RA can be made since IL-38 is only a newcomer. The key mechanisms of RA pathogenesis and all the interleukins involved in their regulation is represented in Figure 1. Figure 1. Open in new tabDownload slide Role of interleukins in each dimension of rheumatoid arthritis. Figure 1. Open in new tabDownload slide Role of interleukins in each dimension of rheumatoid arthritis. Conclusion State of art Many therapies for RA have been developed involving the use of inflammatory modulators like NSAIDs, which dealt with inflammation but only at the surficial level. Later, came the DMARDs which were effective in reducing synovitis and system inflammation but often led to toxic effects. Currently, we believe cytokines are the key factors involved in the pathogenesis of RA and their control as well as therapeutic use may help us finally come to a promising cure. Many cytokine delivery and inhibitory therapies have been developed while some are under development. Is cytokine therapy going to be successful in the complete sense or are we going to be looking for another approach? It is still difficult to answer this question owing to the pleiotropic and relative nature of cytokines. No cytokine can be said to be absolutely inflammatory or anti-inflammatory since there is no black or white but shades of grey in the world of cytokine and inflammation. For now, restoring the cytokine balance of the immune system to the optimum level will probably help in the remission of inflammatory and autoimmune diseases but needless to mention, it is not an easy task. Also, it should be noted that many cytokines may not even be discovered yet but could be insidiously at work in RA. By and large, cytokines is an area which needs more research, as far as RA is concerned, until we completely savvy the elements of the disease. Acknowledgments We are greatly indebted to Vellore Institute of Technology for the constant encouragement, help and support for extending necessary facilities. Conflict of interest None. References Grassi W , De Angelis R, Lamanna G, Cervini C The clinical features of rheumatoid arthritis . Eur J Radiol . 1998 ; 27 ( 1 ): S18 – S24 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Malaviya AN , Kapoor SK, Singh RR, Kumar A, Pande I Prevalence of rheumatoid arthritis in the adult Indian population . Rheumatol Int . 1993 ; 13 : 131 – 4 . Google Scholar Crossref Search ADS PubMed WorldCat Gibofsky A Epidemiology, pathophysiology, and diagnosis of rheumatoid arthritis: a synopsis . Am J Manag Care . 2014 ; 20 : S128 – S35 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Jones V , Taylor PCR, Jacoby RK, Wallington TB Synovial synthesis of rheumatoid factors and immune complex constituents in early arthritis . Ann Rheum Dis . 1984 ; 43 : 235 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat Silverman GJ , Carson DA Roles of B cells in rheumatoid arthritis . Arthritis Res Ther . 2003 ; 5 ( 4 ): S1 – S6 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Kim HJ , Berek C B cells in rheumatoid arthritis . Arthritis Res . 2000 ; 2 : 126 – 31 . Google Scholar Crossref Search ADS PubMed WorldCat Willemze A , Toes REM, Huizinga TWJ, Trouw LA New biomarkers in rheumatoid arthritis . Neth J Med . 2012 ; 70 : 392 – 9 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Song YW , Kang EH Autoantibodies in rheumatoid arthritis: rheumatoid factors and anticitrullinated protein antibodies . QJM . 2010 ; 103 : 139 – 46 . Google Scholar Crossref Search ADS PubMed WorldCat Wigerblad G , Bas DB, Fernades-Cerqueira C, Krishnamurthy A, Nandakumar KS, Rogoz K, et al. . Autoantibodies to citrullinated proteins induce joint pain independent of inflammation via a chemokine-dependent mechanism . Ann Rheum Dis . 2016 ; 75 : 730 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat Wernick RM , Lipsky PE, Marban-Arcos E, Maliakkal JJ, Edelbaum D, and Ziff M IgG and IgM rheumatoid factor synthesis in rheumatoid synovial membrane cell cultures . Arthritis Rheum . 1985 ; 28 : 742 – 52 . Google Scholar Crossref Search ADS PubMed WorldCat Karouzakis E , Gay RE, Gay S, Neidhart M Epigenetic control in rheumatoid arthritis synovial fibroblasts . Nat Rev Rheumatol . 2009 ; 5 : 266 – 72 . Google Scholar Crossref Search ADS PubMed WorldCat Yoshihara Y , Nakamura H, Obata K, Yamada H, Hayakawa T, Fujikawa K, Okada Y Matrix metalloproteinases and tissue inhibitors of metalloproteinases in synovial fluids from patients with rheumatoid arthritis or osteoarthritis . Ann Rheum Dis . 2000 ; 59 : 455 – 61 . Google Scholar Crossref Search ADS PubMed WorldCat Yavropoulou MP , Yovos JG Osteoclastogenesis–current knowledge and future perspectives . J Musculoskelet Neuronal Interact . 2008 ; 8 : 204 – 16 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Udagawa N , Kotake S, Kamatani N, Takahashi N, Suda T The molecular mechanism of osteoclastogenesis in rheumatoid arthritis . Arthritis Res . 2002 ; 4 : 281 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat Hsu H , Lacey DL, Dunstan CR, Solovyev I, Colombero a, Timms E, et al. . Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand . Proc Natl Acad Sci USA . 1999 ; 96 : 3540 – 5 . Google Scholar Crossref Search ADS PubMed WorldCat Kim N , Kadono Y, Takami M, Lee J, Lee SH, Okada F, et al. . Osteoclast differentiation independent of the TRANCE-RANK-TRAF6 axis . J Exp Med . 2005 ; 202 : 589 – 95 . Google Scholar Crossref Search ADS PubMed WorldCat Otero JE , Dai S, Alhawagri MA, Darwech I, Abu-Amer Y IKKbeta activation is sufficient for RANK-independent osteoclast differentiation and osteolysis . J Bone Miner Res . 2010 ; 25 : 1282 – 94 . Google Scholar Crossref Search ADS PubMed WorldCat Mohr W , Hummler N, Pelster B, Wessinghage D Proliferation of pannus tissue cells in rheumatoid arthritis . Rheumatol Int . 1986 ; 6 : 127 – 32 . Google Scholar Crossref Search ADS PubMed WorldCat Kinne RW , Brauer R, Stuhlmüller B, Palomo-Kinnne E, Burmester GR Review—macrophages in rheumatoid arthritis . Arthritis Res . 2000 ; 2 : 189 – 202 . Google Scholar Crossref Search ADS PubMed WorldCat Ishikawa H , Hirata S, Nishibayashin Y, Imura S, Kubo H, Ohno O The role of adhesion molecules in synovial pannus formation in rheumatoid arthritis . Clin Orthop Relat Res . 1994 ; 300 : 297–303 . Google Scholar OpenURL Placeholder Text WorldCat Ishikawa H , Hirata S, Andoh Y, Kubo H, Nakagawa N, Nishibayashi Y, Mizuno K An immunohistochemical and immunoelectron microscopic study of adhesion molecules in synovial pannus formation in rheumatoid arthritis . Rheumatol Int . 1996 ; 16 : 53 – 60 . Google Scholar Crossref Search ADS PubMed WorldCat Szekanecz Z , Besenyei T, Paragh G, Koch AE Angiogenesis in rheumatoid arthritis . Autoimmunity . 2009 ; 42 : 563 – 73 . Google Scholar Crossref Search ADS PubMed WorldCat Koch AE The role of angiogenesis in rheumatoid arthritis: recent developments . Ann Rheum Dis . 2000 ; 59 : i65 – 71 . Google Scholar Crossref Search ADS PubMed WorldCat Qi J , Ye X, Ren G, Kan F, Zhang Y, Guo M, et al. . Pharmacological efficacy of anti-IL-1β scFv, Fab and full-length antibodies in treatment of rheumatoid arthritis . Mol Immunol . 2014 ; 57 : 59 – 65 . Google Scholar Crossref Search ADS PubMed WorldCat Klatzmann D , Abbas AK The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases . Nat Rev Immunol . 2015 ; 15 : 283 – 94 . Google Scholar Crossref Search ADS PubMed WorldCat Wood NC , Symons JA, Duff GW Serum interleukin-2-receptor in rheumatoid arthritis: a prognostic indicator of disease activity? J Autoimmun . 1988 ; 1 : 353 – 61 . Google Scholar Crossref Search ADS PubMed WorldCat Hemmerle T , Doll F, Neri D Antibody-based delivery of IL4 to the neovasculature cures mice with arthritis . Proc Natl Acad Sci USA . 2014 ; 111 : 12008 – 12 . Google Scholar Crossref Search ADS WorldCat Smolen JS , Weinblatt ME, Sheng S, Zhuang Y, Hsu B Sirukumab, a human anti-interleukin-6 monoclonal antibody: a randomised, 2-part (proof-of-concept and dose-finding), phase II study in patients with active rheumatoid arthritis despite methotrexate therapy . Ann Rheum Dis . 2014 ; 73 : 1616 – 25 . Google Scholar Crossref Search ADS PubMed WorldCat Lee SK , Kalinowski JF, Jastrzebski SL, Puddington L, Lorenzo JA Interleukin-7 is a direct inhibitor of in vitro osteoclastogenesis . Endocrinology . 2003 ; 144 : 3524 – 31 . Google Scholar Crossref Search ADS PubMed WorldCat Weitzmann M , Cenci N, Rifas S, Brown L, Pacifici CR Interleukin-7 stimulates osteoclast formation by up-regulating the T-cell production of soluble osteoclastogenic cytokines . Blood . 2000 ; 96 : 1873 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat Troughton P Synovial fluid interleukin-8 and neutrophil function in rheumatoid arthritis and seronegative polyarthritis . Rheumatology . 1996 ; 35 : 1244 – 51 . Google Scholar Crossref Search ADS WorldCat Chernoff a E , Granowitz EV, Shapiro L, Vannier E, Lonnemann G, Angel JB, et al. . A randomized, controlled trial of IL-10 in humans. Inhibition of inflammatory cytokine production and immune responses . J Immunol . 1995 ; 154 : 5492 – 9 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Trepicchio WL , Bozza M, Pedneault G, Dorner a J Recombinant human IL-11 attenuates the inflammatory response through down-regulation of proinflammatory cytokine release and nitric oxide production . J Immunol . 1996 ; 157 : 3627 – 34 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Girasole G , Passeri G, Jilka RL, Manolagas SC Interleukin-11: a new cytokine critical for osteoclast development . J Clin Invest . 1994 ; 93 : 1516 – 24 . Google Scholar Crossref Search ADS PubMed WorldCat Butler DM , Malfait AM, Maini RN, Brennan FM, Feldmann M Anti-IL-12 and anti-TNF antibodies synergistically suppress the progression of murine collagen-induced arthritis . Eur J Immunol . 1999 ; 29 : 2205 – 12 . Google Scholar Crossref Search ADS PubMed WorldCat Woods JM , Katschke KJ, Tokuhira M, Kurata H, Arai KI, Campbell PL, Koch AE Reduction of inflammatory cytokines and prostaglandin E2 by IL-13 gene therapy in rheumatoid arthritis synovium . J Immunol . 2000 ; 165 : 2755 – 63 . Google Scholar Crossref Search ADS PubMed WorldCat Fujisawa T , Joshi BH, Puri RK IL-13 regulates cancer invasion and metastasis through IL-13Rα2 via ERK/AP-1 pathway in mouse model of human ovarian cancer . Int J Cancer . 2012 ; 131 : 344 – 56 . Google Scholar Crossref Search ADS PubMed WorldCat Waldmann TA Targeting the interleukin-15/interleukin-15 receptor system in inflammatory autoimmune diseases . Arthritis Res Ther . 2004 ; 6 : 174 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat Genovese MC , Durez P, Richards HB, Supronik J, Dokoupilova E, Aelion JA, et al. . One-year efficacy and safety results of secukinumab in patients with rheumatoid arthritis: phase II, dose-finding, double-blind, randomized, placebo-controlled study . J Rheumatol . 2014 ; 41 : 414 – 21 . Google Scholar Crossref Search ADS PubMed WorldCat Zhu S , Pan W, Song X, Liu Y, Shao X, Tang Y, et al. . The microRNA miR-23b suppresses IL-17-associated autoimmune inflammation by targeting TAB2, TAB3 and IKK-α . Nat Med . 2012 ; 18 : 1077 – 86 . Google Scholar Crossref Search ADS PubMed WorldCat Plater-Zyberk C , Joosten L, Helsen M, Sattonnet-Roche P, Siegfried C, Alouani S, et al. . IL-18 blockade is a potential disease-modifying therapy for rheumatoid arthritis . Arthritis Res . 2001 ; 3 : P092 . Google Scholar Crossref Search ADS WorldCat Hsu YH , Hsieh PP, Chang MS Interleukin-19 blockade attenuates collagen-induced arthritis in rats . Rheumatology (Oxford) . 2012 ; 51 : 434 – 42 . Google Scholar Crossref Search ADS PubMed WorldCat Šenolt L , Leszczynski P, Dokoupilová E, Göthberg M, Valencia X, Hansen BB, Cañete JD Efficacy and safety of anti-interleukin-20 monoclonal antibody in patients with rheumatoid arthritis: a randomized phase IIa trial . Arthritis Rheumatol . 2015 ; 67 : 1438 – 48 . Google Scholar Crossref Search ADS PubMed WorldCat Young DA , Hegen M, Ma HL, Whitters MJ, Albert LM, Lowe L, et al. . Blockade of the interleukin-21/interleukin-21 receptor pathway ameliorates disease in animal models of rheumatoid arthritis . Arthritis Rheum . 2007 ; 56 : 1152 – 63 . Google Scholar Crossref Search ADS PubMed WorldCat Kim KW , Kim HR, Park JY, Park JS, Oh HJ, Woo YJ, et al. . Interleukin-22 promotes osteoclastogenesis in rheumatoid arthritis through induction of RANKL in human synovial fibroblasts . Arthritis Rheum . 2012 ; 64 : 1015 – 23 . Google Scholar Crossref Search ADS PubMed WorldCat Geboes L , Dumoutier L, Kelchtermans H, Schurgers E, Mitera T, Renauld JC, Matthys P Proinflammatory role of the Th17 cytokine interleukin-22 in collagen-induced arthritis in C57BL/6 mice . Arthritis Rheum . 2009 ; 60 : 390 – 5 . Google Scholar Crossref Search ADS PubMed WorldCat Chen Y , Langrish CL, Mckenzie B, Joyce-Shaikh B, Stumhofer JS, McClanahan T, et al. . Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis . J Clin Invest . 2006 ; 116 : 1317 – 26 . Google Scholar Crossref Search ADS PubMed WorldCat Nishikawa T , Ramesh R, Munshi A, Chada S, Meyn RE Adenovirus-mediated mda-7 (IL24) gene therapy suppresses angiogenesis and sensitizes NSCLC xenograft tumors to radiation . Mol Ther . 2004 ; 9 : 818 – 28 . Google Scholar Crossref Search ADS PubMed WorldCat Amirzada MI , Jin J Therapeutic applications of interleukin 24 (IL24): a review. Trop J Pharm Res . 2012 ; 11 : 1023 – 7 . Google Scholar OpenURL Placeholder Text WorldCat Gong F , Pan YH, Huang X, Chen J, Xiao JH, Zhu HY Interleukin-27 as a potential therapeutic target for rheumatoid arthritis: has the time come? Clin Rheumatol . 2013 ; 32 : 1425 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat Wang F , Xu L, Feng X, Guo D, Tan W, Zhang M Interleukin-29 modulates proinflammatory cytokine production in synovial inflammation of rheumatoid arthritis . Arthritis Res Ther . 2012 ; 14 : R228 . Google Scholar Crossref Search ADS PubMed WorldCat Kageyama Y , Torikai E, Tsujimura K, Kobayashi M Involvement of IL-33 in the pathogenesis of rheumatoid arthritis: the effect of etanercept on the serum levels of IL-33 . Mod Rheumatol . 2012 ; 22 : 89 – 93 . Google Scholar Crossref Search ADS PubMed WorldCat Zhang F , Ding R, Li P, Ma C, Song D, Wang X, et al. . Interleukin-34 in rheumatoid arthritis: potential role in clinical therapy . Int J Clin Exp Med . 2015 ; 8 : 7809 – 15 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Thiolat A , Denys A, Petit M, Biton J, Lemeiter D, Herve R, et al. . Interleukin-35 gene therapy exacerbates experimental rheumatoid arthritis in mice . Cytokine . 2014 ; 69 : 87 – 93 . Google Scholar Crossref Search ADS PubMed WorldCat Ye L , Jiang B, Deng J, Du J, Xiong W, Guan Y, et al. . IL-37 alleviates rheumatoid arthritis by suppressing IL-17 and IL-17-triggering cytokine production and limiting Th17 cell proliferation . J Immunol . 2015 ; 194 : 5110 – 19 . Google Scholar Crossref Search ADS PubMed WorldCat Dinarello CH Biologic basis for interleukin-1 in disease . Blood . 1996 ; 87 : 2095 – 147 . Google Scholar Crossref Search ADS PubMed WorldCat Vigers GP , Anderson LJ, Caffes P, Brandhuber BJ Crystal structure of the type-I interleukin-1 receptor complexed with interleukin-1beta . Nature . 1997 ; 386 : 190 – 4 . Google Scholar Crossref Search ADS PubMed WorldCat Lopalco G , Cantarini L, Vitale A, Iannone F, Anelli MG, Andreozzi L, et al. . Interleukin-1 as a common denominator from autoinflammatory to autoimmune disorders: premises, perils, and perspectives . Mediators Inflamm . 2015 ; 2015 :194864. Google Scholar OpenURL Placeholder Text WorldCat Bingham CO The pathogenesis of rheumatoid arthritis: pivotal cytokines involved in bone degradation and inflammation . J Rheumatol . 2002 ; 29 : 3 – 9 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Henderson B , Pettipher ER Arthritogenic actions of recombinant IL-1 and tumour necrosis factor alpha in the rabbit: evidence for synergistic interactions between cytokines in vivo. Clin Exp Immunol . 1989 ; 75 : 306 – 10 . Google Scholar OpenURL Placeholder Text WorldCat Luft T , Jefford M, Luetjens P, Hochrein H, Masterman KA, Maliszewski C, et al. . IL-1 enhances CD40 ligand-mediated cytokine secretion by human dendritic cells (DC): a mechanism for T cell-independent DC activation . J Immunol . 2002 ; 168 : 713 – 22 . Google Scholar Crossref Search ADS PubMed WorldCat Wesa AK , Galy A IL-1 beta induces dendritic cells to produce IL-12 . Int Immunol . 2001 ; 13 : 1053 – 61 . Google Scholar Crossref Search ADS PubMed WorldCat Tsakiri N , Kimber I, Rothwell NJ, Pinteaux E Interleukin-1-induced interleukin-6 synthesis is mediated by the neutral sphingomyelinase/Src kinase pathway in neurones . Br J Pharmacol . 2008 ; 153 : 775 – 83 . Google Scholar Crossref Search ADS PubMed WorldCat Kasahara T , Mukaida N, Yamashita K, Yagisawa H, Akahoshi T, Matsushima K IL-1 and TNF-alpha induction of IL-8 and monocyte chemotactic and activating factor (MCAF) mRNA expression in a human astrocytoma cell line . Immunology . 1991 ; 74 : 60 – 7 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Patil C , Zhu X, Rossa C, Kim YJ, Kirkwood KL p38 MAPK regulates IL-1beta induced IL-6 expression through mRNA stability in osteoblasts . Immunol Invest . 2004 ; 33 : 213 – 33 . Google Scholar Crossref Search ADS PubMed WorldCat Voronov E , Carmi Y, Apte RN The role IL-1 in tumor-mediated angiogenesis . Front Physiol . 2014 ; 5 : 1 – 11 . Google Scholar Crossref Search ADS PubMed WorldCat Haraldsen G , Kvale D, Lien B, Farstad IN, Brandtzaeg P Cytokine-regulated expression of E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in human microvascular endothelial cells . J Immunol . 1996 ; 156 : 2558 – 65 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Salven P . Interleukin-1alpha promotes angiogenesis in vivo via VEGFR-2 pathway by inducing inflammatory cell VEGF synthesis and secretion . FASEB J . 2002 ; 16 : 1471 – 3 . Google Scholar Crossref Search ADS PubMed WorldCat Carmi Y , Dotan S, Rider P, Kaplanov I, White MR, Baron R, et al. . The role of IL-1β in the early tumor cell-induced angiogenic response . J Immunol . 2013 ; 190 : 3500 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat Lee EG , Sung MS, Yoo HG, Chae HJ, Kim HR, Yoo WH Increased RANKL-mediated osteoclastogenesis by interleukin-1β and endoplasmic reticulum stress. Joint Bone Spine . 2014 ; 81 : 520 – 6 . Google Scholar Crossref Search ADS PubMed WorldCat Lee WS , Lee EG, Sung MS, Yoo WH Kaempferol inhibits IL-1β-stimulated, RANKL-mediated osteoclastogenesis via downregulation of MAPKs, c-Fos, and NFATc1 . Inflammation . 2014 ; 37 : 1221 – 30 . Google Scholar Crossref Search ADS PubMed WorldCat Arend WP Cytokine imbalance in the pathogenesis of rheumatoid arthritis: the role of interleukin-1 receptor antagonist . Semin Arthritis Rheum . 2001 ; 30 : 1 – 6 . Google Scholar Crossref Search ADS PubMed WorldCat Mertens M , Singh J Anakinra for rheumatoid arthritis . Cochrane Database Syst Rev . 2009 ; 36 : CD005121 . Google Scholar OpenURL Placeholder Text WorldCat Mogensen TH Pathogen recognition and inflammatory signaling in innate immune defenses . Clin Microbiol Rev . 2009 ; 22 : 240 – 73 . Google Scholar Crossref Search ADS PubMed WorldCat Sugamura K [Structure and function of IL-2 receptor subunits] . Hum Cell . 1994 ; 7 : 1 – 5 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Karasuyama H , Tohyama N, Tada T Autocrine growth and tumorigenicity of interleukin 2-dependent helper T cells transfected with IL-2 gene . J Exp Med . 1989 ; 169 : 13 – 25 . Google Scholar Crossref Search ADS PubMed WorldCat Waldner C , Mongini C, Alvarez E, Sánchez Lockhart M, Gravisaco M, Hajos S Interleukin 2 exerts autocrine stimulation on murine T-cell leukaemia growth . Br J Cancer . 1997 ; 75 : 946 – 50 . Google Scholar Crossref Search ADS PubMed WorldCat Kim MH , Kitson RP, Albertsson P, Nannmark U, Basse PH, Kuppen PJK, et al. . Secreted and membrane-associated matrix metalloproteinases of IL-2-activated NK cells and their inhibitors . J Immunol . 2000 ; 164 : 5883 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat Kitas GD , Salmon M, Farr M, Gaston JS, Bacon PA Deficient interleukin 2 production in rheumatoid arthritis: association with active disease and systemic complications. Clin Exp Immunol . 1988 ; 73 : 242 – 9 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Liao W , Lin JX, Leonard WJ Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy . Immunity . 2013 ; 38 : 13 – 25 . Google Scholar Crossref Search ADS PubMed WorldCat Liao W , Lin JX, Leonard WJ IL-2 family cytokines: new insights into the complex roles of IL-2 as a broad regulator of T helper cell differentiation . Curr Opin Immunol . 2011 ; 23 : 598 – 604 . Google Scholar Crossref Search ADS PubMed WorldCat Ballesteros-Tato A , León B, Graf BA, Moquin A, Adams PS, Lund FE, Randall TD Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation . Immunity . 2012 ; 36 : 847 – 56 . Google Scholar Crossref Search ADS PubMed WorldCat Davidson TS , DiPaolo RJ, Andersson J, Shevach EM. Cutting edge: IL-2 is essential for TGF-beta-mediated induction of Foxp3+ T regulatory cells . J Immunol . 2007 ; 178 : 4022 – 6 . Google Scholar Crossref Search ADS PubMed WorldCat Sharma R , Fu SM, Ju ST IL-2: a two-faced master regulator of autoimmunity . J Autoimmun . 2011 ; 36 : 91 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat Bouchentouf M , Williams P, Forner KA, Cuerquis J, Michaud V, Paradis P, et al. . Interleukin-2 enhances angiogenesis and preserves cardiac function following myocardial infarction . Cytokine . 2011 ; 56 : 732 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat Pascual J , Marcén R, Ortuño J Anti-interleukin-2 receptor antibodies: basiliximab and daclizumab . Nephrol Dial Transplant . 2001 ; 16 : 1756 – 60 . Google Scholar Crossref Search ADS PubMed WorldCat A Randomized, Double Blind, Placebo-controlled Pilot-study to Evaluate Efficacy and Safety of Low-dose hrIL-2 in the Treatment of Disease Modifying Antirheumatic Drugs (DMARD)-Naive Patients with Rheumatoid Arthritis (n.d.). Available from: https://clinicaltrials.gov/ct2/show/NCT02467504 (accessed 28 April 2016). Broughton SE , Dhagat U, Hercus TR, Nero TL, Grimbaldeston MA, Bonder CS, et al. . The GM-CSF/IL-3/IL-5 cytokine receptor family: from ligand recognition to initiation of signaling . Immunol Rev . 2012 ; 250 : 277 – 302 . Google Scholar Crossref Search ADS PubMed WorldCat Hara T , Miyajima A Function and signal transduction mediated by the interleukin 3 receptor system in hematopoiesis . Stem Cells . 1996 ; 14 : 605 – 18 . Google Scholar Crossref Search ADS PubMed WorldCat Brown MP , Nosaka T, Tripp RA, Brooks J, van Deursen JM, Brenner MK, et al. . Reconstitution of early lymphoid proliferation and immune function in Jak3-deficient mice by interleukin-3 . Blood . 1999 ; 94 : 1906 – 14 . Google Scholar Crossref Search ADS PubMed WorldCat Yogesha SD , Khapli SM, Srivastava RK, Mangashetti LS, Pote ST, Mishra GC, Wani MR. IL-3 inhibits TNF-alpha-induced bone resorption and prevents inflammatory arthritis . J Immunol . 2009 ; 182 : 361 – 70 . Google Scholar Crossref Search ADS PubMed WorldCat Gillespie MT Impact of cytokines and T lymphocytes upon osteoclast differentiation and function . Arthritis Res Ther . 2007 ; 9 : 103 . Google Scholar Crossref Search ADS PubMed WorldCat Srivastava RK , Tomar GB, Barhanpurkar AP, Gupta N, Pote ST, Mishra GC, Wani MR IL-3 attenuates collagen-induced arthritis by modulating the development of Foxp3+ regulatory T cells . J Immunol . 2011 ; 186 : 2262 – 72 . Google Scholar Crossref Search ADS PubMed WorldCat Wang T , Secombes CJ The evolution of IL-4 and IL-13 and their receptor subunits . Cytokine . 2015 ; 75 : 8 – 13 . Google Scholar Crossref Search ADS PubMed WorldCat Noben-Trauth N , Hu-Li J, Paul WE IL-4 secreted from individual naive CD4+ T cells acts in an autocrine manner to induce Th2 differentiation . Eur J Immunol . 2002 ; 32 : 1428 – 33 . Google Scholar Crossref Search ADS PubMed WorldCat Stewart D , Javadi M, Chambers M, Gunsolly C, Gorski G, Borghaei RC Interleukin-4 inhibition of interleukin-1-induced expression of matrix metalloproteinase-3 (MMP-3) is independent of lipoxygenase and PPARgamma activation in human gingival fibroblasts . BMC Mol Biol . 2007 ; 8 : 12 . Google Scholar Crossref Search ADS PubMed WorldCat Fenton MJ , Buras JA, Donnelly RP IL-4 reciprocally regulates IL-1 and IL-1 receptor antagonist expression in human monocytes . J Immunol . 1992 ; 149 : 1283 – 8 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Pakdel MBF , Farhadi F, Pouralibaba F, Kahnamouii SS, Farshi MR, Shirani G IL-4 regulate the pro-inflammatory cytokines in rheumatoid arthritis . Adv Environ Biol . 2014 ; 8 : 383 – 7 . Google Scholar OpenURL Placeholder Text WorldCat Bhattacharjee A , Shukla M, Yakubenko VP, Mulya A, Kundu S, Cathcart MK IL-4 and IL-13 employ discrete signaling pathways for target gene expression in alternatively activated monocytes/macrophages . Free Radic Biol Med . 2013 ; 54 : 1 – 16 . Google Scholar Crossref Search ADS PubMed WorldCat Taki H Interleukin-4 inhibits interleukin-11 production by rheumatoid synovial cells . Rheumatology (Oxford) . 2000 ; 39 : 728 – 31 . Google Scholar Crossref Search ADS PubMed WorldCat Abu-Amer Y . IL-4 abrogates osteoclastogenesis through STAT6-dependent inhibition of NF-kappaB . J Clin Invest . 2001 ; 107 : 1375 – 85 . Google Scholar Crossref Search ADS PubMed WorldCat Bendixen AC , Shevde NK, Dienger KM, Willson TM, Funk CD, Pike JW IL-4 inhibits osteoclast formation through a direct action on osteoclast precursors via peroxisome proliferator-activated receptor gamma 1 . Proc Natl Acad Sci USA . 2001 ; 98 : 2443 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat Moon B , Takaki S, Miyake K, Takatsu K The role of IL-5 for mature B-1 cells in homeostatic proliferation, cell survival, and Ig production . J Immunol . 2004 ; 172 : 6020 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat Kouro T , Takatsu K IL-5- and eosinophil-mediated inflammation: from discovery to therapy . Int Immunol . 2009 ; 21 : 1303 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat Ikutani M , Yanagibashi T, Ogasawara M, Tsuneyama K, Yamamoto S, Hattori Y, et al. . Identification of innate IL-5-producing cells and their role in lung eosinophil regulation and antitumor immunity . J Immunol . 2012 ; 188 : 703 – 13 . Google Scholar Crossref Search ADS PubMed WorldCat Tran GT , Hodgkinson SJ, Carter NM, Verma ND, Plain KM, Boyd R, et al. . IL-5 promotes induction of antigen-specific CD4 + CD25+ T regulatory cells that suppress autoimmunity . Blood . 2012 ; 119 : 4441 – 50 . Google Scholar Crossref Search ADS PubMed WorldCat Pedersen BK , Fischer CP. Beneficial health effects of exercise-the role of IL-6 as a myokine . Trends Pharmacol Sci . 2007 ; 28 : 152 – 6 . Google Scholar Crossref Search ADS PubMed WorldCat Wada TT , Araki Y, Sato K, Aizaki Y, Yokota K, Kim YT, et al. . Aberrant histone acetylation contributes to elevated interleukin-6 production in rheumatoid arthritis synovial fibroblasts . Biochem Biophys Res Commun . 2014 ; 444 : 682 – 6 . Google Scholar Crossref Search ADS PubMed WorldCat Georganas C , Liu H, Perlman H, Hoffmann A, Thimmapaya B, Pope RM Regulation of IL-6 and IL-8 expression in rheumatoid arthritis synovial fibroblasts: the dominant role for NF-kappa B but not C/EBP beta or c-Jun . J Immunol . 2000 ; 165 : 7199 – 206 . Google Scholar Crossref Search ADS PubMed WorldCat Hirano T , Matsuda T, Turner M, Miyasaka N, Buchan G, Tang B, et al. . Excessive production of interleukin 6/B cell stimulatory factor-2 in rheumatoid arthritis . Eur J Immunol . 1988 ; 18 : 1797 – 801 . Google Scholar Crossref Search ADS PubMed WorldCat Hashizume M , Hayakawa N, Suzuki M, Mihara M IL-6/sIL-6R trans-signalling, but not TNF-alpha induced angiogenesis in a HUVEC and synovial cell co-culture system . Rheumatol Int . 2009 ; 29 : 1449 – 54 . Google Scholar Crossref Search ADS PubMed WorldCat Gopinathan G , Milagre C, Pearce OMT, Reynolds LE, Hodivala-Dilke K, Leinster DA, et al. . Interleukin-6 stimulates defective angiogenesis . Cancer Res . 2015 ; 75 : 3098 – 107 . Google Scholar Crossref Search ADS PubMed WorldCat Palmqvist P , Persson E, Conaway HH, Lerner UH IL-6, leukemia inhibitory factor, and oncostatin M stimulate bone resorption and regulate the expression of receptor activator of NF- B ligand, osteoprotegerin, and receptor activator of NF- B in mouse calvariae . J Immunol . 2002 ; 169 : 3353 – 62 . Google Scholar Crossref Search ADS PubMed WorldCat Yoshitake F , Itoh S, Narita H, Ishihara K, Ebisu S Interleukin-6 directly inhibits osteoclast differentiation by suppressing receptor activator of NF-kappaB signaling pathways . J Biol Chem . 2008 ; 283 : 11535 – 40 . Google Scholar Crossref Search ADS PubMed WorldCat Korn T , Mitsdoerffer M, Croxford AL, Awasthi A, Dardalhon VA, Galileos G, et al. . IL-6 controls Th17 immunity in vivo by inhibiting the conversion of conventional T cells into Foxp3+ regulatory T cells . Proc Natl Acad Sci USA . 2008 ; 105 : 18460 – 5 . Google Scholar Crossref Search ADS WorldCat Kimura A , Kishimoto T IL-6: regulator of Treg/Th17 balance . Eur J Immunol . 2010 ; 40 : 1830 – 5 . Google Scholar Crossref Search ADS PubMed WorldCat Helal AMH , Shahine EM, Hassan MM, Hashad DI, Moneim RA Fatigue in rheumatoid arthritis and its relation to interleukin-6 serum level . Egypt Rheumatol . 2012 ; 34 : 153 – 7 . Google Scholar Crossref Search ADS WorldCat Singh JA , Beg S, Lopez-Olivo MA Tocilizumab for rheumatoid arthritis . Cochrane Database Syst Rev . 2010 ; 7 : CD008331 . Google Scholar OpenURL Placeholder Text WorldCat Van Rhee F , Fayad L, Voorhees P, Furman R, Lonial S, Borghaei H, et al. . Siltuximab, a novel anti-interleukin-6 monoclonal antibody, for Castleman’s disease . J Clin Oncol . 2010 ; 28 : 3701 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat Gonzales AM , Orlando RA Curcumin and resveratrol inhibit nuclear factor-kappaB-mediated cytokine expression in adipocytes . Nutr Metab (Lond) . 2008 ; 5 : 17 . Google Scholar Crossref Search ADS PubMed WorldCat Kikuchi K , Kasai H, Watanabe A, Lai AY, Kondo M IL-7 specifies B cell fate at the common lymphoid progenitor to pre-proB transition stage by maintaining early B cell factor expression . J Immunol . 2008 ; 181 : 383 – 92 . Google Scholar Crossref Search ADS PubMed WorldCat Akashi K , Kondo M, Weissman IL Role of interleukin-7 in T-cell development from hematopoietic stem cells . Immunol Rev . 1998 ; 165 : 13 – 28 . Google Scholar Crossref Search ADS PubMed WorldCat Kang J , Coles M IL-7: the global builder of the innate lymphoid network and beyond, one niche at a time . Semin Immunol . 2012 ; 24 : 190 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat Churchman SM , El-Jawhari JJ, Burska AN, Parmar R, Goëb V, Conaghan PG, et al. . Modulation of peripheral T-cell function by interleukin-7 in rheumatoid arthritis . Arthritis Res Ther . 2014 ; 16 : 511 . Google Scholar Crossref Search ADS PubMed WorldCat Chen Z , Kim S, Chamberlain ND, Pickens SR, Volin MV, Volkov S, et al. . The novel role of IL-7 ligation to IL-7 receptor in myeloid cells of rheumatoid arthritis and collagen-induced arthritis . J Immunol . 2013 ; 190 : 5256 – 66 . Google Scholar Crossref Search ADS PubMed WorldCat Ponchel F , Verburg RJ, Bingham SJ, Brown AK, Moore J, Protheroe A, et al. . Interleukin-7 deficiency in rheumatoid arthritis: consequences for therapy-induced lymphopenia . Rthritis Res Ther . 2005 ; 7 : R80 – 92 . Google Scholar Crossref Search ADS WorldCat van Roon JA , Verweij MC, Wijk MW, Jacobs KM, Bijlsma JW Increased intraarticular interleukin-7 in rheumatoid arthritis patients stimulates cell contact-dependent activation of CD4(+) T cells and macrophages . Arthritis Rheum . 2005 ; 52 : 1700 – 10 . Google Scholar Crossref Search ADS PubMed WorldCat Murphy PM Neutrophil receptors for interleukin-8 and related CXC chemokines . Semin Hematol . 1997 ; 34 : 311 – 18 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Hwang SY , Kim JY, Kim KW, Park MK, Moon Y, Kim WU, Kim HY IL-17 induces production of IL-6 and IL-8 in rheumatoid arthritis synovial fibroblasts via NF-kappaB- and PI3-kinase/Akt-dependent pathways . Arthritis Res Ther . 2004 ; 6 : R120 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat Khandpur R , Carmona-Rivera C, Vivekanandan-Giri A, Gizinski A, Yalavarthi S, Knight JS, et al. . NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis . Sci Transl Med . 2013 ; 5 : 178ra40 . Google Scholar Crossref Search ADS PubMed WorldCat Manna SK , Ramesh GT Interleukin-8 induces nuclear transcription factor-kappaB through a TRAF6-dependent pathway . J Biol Chem . 2005 ; 280 : 7010 – 21 . Google Scholar Crossref Search ADS PubMed WorldCat Bendre MS , Montague DC, Peery T, Akel NS, Gaddy D, Suva LJ Interleukin-8 stimulation of osteoclastogenesis and bone resorption is a mechanism for the increased osteolysis of metastatic bone disease . Bone . 2003 ; 33 : 28 – 37 . Google Scholar Crossref Search ADS PubMed WorldCat Li A , Dubey S, Varney ML, Bhavana J, Singh RK IL-8 directly enhanced endothelial cell survival, proliferation, and matrix metalloproteinases production and regulated angiogenesis . J Immunol . 2003 ; 170 : 3369 – 76 . Google Scholar Crossref Search ADS PubMed WorldCat Peichl P , Pursch E, Bröll H, Lindley IJD Anti-IL-8 autoantibodies and complexes in rheumatoid arthritis: polyclonal activation in chronic synovial tissue inflammation . Rheumatol Int . 1999 ; 18 : 141 – 5 . Google Scholar Crossref Search ADS PubMed WorldCat Fang Y , Chen X, Bai Q, Qin C, Mohamud AO, Zhu Z, et al. . IL-9 inhibits HTB-72 melanoma cell growth through upregulation of p21 and TRAIL . J Surg Oncol . 2015 ; 111 : 969 – 74 . Google Scholar Crossref Search ADS PubMed WorldCat Demoulin J , Van Snick BJ, Renauld JC Interleukin-9 (IL-9) induces cell growth arrest associated with sustained signal transducer and activator of transcription activation in lymphoma cells overexpressing the IL-9 receptor . Cell Growth Differ . 2001 ; 12 : 169 – 74 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Dardalhon V , Awasthi A, Kwon H, Galileos G, Gao W, Sobel RA, et al. . IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3(-) effector T cells . Nat Immunol . 2008 ; 9 : 1347 – 55 . Google Scholar Crossref Search ADS PubMed WorldCat Wong MT , Ye JJ, Alonso MN, Landrigan A, Cheung RK, Engleman E, Utz PJ Regulation of human Th9 differentiation by type I interferons and IL-21 . Immunol Cell Biol . 2010 ; 88 : 624 – 31 . Google Scholar Crossref Search ADS PubMed WorldCat Ma CS , Tangye SG, Deenick EK Human Th9 cells: inflammatory cytokines modulate IL-9 production through the induction of IL-21 . Immunol Cell Biol . 2010 ; 88 : 621 – 3 . Google Scholar Crossref Search ADS PubMed WorldCat Elyaman W , Bradshaw EM, Uyttenhove C, Dardalhon V, Awasthi A, Imitola J, et al. . IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells. Proc Natl Acad Sci USA . 2009 ; 106 : 12885 – 90 . Google Scholar Crossref Search ADS PubMed WorldCat Ciccia F , Guggino G, Rizzo A, Manzo A, Vitolo B, Pio M, et al. . Potential involvement of IL-9 and Th9 cells in the pathogenesis of rheumatoid arthritis . Rheumatology . 2015 ; 54 : 1 – 9 . Google Scholar OpenURL Placeholder Text WorldCat Dantas AT , Marques CDL, da Rocha Junior LF, Cavalcanti MB, Gonçalves SMC, Cardoso PRG, et al. . Increased serum interleukin-9 levels in rheumatoid arthritis and systemic lupus erythematosus: pathogenic role or just an epiphenomenon? Dis Markers . 2015 ; 2015 : 519638 . Google Scholar Crossref Search ADS PubMed WorldCat Singh TP , Schön MP, Wallbrecht K, Gruber-Wackernagel A, Wang XJ, Wolf P Involvement of IL-9 in Th17-associated inflammation and angiogenesis of psoriasis . PLoS One . 2013 ; 8 : 1 – 11 . Google Scholar Crossref Search ADS WorldCat Sismanopoulos N , Delivanis DA, Alysandratos KD, Angelidou A, Vasiadi M, Therianou A, Theoharides TC IL-9 induces VEGF secretion from human mast cells and IL-9/IL-9 receptor genes are overexpressed in atopic dermatitis . PLoS One . 2012 ; 7 : 5 – 9 . Google Scholar Crossref Search ADS WorldCat O’Garra A , Moore KW, de Waal Malefyt R, Coffman RL Interleukin-10 and the interleukin-10 Receptor . Annu Rev Immunol . 2001 ; 19 : 683 – 765 . Google Scholar PubMed OpenURL Placeholder Text WorldCat McGuirk P , McCann C, Mills KH Pathogen-specific T regulatory 1 cells induced in the respiratory tract by a bacterial molecule that stimulates interleukin 10 production by dendritic cells: a novel strategy for evasion of protective T helper type 1 responses by Bordetella pertussis . J Exp Med . 2002 ; 195 : 221 – 31 . Google Scholar Crossref Search ADS PubMed WorldCat O’Garra A , Vieira P T(H)1 cells control themselves by producing interleukin-10 . Nat Rev Immunol . 2007 ; 7 : 425 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat Yilma AN , Singh SR, Fairley SJ, Taha MA, Dennis VA The anti-inflammatory cytokine, interleukin-10, inhibits inflammatory mediators in human epithelial cells and mouse macrophages exposed to live and UV-inactivated chlamydia trachomatis . Mediators Inflamm . 2012 ; 2012 :520174. Google Scholar OpenURL Placeholder Text WorldCat de Waal Malefyt R , Abrams J, Bennett B, Figdor CG, de Vries JE Interleukin 10 (IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes . J Exp Med . 1991 ; 174 : 1209 – 20 . Google Scholar Crossref Search ADS PubMed WorldCat Cassatella MA , Meda L, Bonora S, Ceska M, Constantin G Interleukin 10 (IL-10) inhibits the release of proinflammatory cytokines from human polymorphonuclear leukocytes. Evidence for an autocrine role of tumor necrosis factor and IL-1 beta in mediating the production of IL-8 triggered by lipopolysaccharide . J Exp Med . 1993 ; 178 : 2207 – 11 . Google Scholar Crossref Search ADS PubMed WorldCat Zhou L , Nazarian AA, Smale ST Interleukin-10 inhibits interleukin-12 p40 gene transcription by targeting a late event in the activation pathway . Mol Cell Biol . 2004 ; 24 : 2385 – 96 . Google Scholar Crossref Search ADS PubMed WorldCat Driessler F , Venstrom K, Sabat R, Asadullah K, Schottelius AJ Molecular mechanisms of interleukin-10-mediated inhibition of NF-kappaB activity: a role for p50 . Clin Exp Immunol . 2004 ; 135 : 64 – 73 . Google Scholar Crossref Search ADS PubMed WorldCat Yao Y , Li W, Kaplan MH, Chang CH Interleukin (IL)-4 inhibits IL-10 to promote IL-12 production by dendritic cells . J Exp Med . 2005 ; 201 : 1899 – 903 . Google Scholar Crossref Search ADS PubMed WorldCat Groux H , Cottrez F The complex role of interleukin-10 in autoimmunity . J Autoimmun . 2003 ; 20 : 281 – 5 . Google Scholar Crossref Search ADS PubMed WorldCat Jeannin P , Lecoanet S, Delneste Y, Gauchat JF, Bonnefoy JY IgE versus IgG4 production can be differentially regulated by IL-10 . J Immunol . 1998 ; 160 : 3555 – 61 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Satoguina JS , Weyand E, Larbi J, Hoerauf A T regulatory-1 cells induce IgG4 production by B cells: role of IL-10 . J Immunol . 2005 ; 174 : 4718 – 26 . Google Scholar Crossref Search ADS PubMed WorldCat Heo YJ , Joo YB, Oh HJ, Park MK, Heo YM, Cho ML, et al. . IL-10 suppresses Th17 cells and promotes regulatory T cells in the CD4+ T cell population of rheumatoid arthritis patients . Immunol Lett . 2010 ; 127 : 150 – 6 . Google Scholar Crossref Search ADS PubMed WorldCat Huber S , Gagliani N, Esplugues E, O’Connor W, Huber FJ, Chaudhry A, et al. . Th17 cells express interleukin-10 receptor and are controlled by Foxp3? and Foxp3+ regulatory CD4+ T cells in an interleukin-10-dependent manner . Immunity . 2011 ; 34 : 554 – 65 . Google Scholar Crossref Search ADS PubMed WorldCat Alexandrakis MG , Goulidaki N, Pappa CA, Boula A, Psarakis F, Neonakis I, Tsirakis G Interleukin-10 induces both plasma cell proliferation and angiogenesis in multiple myeloma . Pathol Oncol Res . 2015 ; 21 : 929 – 34 . Google Scholar Crossref Search ADS PubMed WorldCat Dace DS , Khan AA, Kelly J, Apte RS Interleukin-10 promotes pathological angiogenesis by regulating macrophage response to hypoxia during development . PLoS One . 2008 ; 3 :e3381. Google Scholar OpenURL Placeholder Text WorldCat Wu WK , Llewellyn OPC, Bates DO, Nicholson LB, Dick AD IL-10 regulation of macrophage VEGF production is dependent on macrophage polarisation and hypoxia . Immunobiology . 2010 ; 215 : 796 – 803 . Google Scholar Crossref Search ADS PubMed WorldCat KohnoMizukami T , Suzuki H, Saga M, Takei Y, Shimpo Y, Matsushita M, et al. . Interleukin-10-mediated inhibition of angiogenesis and tumor growth in mice bearing VEGF-producing ovarian cancer . Cancer Res . 2003 ; 63 : 5091 – 4 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Takayanagi H The role of NFAT in osteoclast formation . Ann N Y Acad Sci . 2007 ; 1116 : 227 – 37 . Google Scholar Crossref Search ADS PubMed WorldCat Evans KE , Fox SW Interleukin-10 inhibits osteoclastogenesis by reducing NFATc1 expression and preventing its translocation to the nucleus . BMC Cell Biol . 2007 ; 8 : 4 . Google Scholar Crossref Search ADS PubMed WorldCat Cush JJ , Splawski JB, Thomas R, McFarlin JE, Schulze-Koops H, Davis LS, et al. . Elevated interleukin-10 levels in patients with rheumatoid arthritis . Arthritis Rheum . 1995 ; 38 : 96 – 104 . Google Scholar Crossref Search ADS PubMed WorldCat Van Roon JAG , Wijngaarden S, Lafeber FPJG, Damen C, Van JG, Winkel JD, Bijlsma JWJ Interleukin 10 treatment of patients with rheumatoid arthritis enhances Fcγ receptor expression on monocytes and responsiveness to immune complex stimulation . J Rheumatol . 2003 ; 30 : 648 – 51 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Keystone E , Wherry J, Grint P IL-10 as a therapeutic strategy in the treatment of rheumatoid arthritis . Rheum Dis Clin North Am . 1998 ; 24 : 629 – 39 . Google Scholar Crossref Search ADS PubMed WorldCat Trepicchio WL , Dorner AJ. Interleukin-11. A gp130 cytokine . Ann N Y Acad Sci . 1998 ; 856 : 12 – 21 . Google Scholar Crossref Search ADS PubMed WorldCat Nandurkar HH , Robb L, Tarlinton D, Barnett L, Köntgen F, Begley CG Adult mice with targeted mutation of the interleukin-11 receptor (IL11Ra) display normal hematopoiesis . Blood . 1997 ; 90 : 2148 – 59 . Google Scholar Crossref Search ADS PubMed WorldCat DA W , Keller DC, Du XX, Srour EF, Hoffman R Interleukin-11 inhibits adipogenesis and stimulates myelopoiesis in human long-term marrow cultures . Blood . 1993 ; 82 : 1428 – 35 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Nandurkar HH , Robb L, Begley CG The role of IL-II in hematopoiesis as revealed by a targeted mutation of its receptor . Stem Cells . 1998 ; 16 ( 2 ): 53 – 65 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Sims NA , Jenkins BJ, Nakamura A, Quinn JMW, Li R, Gillespie MT, et al. . Interleukin-11 receptor signaling is required for normal bone remodeling . J Bone Miner Res . 2005 ; 20 : 1093 – 102 . Google Scholar Crossref Search ADS PubMed WorldCat Teramura M , Kobayashi S, Yoshinaga K, Iwabe K, Mizoguchi H Effect of interleukin 11 on normal and pathological thrombopoiesis . Cancer Chemother Pharmacol . 1996 ; 38 : S99 – S102 . Google Scholar Crossref Search ADS PubMed WorldCat Li TM , Wu CM, Huang HC, Chou PC, Fong YC, Tang CH Interleukin-11 increases cell motility and up-regulates intercellular adhesion molecule-1 expression in human chondrosarcoma cells . J Cell Biochem . 2012 ; 113 : 3353 – 62 . Google Scholar Crossref Search ADS PubMed WorldCat Onnis B , Fer N, Rapisarda A, Perez VS, Melillo G Autocrine production of IL-11 mediates tumorigenicity in hypoxic cancer cells . J Clin Invest . 2013 ; 123 : 1615 – 29 . Google Scholar Crossref Search ADS PubMed WorldCat Matsui T , Nakata N, Nagai S, Nakatani A, Takahashi M, Momose T, et al. . Inflammatory cytokines and hypoxia contribute to 18F-FDG uptake by cells involved in pannus formation in rheumatoid arthritis . J Nucl Med . 2009 ; 50 : 920 – 6 . Google Scholar Crossref Search ADS PubMed WorldCat Kudo O , Sabokbar A, Pocock A, Itonaga I, Fujikawa Y, Athanasou NA Interleukin-6 and interleukin-11 support human osteoclast formation by a RANKL-independent mechanism . Bone . 2003 ; 32 : 1 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat Morgan H , Tumber A, Hill PA Breast cancer cells induce osteoclast formation by stimulating host IL-11 production and downregulating granulocyte/macrophage colony-stimulating factor . Int J Cancer . 2004 ; 109 : 653 – 60 . Google Scholar Crossref Search ADS PubMed WorldCat McCoy EM , Hong H, Pruitt HC, Feng X IL-11 produced by breast cancer cells augments osteoclastogenesis by sustaining the pool of osteoclast progenitor cells . BMC Cancer . 2013 ; 13 : 16 . Google Scholar Crossref Search ADS PubMed WorldCat Hermann JA , Hall MA, Maini RN, Feldmann M, Brennan FM Important immunoregulatory role of interleukin-11 in the inflammatory process in rheumatoid arthritis . Arthritis Rheum . 1998 ; 41 : 1388 – 97 . Google Scholar Crossref Search ADS PubMed WorldCat Presky DH , Yang H, Minetti LJ, Chua AO, Nabavi N, Wu CY, et al. . A functional interleukin 12 receptor complex is composed of two beta-type cytokine receptor subunits . Proc Natl Acad Sci USA . 1996 ; 93 : 14002 – 7 . Google Scholar Crossref Search ADS WorldCat Ylikoski E , Lund R, Kyläniemi M, Filén S, Kilpeläinen M, Savolainen J, Lahesmaa R IL-12 up-regulates T-bet independently of IFN-gamma in human CD4+ T cells . Eur J Immunol . 2005 ; 35 : 3297 – 306 . Google Scholar Crossref Search ADS PubMed WorldCat Koch A , Raidl M, Lux M, Müller K, Büning H, Humme S. IL-12-induced T-bet expression and IFNgamma release in lymphocytes from asthmatics–role of MAPkinases ERK-1/-2, p38(MAPK) and effect of dexamethasone . Respir Med . 2007 ; 101 : 1321 – 30 . Google Scholar Crossref Search ADS PubMed WorldCat Knutson KL , Disis ML IL-12 enhances the generation of tumour antigen-specific Th1 CD4 T cells during ex vivo expansion . Clin Exp Immunol . 2004 ; 135 : 322 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat Windhagen A , Anderson DE, Carrizosa A, Williams RE, Hafler DA IL-12 induces human T cells secreting IL-10 with IFN-gamma . J Immunol . 1996 ; 157 : 1127 – 31 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Wu CY , Demeure C, Kiniwa M, Gately M, Delespesse G IL-12 induces the production of IFN-gamma by neonatal human CD4 T cells . J Immunol (Baltimore, Md 1950) . 1993 ; 151 : 1938 – 49 . Google Scholar OpenURL Placeholder Text WorldCat Yoshimatsu M , Kitaura H, Fujimura Y, Eguchi T, Kohara H, Morita Y, Yoshida N IL-12 inhibits TNF-α induced osteoclastogenesis via a T cell-independent mechanism in vivo . Bone . 2009 ; 45 : 1010 – 16 . Google Scholar Crossref Search ADS PubMed WorldCat Yoshimatsu M , Kitaura H, Fujimura Y, Kohara H, Morita Y, Yoshida N IL-12 inhibits lipopolysaccharide stimulated osteoclastogenesis in mice . J Immunol Res . 2014 ; 2015 :214878. Google Scholar OpenURL Placeholder Text WorldCat Albini A , Brigati C, Ventura A, Lorusso G, Pinter M, Morini M, et al. . Angiostatin anti-angiogenesis requires IL-12: the innate immune system as a key target . J Transl Med . 2009 ; 7 : 5 . Google Scholar Crossref Search ADS PubMed WorldCat Morini M , Albini A, Lorusso G, Moelling K, Lu B, Cilli M, et al. . Prevention of angiogenesis by naked DNA IL-12 gene transfer: angioprevention by immunogene therapy . Gene Ther . 2004 ; 11 : 284 – 91 . Google Scholar Crossref Search ADS PubMed WorldCat Horwood NJ , Elliott J, Martin TJ, Gillespie MT IL-12 alone and in synergy with IL-18 inhibits osteoclast formation in vitro . J Immunol . 2001 ; 166 : 4915 – 21 . Google Scholar Crossref Search ADS PubMed WorldCat Lexberg MH , Taubner A, Albrecht I, Lepenies I, Richter A, Kamradt T, et al. . IFN-γ and IL-12 synergize to convert in vivo generated Th17 into Th1/Th17 cells . Eur J Immunol . 2010 ; 40 : 3017 – 27 . Google Scholar Crossref Search ADS PubMed WorldCat Peeva E , Fishman AD, Goddard G, Wadler S, Barland P Rheumatoid arthritis exacerbation caused by exogenous interleukin-12 . Arthritis Rheum . 2000 ; 43 : 461 . Google Scholar Crossref Search ADS PubMed WorldCat Kim WU , Min SY, Cho ML, Youn J, Min JK, Lee SH, et al. . The role of IL-12 in inflammatory activity of patients with rheumatoid arthritis (RA) . Clin Exp Immunol . 2000 ; 119 : 175 – 81 . Google Scholar Crossref Search ADS PubMed WorldCat Morita Y , Yamamura M, Nishida K, Harada S, Okamoto H, Inoue H, et al. . Expression of interleukin-12 in synovial tissue from patients with rheumatoid arthritis . Arthritis Rheum . 1998 ; 41 : 306 – 14 . Google Scholar Crossref Search ADS PubMed WorldCat Aita T , Yamamura M, Kawashima M, Okamoto A, Iwahashi M, Yamana J, Makino H Expression of interleukin 12 receptor (IL-12R) and IL-18R on CD4+ T cells from patients with rheumatoid arthritis . J Rheumatol . 2004 ; 31 : 448 – 56 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Derocq JM , Dumont X, Guillemot JC, Kaghad M, Labit C, Leplatois P, et al. . Interleukin-13 is a new human lymphokine regulating inflammatory and immune responses . Nature . 1993 ; 362 : 248 – 50 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Khurana Hershey GK IL-13 receptors and signaling pathways: an evolving web . J Allergy Clin Immunol . 2003 ; 111 : 677 – 90 . Google Scholar Crossref Search ADS PubMed WorldCat Barlow JL , Bellosi A, Hardman CS, Drynan LF, Wong SH, Cruickshank JP, McKenzie ANJ Innate IL-13-producing nuocytes arise during allergic lung inflammation and contribute to airways hyperreactivity . J Allergy Clin Immunol . 2012 ; 129 : 191 – 8.e1–4 . Google Scholar Crossref Search ADS PubMed WorldCat Wills-Karp M Interleukin-13 in asthma pathogenesis . Immunol Rev . 2004 ; 202 : 175 – 90 . Google Scholar Crossref Search ADS PubMed WorldCat Westwick J , Watson ML, White AM, Campbell EM, Smith AW, Uddin J, Yoshimura T Anti-inflammatory actions of interleukin-13: suppression of tumor necrosis factor-alpha and antigen-induced leukocyte accumulation in the guinea pig lung . Am J Respir Cell Mol Biol . 1999 ; 20 : 1007 – 12 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Haas CS , Amin MA, Ruth JH, Allen BL, Ahmed S, Pakozdi A, et al. . In vivo inhibition of angiogenesis by interleukin-13 gene therapy in a rat model of rheumatoid arthritis . Arthritis Rheum . 2007 ; 56 : 2535 – 48 . Google Scholar Crossref Search ADS PubMed WorldCat Nishimura Y , Nitto T, Inoue T, Node K IL-13 attenuates vascular tube formation via JAK2-STAT6 pathway . Circ J . 2008 ; 72 : 469 – 75 . Google Scholar Crossref Search ADS PubMed WorldCat Isomäki P , Luukkainen R, Toivanen P, Punnonen J The presence of interleukin-13 in rheumatoid synovium and its antiinflammatory effects on synovial fluid macrophages from patients with rheumatoid arthritis . Arthritis Rheum . 1996 ; 39 : 1693 – 702 . Google Scholar Crossref Search ADS PubMed WorldCat Marinou I , Till SH, Moore DJ, Wilson AG. Lack of association or interactions between the IL-4, IL-4Ralpha and IL-13 genes, and rheumatoid arthritis . Arthritis Res Ther . 2008 ; 10 : R80 . Google Scholar Crossref Search ADS PubMed WorldCat Ford R , Tamayo A, Martin B, Niu K, Claypool K, Cabanillas F, Ambrus J Jr Identification of B-cell growth factors (interleukin-14; high molecular weight-B-cell growth factors) in effusion fluids from patients with aggressive B-cell lymphomas . Blood . 1995 ; 86 : 283 – 93 . Google Scholar Crossref Search ADS PubMed WorldCat Leca N , Laftavi M, Shen L, Matteson K, Ambrus J, Pankewycz O Regulation of human interleukin 14 transcription in vitro and in vivo after renal transplantation. Transplantation . 2008 ; 86 : 336 – 41 . Google Scholar Crossref Search ADS PubMed WorldCat Peng X , Zhou C, Wei D, Luo Z, Zhang C Characteristics of a novel monoclonal antibody against interleukin-14alpha . Hybridoma (Larchmt) . 2009 ; 28 : 235 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat Vámosi G , Bodnár A, Vereb G, Jenei A, Goldman CK, Langowski J, et al. . IL-2 and IL-15 receptor alpha-subunits are coexpressed in a supramolecular receptor cluster in lipid rafts of T cells . Proc Natl Acad Sci USA . 2004 ; 101 : 11082 – 7 . Google Scholar Crossref Search ADS WorldCat Han KP , Zhu X, Liu B, Jeng E, Kong L, Yovandich JL, et al. . IL-15: IL-15 receptor alpha superagonist complex: high-level co-expression in recombinant mammalian cells, purification and characterization . Cytokine . 2011 ; 56 : 804 – 10 . Google Scholar Crossref Search ADS PubMed WorldCat Park JY , Lee SH, Yoon SR, Park YJ, Jung H, Kim TD, Choi I IL-15-induced IL-10 increases the cytolytic activity of human natural killer cells . Mol Cells . 2011 ; 32 : 265 – 72 . Google Scholar Crossref Search ADS PubMed WorldCat Correia MP , Costa AV, Uhrberg M, Cardoso EM, Arosa FA IL-15 induces CD8+ T cells to acquire functional NK receptors capable of modulating cytotoxicity and cytokine secretion . Immunobiology . 2011 ; 216 : 604 – 12 . Google Scholar Crossref Search ADS PubMed WorldCat Budagian V , Bulanova E, Paus R, Bulfone-Paus S IL-15/IL-15 receptor biology: a guided tour through an expanding universe . Cytokine Growth Factor Rev . 2006 ; 17 : 259 – 80 . Google Scholar Crossref Search ADS PubMed WorldCat Leong JW , Chase JM, Romee R, Schneider SE, Sullivan RP, Cooper MA, Fehniger TA Preactivation with IL-12, IL-15, and IL-18 induces cd25 and a functional high-affinity il-2 receptor on human cytokine-induced memory-like natural killer cells . Biol Blood Marrow Transplant . 2014 ; 20 : 463 – 73 . Google Scholar Crossref Search ADS PubMed WorldCat McInnes IB , Liew FY Interleukin 15: a proinflammatory role in rheumatoid arthritis synovitis . Immunol Today . 1998 ; 19 : 75 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat McInnes IB , Leung BP, Sturrock RD, Field M, Liew FY Interleukin-15 mediates T cell-dependent regulation of tumor necrosis factor-alpha production in rheumatoid arthritis . Nat Med . 1997 ; 3 : 189 – 95 . Google Scholar Crossref Search ADS PubMed WorldCat Mcinnes IB , Al Mughales J, Field M, Leung BP The role of interleukin-15 in T-cell migration and activation in rheumatoid arthritis . Nat Med . 1996 ; 2 : 3 – 5 . Google Scholar Crossref Search ADS PubMed WorldCat Halvorsen EH , Strønen E, Hammer HB, Goll GL, Sollid LM. Interleukin-15 induces interleukin-17 production by synovial T cell lines from patients with rheumatoid arthritis . Scand J Immunol . 2011 ; 73 : 243 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat Hart G , Avin-Wittenberg T, Shachar I. IL-15 regulates immature B-cell homing in an Ly49D-, IL-12, and IL-18 dependent manner . Blood . 2008 ; 111 : 50 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat Strengell M , Matikainen S, Siren J, Lehtonen A, Foster D, Julkunen I, Sareneva T IL-21 in synergy with IL-15 or IL-18 enhances IFN-gamma production in human NK and T cells . J Immunol . 2003 ; 170 : 5464 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat Ziolkowska M , Koc A, Luszczykiewicz G, Ksiezopolska-Pietrzak K, Klimczak E, Chwalinska-Sadowska H, Maslinski W High levels of IL-17 in rheumatoid arthritis patients: IL-15 triggers in vitro IL-17 production via cyclosporin a-sensitive mechanism . J Immunol . 2000 ; 164 : 2832 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat Alleva DG , Kaser SB, Monroy MA, Fenton MJ, Beller DI IL-15 functions as a potent autocrine regulator of macrophage proinflammatory cytokine production: evidence for differential receptor subunit utilization associated with stimulation or inhibition . J Immunol . 1997 ; 159 : 2941 – 51 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Angiolillo AL , Kanegane H, Sgadari C, Reaman GH, Tosato G Interleukin-15 promotes angiogenesis in vivo . Biochem Biophys Res Commun . 1997 ; 233 : 231 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat Badolato R , Ponzi AN, Millesimo M, Notarangelo LD, Musso T Interleukin-15 (IL-15) induces IL-8 and monocyte chemotactic protein 1 production in human monocytes . Blood . 1997 ; 90 : 2804 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat Lugering N , Kucharzik T, Maaser C, Kraft M, Domschke W Interleukin-15 strongly inhibits interleukin-8 and monocyte chemoattractant protein-1 production in human colonic epithelial cells . Immunology . 1999 ; 98 : 504 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat Constantinescu CS , Grygar C, Kappos L, Leppert D Interleukin 15 stimulates production of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 by human peripheral blood mononuclear cells . Cytokine . 2001 ; 13 : 244 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat Tao Y , Qiu X, Xu C, Sun B, Shi C Expression and correlation of matrix metalloproteinase-7 and interleukin-15 in human osteoarthritis . Int J Clin Exp Pathol . 2015 ; 8 : 9112 – 18 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Park MK , Her YM, La Cho M, Oh HJ, Park EM, Kwok SK, et al. . IL-15 promotes osteoclastogenesis via the PLD pathway in rheumatoid arthritis . Immunol Lett . 2011 ; 139 : 42 – 51 . Google Scholar Crossref Search ADS PubMed WorldCat Takeda H , Kikuchi T, Soboku K, Okabe I, Mizutani H, Mitani A, et al. . Effect of IL-15 and natural killer cells on osteoclasts and osteoblasts in a mouse coculture . Inflammation . 2014 ; 37 : 657 – 69 . Google Scholar Crossref Search ADS PubMed WorldCat Ogata Y , Kukita A, Kukita T, Komine M, Miyahara A, Miyazaki S, Kohashi O A novel role of IL-15 in the development of osteoclasts: inability to replace its activity with IL-2 . J Immunol . 1999 ; 162 : 2754 – 60 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Machado Diaz AC , Chico Capote A, Arrieta Aguero CA, Rodríguez Alvarez Y, García del Barco Herrera D, Estévez del Toro M, et al. . Proinflammatory soluble interleukin-15 receptor alpha is increased in rheumatoid arthritis . Arthritis . 2012 ; 2012 : 1 – 7 . Google Scholar Crossref Search ADS WorldCat Baslund B , Tvede N, Danneskiold-Samsoe B, Larsson P, Panayi G, Petersen J, et al. . Targeting interleukin-15 in patients with rheumatoid arthritis: a proof-of-concept study . Arthritis Rheum . 2005 ; 52 : 2686 – 92 . Google Scholar Crossref Search ADS PubMed WorldCat Cruikshank WW , Center DM, Nisar N, Wu M, Natke B, Theodore AC, Kornfeld H Molecular and functional analysis of a lymphocyte chemoattractant factor: association of biologic function with CD4 expression . Proc Natl Acad Sci USA . 1994 ; 91 : 5109 – 13 . Google Scholar Crossref Search ADS PubMed WorldCat Cruikshank WW , Kornfeld H, Center DM Interleukin-16 . J Leukoc Biol . 2000 ; 67 : 757 – 66 . Google Scholar Crossref Search ADS PubMed WorldCat Krug N , Cruikshank WW, Tschernig T, Erpenbeck VJ, Balke K, Hohlfeld JM, et al. . Interleukin 16 and T-cell chemoattractant activity in bronchoalveolar lavage 24 hours after allergen challenge in asthma . Am J Respir Crit Care Med . 2000 ; 162 : 105 – 11 . Google Scholar Crossref Search ADS PubMed WorldCat Blaschke S , Schulz H, Schwarz G, Blaschke V, Muller GA, Reuss-Borst M Interleukin 16 expression in relation to disease activity in rheumatoid arthritis . J Rheumatol . 2001 ; 28 : 12 – 21 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Klimiuk PA , Coronzy JJ, Weyand CM. IL-16 as an anti-inflammatory cytokine in rheumatoid synovitis . J Immunol . 1999 ; 162 : 4293 – 9 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Murota A , Suzuki K, Kassai Y, Miyazaki T, Morita R, Kondo Y, et al. . Serum proteomic analysis identifies interleukin 16 as a biomarker for clinical response during early treatment of rheumatoid arthritis . Cytokine . 2015 ; 78 : 87 – 93 . Google Scholar Crossref Search ADS PubMed WorldCat Franz JK , Kolb SA, Hummel KM, Lahrtz F, Neidhart M, Aicher WK, et al. . Interleukin-16, produced by synovial fibroblasts, mediates chemoattraction for CD4+ T lymphocytes in rheumatoid arthritis . Eur J Immunol . 1998 ; 28 : 2661 – 71 . Google Scholar Crossref Search ADS PubMed WorldCat Sharma V , Sparks JL, Vail JD Human B-cell lines constitutively express and secrete interleukin-16 . Immunology . 2000 ; 99 : 266 – 71 . Google Scholar Crossref Search ADS PubMed WorldCat Rumsaeng V , Cruikshank WW, Foster B, Prussin C, Kirshenbaum AS, Davis TA, et al. . Metcalfe, human mast cells produce the CD4+ T lymphocyte chemoattractant factor, IL-16 . J Immunol . 1997 ; 159 : 2904 – 10 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Cruikshank W , Lynch EA, Heijens CA, Horst NF, Center DM Cutting edge: IL-16/CD4 preferentially induces Th1 cell migration: requirement of CCR5 . J Immunol . 2003 ; 171 : 4965 – 8 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Cho ML , Jung YO, Kim KW, Park MK, Oh HJ, Ju JH, et al. . IL-17 induces the production of IL-16 in rheumatoid arthritis . Exp Mol Med . 2008 ; 40 : 237 – 45 . Google Scholar Crossref Search ADS PubMed WorldCat Skundric DS , Cai J, Cruikshank WW, Gveric D Production of IL-16 correlates with CD4+ Th1 inflammation and phosphorylation of axonal cytoskeleton in multiple sclerosis lesions . J Neuroinflammation . 2006 ; 3 : 13 . Google Scholar Crossref Search ADS PubMed WorldCat Park SL , Hwang B, Lee SY, Kim WT, Choi YH, Chang YC, et al. . p21WAF1 Is required for interleukin-16-induced migration and invasion of vascular smooth muscle cells via the p38MAPK/Sp-1/MMP-9 pathway . PLoS One . 2015 ; 10 : e0142153 . Google Scholar Crossref Search ADS PubMed WorldCat Gaffen SL Structure and signalling in the IL-17 receptor family . Nat Rev Immunol . 2009 ; 9 : 556 – 67 . Google Scholar Crossref Search ADS PubMed WorldCat Lohr J , Knoechel B, Wang JJ, Villarino AV, Abbas AK Role of IL-17 and regulatory T lymphocytes in a systemic autoimmune disease . J Exp Med . 2006 ; 203 : 2785 – 91 . Google Scholar Crossref Search ADS PubMed WorldCat Wang L , Yi T, Kortylewski M, Pardoll DM, Zeng D, Yu H IL-17 can promote tumor growth through an IL-6-Stat3 signaling pathway . J Exp Med . 2009 ; 206 : 1457 – 64 . Google Scholar Crossref Search ADS PubMed WorldCat Konya C , Paz Z, Apostolidis SA, Tsokos GC Update on the role of Interleukin 17 in rheumatologic autoimmune diseases . Cytokine . 2015 ; 75 : 1 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat Stockinger B , Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells . Immunity . 2006 ; 24 : 179 – 89 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Park JS , Park MK, Lee SY, Oh HJ, Lim MA, Cho WT, et al. . TWEAK promotes the production of Interleukin-17 in rheumatoid arthritis . Cytokine . 2012 ; 60 : 143 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat Mills K , Sutton CE, Lalor SJ, Sweeney CM, Brereton CF, Lavelle EC Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity . Immunity . 2009 ; 31 : 331 – 41 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Lalor SJ , Dungan LS, Sutton CE, Basdeo SA, Fletcher JM, Mills KHG Caspase-1–processed cytokines IL-1β and IL-18 promote IL-17 production by γδ and CD4 T cells that mediate autoimmunity . J Immunol . 2011 ; 186 : 5738 – 48 . Google Scholar Crossref Search ADS PubMed WorldCat Liu X , Ren S, Qu X, Ge C, Cheng K, Zhao RCH Mesenchymal stem cells inhibit Th17 cells differentiation via IFN-γ-mediated SOCS3 activation . Immunol Res . 2015 ; 61 : 219 – 29 . Google Scholar Crossref Search ADS PubMed WorldCat Littman DR , Ivanov II , McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, et al. . The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells . Cell . 2006 ; 126 : 1121 – 33 . Google Scholar Crossref Search ADS PubMed WorldCat Hirota K , Hashimoto M, Yoshitomi H, Tanaka S, Nomura T, Yamaguchi T, et al. . T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritis . J Exp Med . 2007 ; 204 : 41 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat Roeleveld DM , Koenders MI The role of the Th17 cytokines IL-17 and IL-22 in Rheumatoid Arthritis pathogenesis and developments in cytokine immunotherapy . Cytokine . 2014 ; 74 : 101 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat Alexandrakis MG , Pappa CA, Miyakis S, Sfiridaki A, Kafousi M, Alegakis A, Stathopoulos EN Serum interleukin-17 and its relationship to angiogenic factors in multiple myeloma . Eur J Intern Med . 2006 ; 17 : 412 – 16 . Google Scholar Crossref Search ADS PubMed WorldCat Zhang Y , Li G, Qian Y, Zhang H, Sunagawa M, Guo S, et al. . Interleukin-17A promotes rheumatoid arthritis synoviocytes migration and invasion under hypoxia by increasing MMP2 and MMP9 expression through NF-κB/HIF-1α pathway . Mol Immunol . 2013 ; 53 : 227 – 36 . Google Scholar Crossref Search ADS PubMed WorldCat Pickens SR , Volin MV, Mandelin AM, Kolls JK, Pope RM, Shahrara S IL-17 contributes to angiogenesis in rheumatoid arthritis . J Immunol . 2010 ; 184 : 3233 – 41 . Google Scholar Crossref Search ADS PubMed WorldCat Ito H , Yamada H, Shibata TN, Mitomi H, Nomoto S, Ozaki S Dual role of interleukin-17 in pannus growth and osteoclastogenesis in rheumatoid arthritis . Arthritis Res Ther . 2011 ; 13 : R14 . Google Scholar Crossref Search ADS PubMed WorldCat Lubberts E , van den Bersselaar L, Oppers-Walgreen B, Schwarzenberger P, Coenen-de Roo CJJ, Kolls JK, et al. . IL-17 promotes bone erosion in murine collagen-induced arthritis through loss of the receptor activator of NF-kappa B ligand/osteoprotegerin balance . J Immunol . 2003 ; 170 : 2655 – 62 . Google Scholar Crossref Search ADS PubMed WorldCat Yago T , Nanke Y, Ichikawa N, Kobashigawa T, Mogi M, Kamatani N, Kotake S IL-17 induces osteoclastogenesis from human monocytes alone in the absence of osteoblasts, which is potently inhibited by anti-TNF-alpha antibody: a novel mechanism of osteoclastogenesis by IL-17 . J Cell Biochem . 2009 ; 108 : 947 – 55 . Google Scholar Crossref Search ADS PubMed WorldCat Moon YM , Yoon BY, Her YM, Oh HJ, Lee JS, Kim KW, et al. . IL-32 and IL-17 interact and have the potential to aggravate osteoclastogenesis in rheumatoid arthritis . Arthritis Res Ther . 2012 ; 14 : R246 . Google Scholar Crossref Search ADS PubMed WorldCat Shen L , Zhang H, Yan T, Zhou G, Liu R Association between interleukin 17A polymorphisms and susceptibility to rheumatoid arthritis in a Chinese population . Gene . 2015 ; 566 : 18 – 22 . Google Scholar Crossref Search ADS PubMed WorldCat Kellner H Targeting interleukin-17 in patients with active rheumatoid arthritis: rationale and clinical potential . Ther Adv Musculoskelet Dis . 2013 ; 5 : 141 – 52 . Google Scholar Crossref Search ADS PubMed WorldCat Zhu S , Qian Y IL-17/IL-17 receptor system in autoimmune disease: mechanisms and therapeutic potential . Clin Sci (Lond) . 2012 ; 122 : 487 – 511 . Google Scholar Crossref Search ADS PubMed WorldCat Kikly K , Liu L, Na S, Sedgwick JD. The IL-23/Th(17) axis: therapeutic targets for autoimmune inflammation . Curr Opin Immunol . 2006 ; 18 : 670 – 5 . Google Scholar Crossref Search ADS PubMed WorldCat Röhn TA , Jennings GT, Hernandez M, Grest P, Beck M, Zou Y, et al. . Vaccination against IL-17 suppresses autoimmune arthritis and encephalomyelitis . Eur J Immunol . 2006 ; 36 : 2857 – 67 . Google Scholar Crossref Search ADS PubMed WorldCat Buckland J Rheumatoid arthritis: anti-TNF and anti-IL-17 antibodies—better together!. Nat Rev Rheumatol . 2014 ; 10 : 699 . Google Scholar Crossref Search ADS PubMed WorldCat Debets R , Timans JC, Churakowa T, Zurawski S, de Waal Malefyt R, Moore KW, et al. . IL-18 receptors, their role in ligand binding and function: anti-IL-1RAcPL antibody, a potent antagonist of IL-18 . J Immunol . 2000 ; 165 : 4950 – 6 . Google Scholar Crossref Search ADS PubMed WorldCat Gracie JA , Forsey RJ, Chan WL, Gilmour A, Leung BP, Greer MR, et al. . A proinflammatory role for IL-18 in rheumatoid arthritis . J Clin Invest . 1999 ; 104 : 1393 – 401 . Google Scholar Crossref Search ADS PubMed WorldCat Yoshimoto T , Takeda K, Tanaka T, Ohkusu K, Kashiwamura S, Okamura H, et al. . IL-12 up-regulates IL-18 receptor expression on T cells, Th1 cells, and B cells: synergism with IL-18 for IFN-gamma production . J Immunol . 1998 ; 161 : 3400 – 7 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Sareneva T , Julkunen I, Matikainen S IFN-alpha and IL-12 induce IL-18 receptor gene expression in human NK and T cells . J Immunol . 2000 ; 165 : 1933 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat Smeltz RB , Chen J, Hu-Li J, Shevach EM Regulation of interleukin (IL)-18 receptor alpha chain expression on CD4(+) T cells during T helper (Th)1/Th2 differentiation. Critical downregulatory role of IL-4 . J Exp Med . 2001 ; 194 : 143 – 53 . Google Scholar Crossref Search ADS PubMed WorldCat Enoksson SL , Grasset EK, Hagglof T, Mattsson N, Kaiser Y, Gabrielsson S, et al. . PNAS plus: the inflammatory cytokine IL-18 induces self-reactive innate antibody responses regulated by natural killer T cells . Proc Natl Acad Sci . 2011 ; 108 : E1399 – 407 . Google Scholar Crossref Search ADS PubMed WorldCat Amin MA , Rabquer BJ, Mansfield PJ, Ruth JH, Marotte H, Haas CS, et al. . Interleukin 18 induces angiogenesis in vitro and in vivo via Src and Jnk kinases . Ann Rheum Dis . 2010 ; 69 : 2204 – 12 . Google Scholar Crossref Search ADS PubMed WorldCat Park CC , Morel JC, Amin MA, Connors MA, Harlow LA, Koch AE Evidence of IL-18 as a novel angiogenic mediator . J Immunol . 2001 ; 167 : 1644 – 53 . Google Scholar Crossref Search ADS PubMed WorldCat Amin MA , Mansfield PJ, Pakozdi A, Campbell PL, Ahmed S, Martinez RJ, Koch AE Interleukin-18 induces angiogenic factors in rheumatoid arthritis synovial tissue fibroblasts via distinct signaling pathways . Arthritis Rheum . 2007 ; 56 : 1787 – 97 . Google Scholar Crossref Search ADS PubMed WorldCat Volin MV , Koch AE Interleukin-18: a mediator of inflammation and angiogenesis in rheumatoid arthritis . J Interferon Cytokine Res . 2011 ; 31 : 745 – 51 . Google Scholar Crossref Search ADS PubMed WorldCat Mallat Z , Silvestre JS, Le Ricousse-Roussanne S, Lecomte-Raclet L, Corbaz A, Clergue M, et al. . Interleukin-18/interleukin-18 binding protein signaling modulates ischemia-induced neovascularization in mice hindlimb . Circ Res . 2002 ; 91 : 441 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat Cao R , Farnebo J, Kurimoto M, Cao Y Interleukin-18 acts as an angiogenesis and tumor suppressor . FASEB J . 1999 ; 13 : 2195 – 202 . Google Scholar Crossref Search ADS PubMed WorldCat Kanda N , Shimizu T, Tada Y, Watanabe S IL-18 enhances IFN-gamma-induced production of CXCL9, CXCL10, and CXCL11 in human keratinocytes . Eur J Immunol . 2007 ; 37 : 338 – 50 . Google Scholar Crossref Search ADS PubMed WorldCat Ji JD , Lee WJ Interleukin-18 gene polymorphisms and rheumatoid arthritis: a meta-analysis . Gene . 2013 ; 523 : 27 – 32 . Google Scholar Crossref Search ADS PubMed WorldCat Della Justina Fariasa T , do Canto LM, Medeiros MD, Rodrigues Sereia AF, de Carlos Back LK, de Mello FM, et al. . Lack of association between interleukin-18 polymorphisms and rheumatoid arthritis . Rev Bras Reumatol . 2013 ; 53 : 199 – 205 . Google Scholar Crossref Search ADS PubMed WorldCat Horwood NJ , Udagawa N, Elliott J, Grail D, Okamura H, Kurimoto M, et al. . Interleukin 18 inhibits osteoclast formation via T cell production of granulocyte macrophage colony-stimulating factor . J Clin Invest . 1998 ; 101 : 595 – 603 . Google Scholar Crossref Search ADS PubMed WorldCat Zhang W , Cong X, Qin YH, He ZW, He DY, Dai S IL-18 upregulates the production of key regulators of osteoclastogenesis from fibroblast-like synoviocytes in rheumatoid arthritis . Inflammation . 2013 ; 36 : 103 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat Takei S , Hoshino T, Matsunaga K, Sakazaki Y, Sawada M, Oda H, et al. . Soluble interleukin-18 receptor complex is a novel biomarker in rheumatoid arthritis . Arthritis Res Ther . 2011 ; 13 : R52 . Google Scholar Crossref Search ADS PubMed WorldCat Fantuzzi G , Reed DA, Dinarello CA. IL-12-induced IFN-gamma is dependent on caspase-1 processing of the IL-18 precursor . J Clin Invest . 1999 ; 104 : 761 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat Liao YC , Liang WG, Chen FW, Hsu JH, Yang JJ, Chang MS IL-19 induces production of IL-6 and TNF-alpha and results in cell apoptosis through TNF-alpha . J Immunol (Baltimore, Md 1950) . 2002 ; 169 : 4288 – 97 . Google Scholar Crossref Search ADS WorldCat Leng RX , Pan HF, Tao JH, Ye DQ IL-19, IL-20 and IL-24: potential therapeutic targets for autoimmune diseases . Expert Opin Ther Targets . 2011 ; 15 : 119 – 26 . Google Scholar Crossref Search ADS PubMed WorldCat Parrish-Novak J , Xu W, Brender T, Yao L, Jones C, West J, et al. . Interleukins 19, 20, and 24 signal through two distinct receptor complexes: differences in receptor-ligand interactions mediate unique biological functions . J Biol Chem . 2002 ; 277 : 47517 – 23 . Google Scholar Crossref Search ADS PubMed WorldCat Jain S , Gabunia K, Kelemen SE, Panetti TS, Autieri MV The anti-inflammatory cytokine interleukin 19 is expressed by and angiogenic for human endothelial cells . Arterioscler Thromb Vasc Biol . 2011 ; 31 : 167 – 75 . Google Scholar Crossref Search ADS PubMed WorldCat Richards J , Gabunia K, Kelemen SE, Kako F, Choi ET, Autieri MV Interleukin-19 increases angiogenesis in ischemic hind limbs by direct effects on both endothelial cells and macrophage polarization . J Mol Cell Cardiol . 2015 ; 79 : 21 – 31 . Google Scholar Crossref Search ADS PubMed WorldCat Gabunia K , Autieri MV Interleukin-19 can enhance angiogenesis by macrophage polarization . Macrophage . 2015 ; 2 : 2 – 5 . Google Scholar OpenURL Placeholder Text WorldCat Sabat R , Wallace E, Endesfelder S, Wolk K IL-19 and IL-20: two novel cytokines with importance in inflammatory diseases . Expert Opin Ther Targets . 2007 ; 11 : 601 – 12 . Google Scholar Crossref Search ADS PubMed WorldCat Heuzé-Vourc’h N , Liu M, Dalwadi H, Baratelli FE, Zhu L, Goodglick L, et al. . IL-20, an anti-angiogenic cytokine that inhibits COX-2 expression . Biochem Biophys Res Commun . 2005 ; 333 : 470 – 5 . Google Scholar Crossref Search ADS PubMed WorldCat Hsieh MY , Chen WY, Jiang MJ, Cheng BC, Huang TY, Chang MS Interleukin-20 promotes angiogenesis in a direct and indirect manner . Genes Immun . 2006 ; 7 : 234 – 42 . Google Scholar Crossref Search ADS PubMed WorldCat Kragstrup TW , Otkjaer K, Holm C, Jørgensen A, Hokland M, Iversen L, Deleuran B The expression of IL-20 and IL-24 and their shared receptors are increased in rheumatoid arthritis and spondyloarthropathy . Cytokine . 2008 ; 41 : 16 – 23 . Google Scholar Crossref Search ADS PubMed WorldCat Hsu YH , Chen WY, Chan CH, Wu CH, Sun ZJ, Chang MS Anti-IL-20 monoclonal antibody inhibits the differentiation of osteoclasts and protects against osteoporotic bone loss . J Exp Med . 2011 ; 208 : 1849 – 61 . Google Scholar Crossref Search ADS PubMed WorldCat Hsu YH , Wei CC, Shieh DB, Chan CH, Chang MS Anti-IL-20 monoclonal antibody alleviates inflammation in oral cancer and suppresses tumor growth . Mol Cancer Res . 2012 ; 10 : 1430 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat Hsu YH , Hsing CH, Li CF, Chan CH, Chang MC, Yan JJ, Chang MS Anti-IL-20 monoclonal antibody suppresses breast cancer progression and bone osteolysis in murine models . J Immunol . 2012 ; 188 : 1981 – 91 . Google Scholar Crossref Search ADS PubMed WorldCat Imaoka A , Zhang L, Kuboyama N, Abiko Y Reduction of IL-20 expression in rheumatoid arthritis by linear polarized infrared light irradiation . Laser Ther . 2014 ; 23 : 109 – 14 . Google Scholar Crossref Search ADS PubMed WorldCat Asao H , Okuyama C, Kumaki S, Ishii N, Tsuchiya S, Foster D, Sugamura K Cutting edge: the common gamma-chain is an indispensable subunit of the IL-21 receptor complex . J Immunol . 2001 ; 167 : 1 – 5 . Google Scholar Crossref Search ADS PubMed WorldCat Mehta DS , Wurster AL, Grusby MJ Biology of IL-21 and the IL-21 receptor . Immunol Rev . 2004 ; 202 : 84 – 95 . Google Scholar Crossref Search ADS PubMed WorldCat Habib T , Senadheera S, Weinberg K, Kaushansky K. The common gamma chain (gamma c) is a required signaling component of the IL-21 receptor and supports IL-21-induced cell proliferation via JAK3 . Biochemistry . 2002 ; 41 : 8725 – 31 . Google Scholar Crossref Search ADS PubMed WorldCat Frederiksen KS , Lundsgaard D, Freeman JA, Hughes SD, Holm TL, Skrumsager BK, et al. . IL-21 induces in vivo immune activation of NK cells and CD8+ T cells in patients with metastatic melanoma and renal cell carcinoma . Cancer Immunol Immunother . 2008 ; 57 : 1439 – 49 . Google Scholar Crossref Search ADS PubMed WorldCat Skak K , Frederiksen KS, Lundsgaard D Interleukin-21 activates human natural killer cells and modulates their surface receptor expression . Immunology . 2008 ; 123 : 575 – 83 . Google Scholar Crossref Search ADS PubMed WorldCat Perez SA Effect of IL-21 on NK cells derived from different umbilical cord blood populations . Int Immunol . 2005 ; 18 : 49 – 58 . Google Scholar Crossref Search ADS PubMed WorldCat Brady J , Hayakawa Y, Smyth MJ, Nutt SL IL-21 induces the functional maturation of murine NK cells . J Immunol . 2004 ; 172 : 2048 – 58 . Google Scholar Crossref Search ADS PubMed WorldCat Spolski R , Leonard WJ Interleukin-21: a double-edged sword with therapeutic potential . Nat Rev Drug Discov . 2014 ; 13 : 379 – 95 . Google Scholar Crossref Search ADS PubMed WorldCat Deenick EK , Tangye SG. Autoimmunity: IL-21: a new player in Th17-cell differentiation . Immunol Cell Biol . 2007 ; 85 : 503 – 5 . Google Scholar Crossref Search ADS PubMed WorldCat Wei L , Laurence A, Elias KM, O’Shea JJ IL-21 is produced by Th17 cells and drives IL-17 production in a STAT3-dependent manner . J Biol Chem . 2007 ; 282 : 34605 – 10 . Google Scholar Crossref Search ADS PubMed WorldCat Nurieva R , Yang XO, Martinez G, Zhang Y, Panopoulos AD, Ma L, et al. . Essential autocrine regulation by IL-21 in the generation of inflammatory T cells . Nature . 2007 ; 448 : 480 – 3 . Google Scholar Crossref Search ADS PubMed WorldCat Yang L , Anderson DE, Baecher-Allan C, Hastings WD, Bettelli E, Oukka M, et al. . IL-21 and TGF-beta are required for differentiation of human T(H)17 cells . Nature . 2008 ; 454 : 350 – 2 . Google Scholar Crossref Search ADS PubMed WorldCat Korn T , Bettelli E, Gao W, Awasthi A, Jäger A, Strom TB, et al. . IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells . Nature . 2007 ; 448 : 484 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat Niu X , He D, Zhang X, Yue T, Li N, Zhang JZ, et al. . IL-21 regulates Th17 cells in rheumatoid arthritis . Hum Immunol . 2010 ; 71 : 334 – 41 . Google Scholar Crossref Search ADS PubMed WorldCat Spolski R , Leonard WJ IL-21 and T follicular helper cells . Int Immunol . 2010 ; 22 : 7 – 12 . Google Scholar Crossref Search ADS PubMed WorldCat Ozaki K , Spolski R, Feng CG, Qi C, Cheng J, Sher A, et al. . A critical role for IL-21 in regulating immunoglobulin production . Science . 2002 ; 298 : 1630 – 4 . Google Scholar Crossref Search ADS PubMed WorldCat Ettinger R , Sims GP, Fairhurst AM, Robbins R, da Silva YS, Spolski R, et al. . IL-21 Induces differentiation of human naive and memory B cells into antibody-secreting plasma cells . J Immunol . 2005 ; 175 : 7867 – 79 . Google Scholar Crossref Search ADS PubMed WorldCat Ettinger R , Sims GP, Robbins R, Withers D, Fischer RT, Grammer AC, et al. . IL-21 and BAFF/BLyS synergize in stimulating plasma cell differentiation from a unique population of human splenic memory B cells . J Immunol . 2007 ; 178 : 2872 – 82 . Google Scholar Crossref Search ADS PubMed WorldCat Carbone G , Wilson A, Diehl SA, Bunn J, Cooper SM, Rincon M Interleukin-6 receptor blockade selectively reduces IL-21 production by CD4 T cells and IgG4 autoantibodies in rheumatoid arthritis . Int J Biol Sci . 2013 ; 9 : 279 – 88 . Google Scholar Crossref Search ADS PubMed WorldCat Diehl SA , Schmidlin H, Nagasawa M, Blom B, Spits H IL-6 triggers IL-21 production by human CD4+ T cells to drive STAT3-dependent plasma cell differentiation in B cells . Immunol Cell Biol . 2012 ; 90 : 802 – 11 . Google Scholar Crossref Search ADS PubMed WorldCat Castermans K , Tabruyn SP, Zeng R, Van Beijnum JR, Eppolito C, Leonard WJ, et al. . Angiostatic activity of the antitumor cytokine interleukin-21 . Blood . 2008 ; 112 : 4940 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat Whitters MJ , Konz RF, Young DA, Grusby MJ, Collins M, Dunussi-joannopoulos K, Ma HL IL-21 activates both innate and adaptive immunity to generate potent antitumor responses that require perforin but are independent of IFN- γ . J Immunol . 2012 ; 171 : 608 – 15 . Google Scholar OpenURL Placeholder Text WorldCat Kim KW , Kim HR, Kim BM, La Cho M, Lee SH Th17 cytokines regulate osteoclastogenesis in rheumatoid arthritis . Am J Pathol . 2015 ; 185 : 3011 – 24 . Google Scholar Crossref Search ADS PubMed WorldCat Kwok SK , La Cho M, Park MK, Oh HJ, Park JS, Her YM, et al. . Interleukin-21 promotes osteoclastogenesis in humans with rheumatoid arthritis and in mice with collagen-induced arthritis . Arthritis Rheum . 2012 ; 64 : 740 – 51 . Google Scholar Crossref Search ADS PubMed WorldCat Sglunda O , Mann HF, Hulejová H, Pecha O, Pleštilová L, Růžičková O, et al. . Decrease in serum interleukin 21 levels is associated with disease activity improvement in patients with recent-onset rheumatoid arthritis . Physiol Res . 2014 ; 63 : 475 – 81 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Cho SG Interleukin 21 blockade modulates activated T- and B-cell homeostasis via B-cell activating factor pathway-mediated inhibition in a murine model of acute graft-versus-host disease . Exp Hematol . 2015 ; 43 :23–31. Google Scholar OpenURL Placeholder Text WorldCat Yuan FL , Hu W, Lu WG, Li X, Li JP, Xu RS, et al. . Targeting interleukin-21 in rheumatoid arthritis . Mol Biol Rep . 2011 ; 38 : 1717 – 21 . Google Scholar Crossref Search ADS PubMed WorldCat Xie MH , Aggarwal S, Ho WH, Foster J, Zhang Z, Stinson J, et al. . Interleukin (IL)-22, a novel human cytokine that signals through the interferon receptor-related proteins CRF2-4 and IL-22R . J Biol Chem . 2000 ; 275 : 31335 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat Wolk K , Kunz S, Witte E, Friedrich M, Asadullah K, Sabat R IL-22 increases the innate immunity of tissues . Immunity . 2004 ; 21 : 241 – 54 . Google Scholar Crossref Search ADS PubMed WorldCat ShangYu W , Zhu J, Zhou L, Chang W, Wang K, Li QM Blocking IL-22, a potential treatment strategy for adenomyosis by inhibiting crosstalk between vascular endothelial and endometrial stromal cells . Am J Transl Res . 2015 ; 7 : 1782 – 97 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Barone F , Nayar S, Campos J, Cloake T, Withers DR, Toellner KM, et al. . IL-22 regulates lymphoid chemokine production and assembly of tertiary lymphoid organs . Proc Natl Acad Sci . 2015 ; 112 : 11024 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat Ikeuchi H , Kuroiwa T, Hiramatsu N. Expression of interleukin-22 in rheumatoid arthritis: potential role as a proinflammatory cytokine . Arthritis Rheum . 2005 ; 52 : 1037 . Google Scholar Crossref Search ADS PubMed WorldCat Yang X , Zheng SG Interleukin-22: a likely target for treatment of autoimmune diseases . Autoimmun Rev . 2014 ; 13 : 615 – 20 . Google Scholar Crossref Search ADS PubMed WorldCat Gottlieb AB , Krueger JG, Lundblad MS, Gothberg M, Skolnick BE First-in-human, phase 1, randomized, dose-escalation trial with recombinant anti-IL-20 monoclonal antibody in patients with psoriasis . PLoS One . 2015 ; 10 : e0134703 . Google Scholar Crossref Search ADS PubMed WorldCat Parham C , Chirica M, Timans J, Vaisberg E, Travis M, Cheung J, et al. . A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R . J Immunol . 2002 ; 168 : 5699 – 708 . Google Scholar Crossref Search ADS PubMed WorldCat Oppmann B , Lesley R, Blom B, Timans JC, Xu Y, Hunte B, et al. . Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12 . Immunity . 2000 ; 13 : 715 – 25 . Google Scholar Crossref Search ADS PubMed WorldCat Kortylewski M , Xin H, Kujawski M, Lee H, Liu Y, Harris T, et al. . Regulation of the IL-23 and IL-12 balance by Stat3 signaling in the tumor microenvironment . Cancer Cell . 2009 ; 15 : 114 – 23 . Google Scholar Crossref Search ADS PubMed WorldCat Langowski JL , Zhang X, Wu L, Mattson JD, Chen T, Smith K, et al. . IL-23 promotes tumour incidence and growth . Nature . 2006 ; 442 : 461 – 5 . Google Scholar Crossref Search ADS PubMed WorldCat Hamdy G , Darweesh H, Fawzy S, Khattab EA, Fawzy E, Sheta M Association of interleukin-23 receptor (IL-23R) gene polymorphisms (rs11209026, rs2201841 and rs10889677) with Egyptian rheumatoid arthritis patients, Egypt . Rheumatol . 2015 ; 37 : 159 – 63 . Google Scholar OpenURL Placeholder Text WorldCat Iwakura Y , Ishigame H The IL-23/IL-17 axis in inflammation . J Clin Invest . 2006 ; 116 : 1218 – 22 . Google Scholar Crossref Search ADS PubMed WorldCat Abraham C , Cho JH IL-23 and autoimmunity: new insights into the pathogenesis of inflammatory bowel disease . Annu Rev Med . 2009 ; 60 : 97 – 110 . Google Scholar Crossref Search ADS PubMed WorldCat Yago T , Nanke Y, Kawamoto M, Furuya T, Kobashigawa T, Kamatani N, Kotake S IL-23 induces human osteoclastogenesis via IL-17 in vitro, and anti-IL-23 antibody attenuates collagen-induced arthritis in rats . Arthritis Res Ther . 2007 ; 9 : R96 . Google Scholar Crossref Search ADS PubMed WorldCat Kamiya S , Nakamura C, Fukawa T, Ono K, Ohwaki T, Yoshimoto T, Wada S Effects of IL-23 and IL-27 on osteoblasts and osteoclasts: inhibitory effects on osteoclast differentiation . J Bone Miner Metab . 2007 ; 25 : 277 – 85 . Google Scholar Crossref Search ADS PubMed WorldCat Przepiera-Będzak H , Fischer K, Brzosko M Serum IL-6 and IL-23 levels and their correlation with angiogenic cytokines and disease activity in ankylosing spondylitis, psoriatic arthritis, and SAPHO syndrome . Mediators Inflamm . 2015 ; 2015 : 1 – 7 . Google Scholar Crossref Search ADS WorldCat Li J , Lau G, Chen L, Yuan YF, Huang J, Luk JM, et al. . Interleukin 23 promotes hepatocellular carcinoma metastasis via NF-kappa B induced matrix metalloproteinase 9 expression . PLoS One . 2012 ; 7 :e46264. Google Scholar OpenURL Placeholder Text WorldCat Murphy CA , Langrish CL, Chen Y, Blumenschein W, McClanahan T, Kastelein RA, et al. . Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation . J Exp Med . 2003 ; 198 : 1951 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat Tang C , Chen S, Qian H, Huang W Interleukin-23: as a drug target for autoimmune inflammatory diseases . Immunology . 2012 ; 135 : 112 – 24 . Google Scholar Crossref Search ADS PubMed WorldCat Wang M , Liang P Interleukin-24 and its receptors . Immunology . 2005 ; 114 : 166 – 70 . Google Scholar Crossref Search ADS PubMed WorldCat Wang M , Tan Z, Zhang R, Kotenko SV, Liang P Interleukin 24 (MDA-7/MOB-5) signals through two heterodimeric receptors, IL-22R1/IL-20R2 and IL-20R1/IL-20R2 . J Biol Chem . 2002 ; 277 : 7341 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat Ramesh R , Mhashilkar A, Tanaka M, Saito FY, Branch C, Sieger DK, et al. . Melanoma differentiation-associated gene 7/interleukin (IL)-24 is a novel ligand that regulates angiogenesis via the IL-22 receptor . Cancer Res . 2003 ; 63 : 5105 – 13 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Fisher PB , Sarkar D, Lebedeva IV, Emdad L, Gupta P, Sauane M, et al. . Melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24): novel gene therapeutic for metastatic melanoma . Toxicol Appl Pharmacol . 2007 ; 224 : 300 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat Li L , Wang ZX, Wang ZH Combination of IL-24 and cisplatin inhibits cervical cancer growth in a Xenograft nude mice model . Asian Pac J Cancer Prev . 2011 ; 12 : 3293 – 8 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Sauane M , Gopalkrishnan RV, Sarkar D, Su ZZ, Lebedeva IV, Dent P, et al. . MDA-7/IL-24: novel cancer growth suppressing and apoptosis inducing cytokine . Cytokine Growth Factor Rev . 2003 ; 14 : 35 – 51 . Google Scholar Crossref Search ADS PubMed WorldCat Fort MM , Cheung J, Yen D, Li J, Zurawski SM, Lo S, et al. . IL-25 Induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo . Immunity . 2001 ; 15 : 985 – 95 . Google Scholar Crossref Search ADS PubMed WorldCat Gabay C Interleukin-6 and chronic inflammation . Arthritis Res Ther . 2006 ; 8 : S3 . Google Scholar Crossref Search ADS PubMed WorldCat Wong CK , Cheung PFY, Ip WK, Lam CWK Interleukin-25-induced chemokines and interleukin-6 release from eosinophils is mediated by p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, and nuclear factor-kappaB . Am J Respir Cell Mol Biol . 2005 ; 33 : 186 – 94 . Google Scholar Crossref Search ADS PubMed WorldCat Corrigan CJ , Wang W, Meng Q, Fang C, Eid G, Caballero MR, et al. . Allergen-induced expression of IL-25 and IL-25 receptor in atopic asthmatic airways and late-phase cutaneous responses . J Allergy Clin Immunol . 2011 ; 128 : 119 – 24 . Google Scholar Crossref Search ADS WorldCat Tamachi T , Maezawa Y, Ikeda K, Iwamoto I, Nakajima H Interleukin 25 in allergic airway inflammation . Int Arch Allergy Immunol . 2006 ; 140 : 59 – 62 . Google Scholar Crossref Search ADS PubMed WorldCat Tang W , Smith SG, Beaudin S, Dua B, Howie K, Gauvreau G, O’Byrne PM IL-25 and IL-25 receptor expression on eosinophils from subjects with allergic asthma . Int Arch Allergy Immunol . 2014 ; 163 : 5 – 10 . Google Scholar Crossref Search ADS PubMed WorldCat Maezawa Y , Nakajima H, Suzuki K, Tamachi T, Ikeda K, Inoue J, et al. . Involvement of TNF receptor-associated factor 6 in IL-25 receptor signaling . J Immunol . 2006 ; 176 : 1013 – 18 . Google Scholar Crossref Search ADS PubMed WorldCat Hällgren R , Feltelius N, Svenson N, Venge KP Eosinophil involvement in rheumatoid arthritis as reflected by elevated serum levels of eosinophil cationic protein . Clin Exp Immunol . 1985 ; 59 : 539 – 46 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Knappe A , Hör S, Wittmann S, Fickenscher H Induction of a novel cellular homolog of interleukin-10, AK155, by transformation of T lymphocytes with herpesvirus saimiri . J Virol . 2000 ; 74 : 3881 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat Hör S , Pirzer H, Dumoutier L, Bauer F, Wittmann S, Sticht H, et al. . The T-cell lymphokine interleukin-26 targets epithelial cells through the interleukin-20 receptor 1 and interleukin-10 receptor 2 chains . J Biol Chem . 2004 ; 279 : 33343 – 51 . Google Scholar Crossref Search ADS PubMed WorldCat Sheikh F , Baurin VV, Lewis-Antes A, Shah NK, Smirnov SV, Anantha S, et al. . Cutting edge: IL-26 signals through a novel receptor complex composed of IL-20 receptor 1 and IL-10 receptor 2 . J Immunol . 2004 ; 172 : 2006 – 10 . Google Scholar Crossref Search ADS PubMed WorldCat Corvaisier M , Delneste Y, Jeanvoine H, Preisser L, Blanchard S, Garo E, et al. . IL-26 Is overexpressed in rheumatoid arthritis and induces proinflammatory cytokine production and Th17 cell generation . PLoS Biol . 2012 ; 10 :e1001395. Google Scholar OpenURL Placeholder Text WorldCat Donnelly RP , Sheikh F, Dickensheets H, Savan R, Young HA, Walter MR Interleukin-26: an IL-10-related cytokine produced by Th17 cells . Cytokine Growth Factor Rev . 2010 ; 21 : 393 – 401 . Google Scholar Crossref Search ADS PubMed WorldCat Meller S , Di Domizio J, Voo KS, Friedrich HC, Chamilos G, Ganguly D, et al. . TH17 cells promote microbial killing and innate immune sensing of DNA via interleukin 26 . Nat Immunol . 2015 ; 16 : 970 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat Phillips RAK , McClanahan TK, De Waal R, Rosales M, Vaisberg E, Bazan JF, et al. . WSX-1 and glycoprotein 130 constitute a signal-transducing receptor for IL-27 . J Immunol . 2004 ; 172 : 2225 – 31 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Wang H , Li Z, Yang B, Yu S, Wu C. IL-27 suppresses the production of IL-22 in human CD4(+) T cells by inducing the expression of SOCS1 . Immunol Lett . 2013 ; 152 : 96 – 103 . Google Scholar Crossref Search ADS PubMed WorldCat Owaki T , Asakawa M, Kamiya S, Takeda K, Fukai F, Mizuguchi J, et al. . IL-27 suppresses CD28-medicated IL-2 production through suppressor of cytokine signaling 3 . J Immunol . 2006 ; 176 : 2773 – 80 . Google Scholar Crossref Search ADS PubMed WorldCat Murugaiyan G , Mittal A, Lopez-Diego R, Maier LM, Anderson DE, Weiner HL IL-27 is a key regulator of IL-10 and IL-17 production by human CD4+ T cells . J Immunol . 2009 ; 183 : 2435 – 43 . Google Scholar Crossref Search ADS PubMed WorldCat Young A , Linehan E, Hams E, O’Hara Hall AC, McClurg A, Johnston JA, et al. . Cutting edge: suppression of GM-CSF expression in murine and human T cells by IL-27 . J Immunol . 2012 ; 189 : 2079 – 83 . Google Scholar Crossref Search ADS PubMed WorldCat Batten M , Kljavin NM, Li J, Walter MJ, de Sauvage FJ, Ghilardi N Cutting edge: IL-27 is a potent inducer of IL-10 but not FoxP3 in murine T cells . J Immunol . 2008 ; 180 : 2752 – 6 . Google Scholar Crossref Search ADS PubMed WorldCat Kalliolias GD , Gordon RA, Ivashkiv LB Suppression of TNF-α and IL-1 signaling identifies a mechanism of homeostatic regulation of macrophages by IL-27 . J Immunol . 2010 ; 185 : 7047 – 56 . Google Scholar Crossref Search ADS PubMed WorldCat Pflanz S , Timans JC, Cheung J, Rosales R, Kanzler H, Gilbert J, et al. . IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4+ T cells . Immunity . 2002 ; 16 : 779 – 90 . Google Scholar Crossref Search ADS PubMed WorldCat Lucas S , Ghilardi N, Li J, de Sauvage FJ IL-27 regulates IL-12 responsiveness of naive CD4+ T cells through Stat1-dependent and -independent mechanisms . Proc Natl Acad Sci USA . 2003 ; 100 : 15047 – 52 . Google Scholar Crossref Search ADS WorldCat Kamiya S , Owaki T, Morishima N, Fukai F, Mizuguchi J, Yoshimoto T An indispensable role for STAT1 in IL-27-induced T-bet expression but not proliferation of naive CD4+ T cells . J Immunol . 2004 ; 173 : 3871 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat Szabo SJ , Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH A novel transcription factor, T-bet, directs Th1 lineage commitment . Cell . 2000 ; 100 : 655 – 69 . Google Scholar Crossref Search ADS PubMed WorldCat Huber M , Steinwald V, Guralnik A, Brüstle A, Kleemann P, Rosenplänter C, et al. . IL-27 inhibits the development of regulatory T cells via STAT3 . Int Immunol . 2008 ; 20 : 223 – 34 . Google Scholar Crossref Search ADS PubMed WorldCat Hall AO , Beiting DP, Tato C, John B, Oldenhove G, Lombana CG, et al. . The cytokines interleukin 27 and interferon-γ promote distinct Treg cell populations required to limit infection-induced pathology . Immunity . 2012 ; 37 : 511 – 23 . Google Scholar Crossref Search ADS PubMed WorldCat Diveu C , McGeachy MJ, Boniface K, Stumhofer JS, Sathe M, Joyce-Shaikh B, et al. . IL-27 blocks RORc expression to inhibit lineage commitment of Th17 cells . J Immunol . 2009 ; 182 : 5748 – 56 . Google Scholar Crossref Search ADS PubMed WorldCat Moon SJ , Park JS, Heo YJ, Kang CM, Kim EK, Lim MA, et al. . In vivo action of IL-27: reciprocal regulation of Th17 and Treg cells in collagen-induced arthritis . Exp Mol Med . 2013 ; 45 : e46 . Google Scholar Crossref Search ADS PubMed WorldCat Yoshimura T , Takeda A, Hamano S, Miyazaki Y, Kinjyo I, Ishibashi T, et al. . Two-sided roles of IL-27: induction of Th1 differentiation on naive CD4+ T cells versus suppression of proinflammatory cytokine production including IL-23-induced IL-17 on activated CD4+ T cells partially through STAT3-dependent mechanism . J Immunol . 2006 ; 177 : 5377 – 85 . Google Scholar Crossref Search ADS PubMed WorldCat Ye ZJ , Xu LL, Zhou Q, Cui A, Wang XJ, Zhai K, et al. . Recruitment of IL-27-producing CD4+ T cells and effect of IL-27 on pleural mesothelial cells in tuberculous pleurisy . Lung . 2015 ; 193 : 539 – 48 . Google Scholar Crossref Search ADS PubMed WorldCat Morandi F , Di Carlo E, Ferrone S, Pistoia V, Airoldi I, Petretto A IL-27 in human secondary lymphoid organs attracts myeloid dendritic cells and impairs HLA class I-restricted antigen presentation . J Immunol . 2014 ; 192 : 2634 – 42 . Google Scholar Crossref Search ADS PubMed WorldCat Kamiya S , Okumura M, Chiba Y, Fukawa T, Nakamura C, Nimura N, et al. . IL-27 suppresses RANKL expression in CD4+ T cells in part through STAT3 . Immunol Lett . 2011 ; 138 : 47 – 53 . Google Scholar Crossref Search ADS PubMed WorldCat Furukawa M , Takaishi H, Takito J, Yoda M, Sakai S, Hikata T, et al. . IL-27 abrogates receptor activator of NF- B ligand-mediated osteoclastogenesis of human granulocyte-macrophage colony-forming unit cells through STAT1-dependent inhibition of c-Fos . J Immunol . 2009 ; 183 : 2397 – 406 . Google Scholar Crossref Search ADS PubMed WorldCat Kalliolias GD , Zhao B, Triantafyllopoulou A, Park-Min KH, Ivashkiv LB Interleukin-27 inhibits human osteoclastogenesis by abrogating RANKL-mediated induction of nuclear factor of activated T cells c1 and suppressing proximal RANK signaling . Arthritis Rheum . 2010 ; 62 : 402 – 13 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Liu L , Wang S, Shan B, Shao L, Sato A, Kawamura K, et al. . IL-27-mediated activation of natural killer cells and inflammation produced antitumour effects for human oesophageal carcinoma cells . Scand J Immunol . 2008 ; 68 : 22 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat Giuliani N , Airoldi I Novel insights into the role of interleukin-27 and interleukin-23 in human malignant and normal plasma cells . Clin Cancer Res . 2011 ; 17 : 6963 – 70 . Google Scholar Crossref Search ADS PubMed WorldCat Kachroo P , Lee MH, Zhang L, Baratelli F, Lee G, Srivastava MK, et al. . IL-27 inhibits epithelial-mesenchymal transition and angiogenic factor production in a STAT1-dominant pathway in human non-small cell lung cancer . J Exp Clin Cancer Res . 2013 ; 32 : 97 . Google Scholar Crossref Search ADS PubMed WorldCat Shimizu M , Shimamura M, Owaki T, Asakawa M, Fujita K, Kudo M, et al. . Antiangiogenic and antitumor activities of IL-27 . J Immunol . 2006 ; 176 : 7317 – 24 . Google Scholar Crossref Search ADS PubMed WorldCat Wong CK , Chen DP, Tam LS, Li EK, Yin YB, Lam CWK Effects of inflammatory cytokine IL-27 on the activation of fibroblast-like synoviocytes in rheumatoid arthritis . Arthritis Res Ther . 2010 ; 12 : R129 . Google Scholar Crossref Search ADS PubMed WorldCat Sheppard P , Kindsvogel W, Xu W, Henderson K, Schlutsmeyer S, Whitmore TE, et al. . IL-28, IL-29 and their class II cytokine receptor IL-28R . Nat Immunol . 2003 ; 4 : 63 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat Brand S , Beigel F, Olszak T, Zitzmann K, Eichhorst ST, Otte JM, et al. . IL-28A and IL-29 mediate antiproliferative and antiviral signals in intestinal epithelial cells and murine CMV infection increases colonic IL-28A expression . Am J Physiol Gastrointest Liver Physiol . 2005 ; 289 : G960 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat Witte K , Witte E, Sabat R, Wolk K IL-28A, IL-28B, and IL-29: promising cytokines with type I interferon-like properties . Cytokine Growth Factor Rev . 2010 ; 21 : 237 – 51 . Google Scholar Crossref Search ADS PubMed WorldCat Uzé G , Monneron D IL-28 and IL-29: newcomers to the interferon family . Biochimie . 2007 ; 89 : 729 – 34 . Google Scholar Crossref Search ADS PubMed WorldCat Dolganiuc A , Kodys K, Marshall C, Saha B, Zhang S, Bala S, Szabo G Type III interferons, IL-28 and IL-29, are increased in chronic HCV infection and induce myeloid dendritic cell-mediated FoxP3+ regulatory T cells . PLoS One . 2012 ; 7 : e44915 . Google Scholar Crossref Search ADS PubMed WorldCat Xu L , Feng X, Tan W, Gu W, Guo D, Zhang M, Wang F IL-29 enhances Toll-like receptor-mediated IL-6 and IL-8 production by the synovial fibroblasts from rheumatoid arthritis patients . Arthritis Res Ther . 2013 ; 15 : R170 . Google Scholar Crossref Search ADS PubMed WorldCat Xu D , Yan S, Wang H, Gu B, Sun K, Yang X, et al. . IL-29 enhances LPS/TLR4-mediated inflammation in rheumatoid arthritis . Cell Physiol Biochem . 2015 ; 37 : 27 – 34 . Google Scholar Crossref Search ADS PubMed WorldCat Liu X , Wang Z, Ye N, Chen Z, Zhou X, Teng X, et al. . A protective role of IL-30 via STAT and ERK signaling pathways in macrophage-mediated inflammation . Biochem Biophys Res Commun . 2013 ; 435 : 306 – 12 . Google Scholar Crossref Search ADS PubMed WorldCat Garbers C , Spudy B, Aparicio-Siegmund S, Waetzig GH, Sommer J, Holscher C, et al. . An lnterleukin-6 receptor-dependent molecular switch mediates signal transduction of the IL-27 cytokine subunit p28 (IL-30) via a gp130 protein receptor homodimer . J Biol Chem . 2013 ; 288 : 4346 – 54 . Google Scholar Crossref Search ADS PubMed WorldCat Dibra D , Cutrera JJ, Li S Coordination between TLR9 signaling in macrophages and CD3 signaling in T cells induces robust expression of IL-30 . J Immunol . 2012 ; 188 : 3709 – 15 . Google Scholar Crossref Search ADS PubMed WorldCat Zhang Q , Putheti P, Zhou Q, Liu Q, Gao W Structures and biological functions of IL-31 and IL-31 receptors . Cytokine Growth Factor Rev . 2008 ; 19 : 347 – 56 . Google Scholar Crossref Search ADS PubMed WorldCat Bilsborough J , Mudri S, Chadwick E, Harder B, Dillon SR IL-31 receptor (IL-31RA) knockout mice exhibit elevated responsiveness to oncostatin M . J Immunol . 2010 ; 185 : 6023 – 30 . Google Scholar Crossref Search ADS PubMed WorldCat Broxmeyer HE , Li J, Hangoc G, Cooper S, Tao W, Mantel C, et al. . Regulation of myeloid progenitor cell proliferation/survival by IL-31 receptor and IL-31 . Exp Hematol . 2007 ; 35 : 78 – 86 . Google Scholar Crossref Search ADS PubMed WorldCat Perrigoue JG , Li J, Zaph C, Goldschmidt M, Scott P, de Sauvage FJ, et al. . IL-31-IL-31R interactions negatively regulate type 2 inflammation in the lung . J Exp Med . 2007 ; 204 : 481 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat Yagi Y , Andoh A, Nishida A, Shioya M, Nishimura T, Hashimoto T, et al. . Interleukin-31 stimulates production of inflammatory mediators from human colonic subepithelial myofibroblasts . Int J Mol Med . 2007 ; 19 : 941 – 6 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Castellani ML , Felaco P, Galzio RJ, Tripodi D, Toniato E, De Lutiis MA, et al. . IL-31 a TH2 cytokine involved in immunity and inflammation . Int J Immunopathol Pharmacol . 2010 ; 23 : 709 – 13 . Google Scholar Crossref Search ADS PubMed WorldCat Dillon SR , Sprecher C, Hammond A, Bilsborough J, Rosenfeld-Franklin M, Presnell SR, et al. . Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice . Nat Immunol . 2004 ; 5 : 752 – 60 . Google Scholar Crossref Search ADS PubMed WorldCat Ip WK , Wong CK, Li ML, Li PW, Cheung PF, Lam CW Interleukin-31 induces cytokine and chemokine production from human bronchial epithelial cells through activation of mitogen-activated protein kinase signalling pathways: implications for the allergic response . Immunology . 2007 ; 122 : 532 – 41 . Google Scholar Crossref Search ADS PubMed WorldCat Ginaldi L , De Martinis M, Ciccarelli F, Saitta S, Imbesi S, Mannucci C, Gangemi S Increased levels of interleukin 31 (IL-31) in osteoporosis . BMC Immunol . 2015 ; 16 : 60 . Google Scholar Crossref Search ADS PubMed WorldCat Stott B , Lavender P, Lehmann S, Pennino D, Durham S, Schmidt-Weber CB Human IL-31 is induced by IL-4 and promotes TH2-driven inflammation . J Allergy Clin Immunol . 2013 ; 132 :446–54. Google Scholar OpenURL Placeholder Text WorldCat Kasraie S , Niebuhr M, Werfel T Interleukin (IL)-31 induces pro-inflammatory cytokines in human monocytes and macrophages following stimulation with staphylococcal exotoxins. Allergy . 2010 ; 65 : 712 – 21 . Google Scholar Crossref Search ADS PubMed WorldCat Nobbe S , Dziunycz P, Mühleisen B, Bilsborough J, Dillon SR, French LE, Hofbauer GFL IL-31 expression by inflammatory cells is preferentially elevated in atopic dermatitis . Acta Derm Venereol . 2012 ; 92 : 24 – 8 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Yu JI , Park YR, Lee SS, Chae SC Polymorphisms of interleukin-31 are associated with anti-CCP levels in females with rheumatoid arthritis . J Genet . 2014 ; 93 : 813 – 17 . Google Scholar Crossref Search ADS PubMed WorldCat Kim SH , Han SY, Azam T, Yoon DY, Dinarello CA. Interleukin-32: a cytokine and inducer of TNFalpha . Immunity . 2005 ; 22 : 131 – 42 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Shoda H , Fujio K, Yamaguchi Y, Okamoto A, Sawada T, Kochi Y, Yamamoto K Interactions between IL-32 and tumor necrosis factor alpha contribute to the exacerbation of immune-inflammatory diseases . Arthritis Res Ther . 2006 ; 8 : R166 . Google Scholar Crossref Search ADS PubMed WorldCat Lee SW , Park HJ, Lee KS, Park SH, Kim S, Jeon SH, Hong S IL32γ activates natural killer receptor-expressing innate immune cells to produce IFNγ via dendritic cell-derived IL12 . Biochem Biophys Res Commun . 2015 ; 461 : 86 – 94 . Google Scholar Crossref Search ADS PubMed WorldCat Nold-Petry CA , Nold MF, Zepp JA, Kim SH, Voelkel NF, Dinarello CA. IL-32-dependent effects of IL-1beta on endothelial cell functions . Proc Natl Acad Sci USA . 2009 ; 106 : 3883 – 8 . Google Scholar Crossref Search ADS WorldCat Suga H , Sugaya M, Miyagaki T, Kawaguchi M, Fujita H, Asano Y, et al. . The role of IL-32 in cutaneous T-cell lymphoma . J Invest Dermatol . 2014 ; 134 : 1428 – 35 . Google Scholar Crossref Search ADS PubMed WorldCat Turner-Brannen E , Choi KG, Arsenault R, El-Gabalawy H, Napper S, Mookherjee N Inflammatory cytokines IL-32 and IL-17 have common signaling intermediates despite differential dependence on TNF-receptor 1 . J Immunol . 2011 ; 186 : 7127 – 35 . Google Scholar Crossref Search ADS PubMed WorldCat Kang J , Cho M, Kim J, Kim S A proinflammatory cytokine interleukin- 32beta promotes the production of an anti-inflammatory cytokine interleukin-10 . Immunology . 2009 ; 128 :e532–40. Google Scholar OpenURL Placeholder Text WorldCat Mabilleau G , Sabokbar A Interleukin-32 promotes osteoclast differentiation but not osteoclast activation . PLoS One . 2009 ; 4 :e4173. Google Scholar OpenURL Placeholder Text WorldCat Kim YG , Lee CK, Oh JS, Kim SH, Kim KA, Yoo B. Effect of interleukin-32gamma on differentiation of osteoclasts from CD14+ monocytes . Arthritis Rheum . 2010 ; 62 : 515 – 23 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Meyer N IL-32, a negative regulator of angiogenesis in chronic airway diseases . J Vasc Med Surg . 2013 ; 1 : 6925 . Google Scholar OpenURL Placeholder Text WorldCat Nold-Petry CA , Rudloff I, Baumer Y, Ruvo M, Marasco D, Botti P, et al. . IL-32 promotes angiogenesis . J Immunol . 2014 ; 192 : 589 – 602 . Google Scholar Crossref Search ADS PubMed WorldCat Joosten LAB , Netea MG, Kim SH, Yoon DY, Oppers-Walgreen B, Radstake TRD, et al. . IL-32, a proinflammatory cytokine in rheumatoid arthritis . Proc Natl Acad Sci USA . 2006 ; 103 : 3298 – 303 . Google Scholar Crossref Search ADS WorldCat Liu X , Hammel M, He Y, Tainer JA, Jeng U, Zhang L, et al. . Structural insights into the interaction of IL-33 with its receptors . Proc Natl Acad Sci USA . 2013 ; 110 : 14918 – 23 . Google Scholar Crossref Search ADS WorldCat Lingel A , Weiss TM, Niebuhr M, Pan B, Appleton BA, Wiesmann C, et al. . The structure of interleukin-33 and its interaction with the ST2 and IL-1RAcP receptors—insight into the arrangement of heterotrimeric interleukin-1 signaling complexes . Structure . 2009 ; 17 : 1398 – 410 . Google Scholar Crossref Search ADS PubMed WorldCat Chackerian AA , Oldham ER, Murphy EE, Schmitz J, Pflanz S, Kastelein RA IL-1 receptor accessory protein and ST2 comprise the IL-33 receptor complex . J Immunol . 2007 ; 179 : 2551 – 5 . Google Scholar Crossref Search ADS PubMed WorldCat Schmitz J , Owyang A, Oldham E, Song Y, Murphy E, Mcclanahan TK, et al. . IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines . Immunity . 2005 ; 23 : 479 – 90 . Google Scholar Crossref Search ADS PubMed WorldCat Jiang HR , Milovanović M, Allan D, Niedbala W, Besnard AG, Fukada SY, et al. . IL-33 attenuates EAE by suppressing IL-17 and IFN-γ production and inducing alternatively activated macrophages . Eur J Immunol . 2012 ; 42 : 1804 – 14 . Google Scholar Crossref Search ADS PubMed WorldCat Allakhverdi Z , Smith DE, Comeau MR, Delespesse G Cutting edge: the ST2 ligand IL-33 potently activates and drives maturation of human mast cells . J Immunol . 2007 ; 179 : 2051 – 4 . Google Scholar Crossref Search ADS PubMed WorldCat Komai-koma M , Xu D, Li Y, Mckenzie ANJ IL-33 is a chemoattractant for human Th2 cells . Eur J Immunol . 2007 ; 37 : 2779 – 86 . Google Scholar Crossref Search ADS PubMed WorldCat Cherry WB , Yoon J, Bartemes KR, Iijima K, Kita H A novel IL-1 family cytokine, IL-33, potently activates human eosinophils . J Allergy Clin Immunol . 2008 ; 121 : 1484 – 90 . Google Scholar Crossref Search ADS PubMed WorldCat Carriere V , Roussel L, Ortega N, Lacorre DA, Americh L, Aguilar L, et al. . IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo. Proc Natl Acad Sci USA . 2007 ; 104 : 282 – 7 . Google Scholar Crossref Search ADS WorldCat Oboki K , Ohno T, Kajiwara N, Arae K, Morita H, Ishii A, et al. . IL-33 is a crucial amplifier of innate rather than acquired immunity . Proc Natl Acad Sci USA . 2010 ; 107 : 18581 – 6 . Google Scholar Crossref Search ADS WorldCat Zhao Q , Chen G Role of IL-33 and its receptor in T cell-mediated autoimmune diseases . Biomed Res Int . 2014 ; 2014 : 587376 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Saidi S , Bouri F, Lencel P, Duplomb L, Baud’huin M, Delplace S, et al. . IL-33 is expressed in human osteoblasts, but has no direct effect on bone remodeling . Cytokine . 2011 ; 53 : 347 – 54 . Google Scholar Crossref Search ADS PubMed WorldCat Zaiss MM , Kurowska-Stolarska M, Böhm C, Gary R, Scholtysek C, Stolarski B, et al. . IL-33 shifts the balance from osteoclast to alternatively activated macrophage differentiation and protects from TNF-alpha-mediated bone loss . J Immunol . 2011 ; 186 : 6097 – 105 . Google Scholar Crossref Search ADS PubMed WorldCat Schulze J , Bickert T, Beil FT, Zaiss MM, Albers J, Wintges K, et al. . Interleukin-33 is expressed in differentiated osteoblasts and blocks osteoclast formation from bone marrow precursor cells . J Bone Miner Res . 2011 ; 26 : 704 – 17 . Google Scholar Crossref Search ADS PubMed WorldCat Lima ILA , Macari S, Madeira MFM, Rodrigues LFD, Colavite PM, Garlet GP, et al. . Osteoprotective effects of IL-33/ST2 link to osteoclast apoptosis . Am J Pathol . 2015 ; 185 : 3338 – 48 . Google Scholar Crossref Search ADS PubMed WorldCat Xiangyang Z , Lutian Y, Lin Z, Liping X, Hui S, Jing L Increased levels of interleukin-33 associated with bone erosion and interstitial lung diseases in patients with rheumatoid arthritis . Cytokine . 2012 ; 58 : 6 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat Xu D , Jiang H, Li Y, Pushparaj PN, Kurowska-Stolarska M, Leung BP, et al. . IL-33 exacerbates autoantibody-induced arthritis . J Immunol . 2010 ; 184 : 2620 – 6 . Google Scholar Crossref Search ADS PubMed WorldCat Xu D , Jiang H, Kewin P, Li Y, Mu R, Fraser AR, et al. . IL-33 exacerbates antigen-induced arthritis by activating mast cells . Proc Natl Acad Sci USA . 2008 ; 105 : 10913 – 18 . Google Scholar Crossref Search ADS WorldCat SayedAli O , Ismail M, Khalifa AM Levels of interleukin 33 and interleukin 27 in rheumatoid arthritis and osteoarthritis Egyptian patients . Int J Adv Biotechnol Res . 2014 ; 5 : 465 – 73 . Google Scholar OpenURL Placeholder Text WorldCat Hong Y , Moon S, Joo YB, Jeon CH, Cho M, Ju JH, et al. . Measurement of interleukin-33 (IL-33) and IL-33 receptors (sST2 and ST2L) in patients with rheumatoid arthritis . J Korean Med Sci . 2011 ; 26 : 1132 . Google Scholar Crossref Search ADS PubMed WorldCat Donnell CO , Mahmoud A, Keane J, Murphy C, White D, Carey S, et al. . An antitumorigenic role for the IL-33 receptor, ST2L, in colon cancer . Br J Cancer . 2016 ; 114 : 37 – 43 . Google Scholar Crossref Search ADS PubMed WorldCat Choi Y , Choi H, Min J, Pyun B, Maeng Y, Park H, et al. . ST2/TRAF6-mediated endothelial nitric oxide production Interleukin-33 induces angiogenesis and vascular permeability through ST2/TRAF6-mediated endothelial nitric oxide production . Blood . 2009 ; 114 : 3117 – 26 . Google Scholar Crossref Search ADS PubMed WorldCat Stojkovic S , Kaun C, Heinz M, Krychtiuk KA, Rauscher S, Lemberger CE, et al. . Interleukin-33 induces urokinase in human endothelial cells―possible impact on angiogenesis . J Thromb Haemost . 2014 ; 12 : 948 – 57 . Google Scholar Crossref Search ADS PubMed WorldCat Kamradt T , Drube S A complicated liaison: IL-33 and IL-33R in arthritis pathogenesis . Arthritis Res Ther . 2013 ; 15 : 115 . Google Scholar Crossref Search ADS PubMed WorldCat Theoharides TC , Petra AI, Taracanova A, Panagiotidou S, Conti P Targeting IL-33 in autoimmunity and inflammation . J Pharmacol Exp Ther . 2015 ; 354 : 24 – 31 . Google Scholar Crossref Search ADS PubMed WorldCat Chihara T , Suzu S, Hassan R, Chutiwitoonchai N, Hiyoshi M, Motoyoshi K, et al. . IL-34 and M-CSF share the receptor Fms but are not identical in biological activity and signal activation . Cell Death Differ . 2010 ; 17 : 1917 – 27 . Google Scholar Crossref Search ADS PubMed WorldCat Foucher ED , Blanchard S, Preisser L, Garo E, Ifrah N, Guardiola P, et al. . IL-34 Induces the differentiation of human monocytes into immunosuppressive macrophages. Antagonistic effects of GM-CSF and IFNγ . PLoS One . 2013 ; 8 : e56045 . Google Scholar Crossref Search ADS PubMed WorldCat Wei S , Nandi S, Chitu V, Yeung YG, Yu W, Huang M, et al. . Functional overlap but differential expression of CSF-1 and IL-34 in their CSF-1 receptor-mediated regulation of myeloid cells . J Leukoc Biol . 2010 ; 88 : 495 – 505 . Google Scholar Crossref Search ADS PubMed WorldCat Wang Y , Szretter KJ, Vermi W, Gilfillan S, Rossini C, Cella M, et al. . IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia . Nat Immunol . 2012 ; 13 : 753 – 60 . Google Scholar Crossref Search ADS PubMed WorldCat Bézie S , Picarda E, Ossart J, Tesson L, Usal C, Renaudin K, et al. . IL-34 is a Treg-specific cytokine and mediates transplant tolerance . J Clin Invest . 2015 ; 125 : 3952 – 64 . Google Scholar Crossref Search ADS PubMed WorldCat Boström EA , Lundberg P The newly discovered cytokine IL-34 is expressed in gingival fibroblasts, shows enhanced expression by pro-inflammatory cytokines, and stimulates osteoclast differentiation . PLoS One . 2013 ; 8 : e81665 . Google Scholar Crossref Search ADS PubMed WorldCat Hwang SJ , Choi B, Kang SS, Chang JH, Kim YG, Chung YH, et al. . Interleukin-34 produced by human fibroblast-like synovial cells in rheumatoid arthritis supports osteoclastogenesis . Arthritis Res Ther . 2012 ; 14 : R14 . Google Scholar Crossref Search ADS PubMed WorldCat Chen Z , Buki K, Vääräniemi J, Gu G, Väänänen HK The critical role of IL-34 in osteoclastogenesis . PLoS One . 2011 ; 6 : e18689 . Google Scholar Crossref Search ADS PubMed WorldCat Baud’Huin M , Renault R, Charrier C, Riet A, Moreau A, Brion R, et al. . Interleukin-34 is expressed by giant cell tumours of bone and plays a key role in RANKL-induced osteoclastogenesis . J Pathol . 2010 ; 221 : 77 – 86 . Google Scholar Crossref Search ADS PubMed WorldCat Ségaliny AI , Mohamadi A, Dizier B, Lokajczyk A, Brion R, Lanel R, et al. . Interleukin-34 promotes tumor progression and metastatic process in osteosarcoma through induction of angiogenesis and macrophage recruitment . Int J Cancer . 2015 ; 137 : 73 – 85 . Google Scholar Crossref Search ADS PubMed WorldCat Balogh E , Connolly M, Biniecka M, McCormick J, Veale DJ, Fearon U. Interleukin-34 regulates angiogenesis and cell proliferation in inflammatory arthritis, this effect is potentiated by hypoxia . Arthritis Rheum . 2013 ; 65 : 946 . Google Scholar OpenURL Placeholder Text WorldCat Chemel M , Le Goff B, Brion R, Cozic C, Berreur M, Amiaud J, et al. . Interleukin 34 expression is associated with synovitis severity in rheumatoid arthritis patients . Ann Rheum Dis . 2012 ; 71 : 150 – 4 . Google Scholar Crossref Search ADS PubMed WorldCat Atef M , Saber N , Aziz DA Joint destruction and osteoporosis are associated with upregulation of IL34 and cathepsin k expression in rheumatoid arthritis. Clinical trial with anti TNF ñ therapy . J Arthritis . 2015 ; 4 :167. Google Scholar OpenURL Placeholder Text WorldCat Masteller EL , Wong BR Targeting IL-34 in chronic inflammation . Drug Discov Today . 2014 ; 19 : 1212 – 16 . Google Scholar Crossref Search ADS PubMed WorldCat Collison LW , Delgoffe GM, Guy CS, Vignali KM, Chaturvedi V, Fairweather D, et al. . The composition and signaling of the IL-35 receptor are unconventional . Nat Immunol . 2012 ; 13 : 290 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat Collison LW , Chaturvedi V, Henderson AL, Giacomin PR, Guy C, Bankoti J, et al. . IL-35-mediated induction of a potent regulatory T cell population . Nat Immunol . 2010 ; 11 : 1093 – 101 . Google Scholar Crossref Search ADS PubMed WorldCat Castellani M , Anogeianaki L, Felaco A, Toniato PE, De Lutiis M, Shaik A, et al. . IL-35, an anti-inflammatory cytokine which expands CD4 + CD25+ Treg Cells . J Biol Regul Homeost Agents . 2010 ; 24 : 131 – 5 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Kochetkova I , Golden S, Holderness K, Callis G, Pascual DW IL-35 stimulation of CD39+ regulatory T cells confers protection against collagen II-induced arthritis via the production of IL-10 . J Immunol . 2010 ; 184 : 7144 – 53 . Google Scholar Crossref Search ADS PubMed WorldCat Whitehead GS , Wilson RH, Nakano K, Burch LH, Nakano H, Cook DN IL-35 production by inducible costimulator (ICOS)–positive regulatory T cells reverses established IL-17–dependent allergic airways disease . J Allergy Clin Immunol . 2012 ; 129 : 207 – 15.e1–5 . Google Scholar Crossref Search ADS PubMed WorldCat Collison LW , Workman CJ, Kuo TT, Boyd K, Wang Y, Vignali KM, et al. . The inhibitory cytokine IL-35 contributes to regulatory T-cell function . Nature . 2007 ; 450 : 566 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat Li X , Mai J, Virtue A, Yin Y, Gong R, Sha X, et al. . IL-35 is a novel responsive anti-inflammatory cytokine—a new system of categorizing anti-inflammatory cytokines . PLoS One . 2012 ; 7 :e33628. Google Scholar OpenURL Placeholder Text WorldCat Olson BM , Sullivan JA, Burlingham WJ Interleukin 35: a key mediator of suppression and the propagation of infectious tolerance . Front Immunol . 2013 ; 4 : 315 . Google Scholar Crossref Search ADS PubMed WorldCat Wang R , Yu C, Dambuza IM, Mahdi RM, Dolinska M, Sergeey YV, et al. . Interleukin-35 induces regulatory B cells that suppress autoimmune disease . Nat Med . 2014 ; 20 : 633 – 41 . Google Scholar Crossref Search ADS PubMed WorldCat Ning-Wei Z Interleukin (IL)-35 is raising our expectations . Rev Med Chil . 2010 ; 138 : 758 – 66 . Google Scholar Crossref Search ADS PubMed WorldCat Choi J , Leung PSC, Bowlus C, Gershwin ME IL-35 and autoimmunity: a comprehensive perspective . Clin Rev Allergy Immunol . 2015 ; 49 : 327 – 32 . Google Scholar Crossref Search ADS PubMed WorldCat Saha SS , Singh D, Raymond EL, Ganesan R, Caviness G, Grimaldi C, et al. . Signal transduction and intracellular trafficking by the interleukin 36 receptor . J Biol Chem . 2015 ; 290 : 23997 – 4006 . Google Scholar Crossref Search ADS PubMed WorldCat Dietrich D , Gabay C Inflammation: IL-36 has proinflammatory effects in skin but not in joints . Nat Rev Rheumatol . 2014 ; 10 : 639 – 40 . Google Scholar Crossref Search ADS PubMed WorldCat Foster AM , Baliwag J, Chen CS, Guzman AM, Stoll SW, Gudjonsson JE, et al. . IL-36 promotes myeloid cell infiltration, activation, and inflammatory activity in skin . J Immunol . 2014 ; 192 : 6053 – 61 . Google Scholar Crossref Search ADS PubMed WorldCat Conde J , Scotece M, Abella V, Lopez V, Lazzaro V, Pino J, et al. . IL-36alpha: a novel cytokine involved in the inflammatory response in human chondrocytes . Osteoarthr Cartil . 2014 ; 22 : S289 . Google Scholar Crossref Search ADS WorldCat Carrier Y , Ma HL, Ramon HE, Napierata L, Small C, O’Toole M, et al. . Inter-regulation of Th17 cytokines and the IL-36 cytokines in vitro and in vivo: implications in psoriasis pathogenesis . J Invest Dermatol . 2011 ; 131 : 2428 – 37 . Google Scholar Crossref Search ADS PubMed WorldCat Lamacchia C , Palmer G, Rodriguez E, Martin P, Vigne S, Seemayer CA, et al. . The severity of experimental arthritis is independent of IL-36 receptor signaling . Arthritis Res Ther . 2013 ; 15 : R38 . Google Scholar Crossref Search ADS PubMed WorldCat Derer A , Groetsch B, Harre U, Bohm C, Towne J, Schett G, et al. . Blockade of IL-36 receptor signaling does not prevent from TNF-induced arthritis . PLoS One . 2014 ; 9 : 2 – 8 . Google Scholar Crossref Search ADS WorldCat Boraschi D , Lucchesi D, Hainzl S, Leitner M, Maier E, Mangelberger D, et al. . IL-37: a new anti-inflammatory cytokine of the IL-1 family . Eur Cytokine Netw . 2011 ; 22 : 127 – 47 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Nold MF , Nold-Petry CA, Zepp JA, Palmer BE, Bufler P, Dinarello CA IL-37 is a fundamental inhibitor of innate immunity . Nat Immunol . 2010 ; 11 : 1014 – 22 . Google Scholar Crossref Search ADS PubMed WorldCat Bulau AM , Nold MF, Li S, Nold-Petry CA, Fink M, Mansell A, et al. . Role of caspase-1 in nuclear translocation of IL-37, release of the cytokine, and IL-37 inhibition of innate immune responses . Proc Natl Acad Sci USA . 2014 ; 111 : 2650 – 5 . Google Scholar Crossref Search ADS WorldCat Li S , Neff CP, Barber K, Hong J, Luo Y, Azam T, et al. . Extracellular forms of IL-37 inhibit innate inflammation in vitro and in vivo but require the IL-1 family decoy receptor IL-1R8 . Proc Natl Acad Sci USA . 2015 ; 112 : 2497–502 . Google Scholar PubMed OpenURL Placeholder Text WorldCat Xu S , Li W, Tong Y, Dong N, Sheng Z, Yao Y Expression of IL-37 contributes to the immunosuppressive property of human CD4 + CD25 + regulatory T cells . Sci Rep . 2015 ; 28 : 14478 . Google Scholar OpenURL Placeholder Text WorldCat Zeng M , Dang W, Chen B, Qing Y, Xie W, Zhao M, Zhou J IL-37 inhibits the production of pro-inflammatory cytokines in MSU crystal-induced inflammatory response . Clin Rheumatol . 2015 ; 35 : 2251 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat Xu WD , Zhao Y, Liu Y Insights into IL-37, the role in autoimmune diseases . Autoimmun Rev . 2015 ; 14 : 1170 – 5 . Google Scholar Crossref Search ADS PubMed WorldCat Ye L , Huang Z IL-37 restrains autoimmune diseases . Oncotarget . 2015 ; 6 : 21775 – 6 . Google Scholar Crossref Search ADS PubMed WorldCat Clavel G , Thiolat A, Boissier MC Interleukin newcomers creating new numbers in rheumatology: IL-34 to IL-38, Jt . Joint Bone Spine . 2013 ; 80 : 449 – 53 . Google Scholar Crossref Search ADS PubMed WorldCat Al-Saadany HM , Hussein MS, Gaber RA, Zaytoun HA Th-17 cells and serum IL-17 in rheumatoid arthritis patients: correlation with disease activity and severity . Egypt Rheumatol . 2016 ; 38 : 1 – 7 . Google Scholar Crossref Search ADS WorldCat Xia T , Zheng X, Qian B, Fang H, Wang J, Zhang L, et al. . Plasma interleukin-37 is elevated in patients with rheumatoid arthritis: its correlation with disease activity and Th1/Th2/Th17-related cytokines . Dis Markers . 2015 ; 2015 : 1 – 6 . Google Scholar Crossref Search ADS WorldCat Zhao PW , Jiang WG, Wang L, Jiang ZY, Shan YX, Jiang YF Plasma levels of IL-37 and correlation with TNF-α, IL-17A, and disease activity during DMARD treatment of rheumatoid arthritis . PLoS One . 2014 ; 9 : e95346 . Google Scholar Crossref Search ADS PubMed WorldCat Xia L , Shen H, Lu J Elevated serum and synovial fluid levels of interleukin-37 in patients with rheumatoid arthritis: attenuated the production of inflammatory cytokines . Cytokine . 2015 ; 76 : 553 – 7 . Google Scholar Crossref Search ADS PubMed WorldCat Ge G , Wang A, Yang J, Chen Y, Yang J, Li Y, Xue Y Interleukin-37 suppresses tumor growth through inhibition of angiogenesis in non-small cell lung cancer . J Exp Clin Cancer Res . 2016 ; 35 : 13 . Google Scholar Crossref Search ADS PubMed WorldCat Yang T , Lin Q, Zhao M, Hu Y, Yu Y, Jin J, et al. . IL-37 Is a novel proangiogenic factor of developmental and pathological angiogenesis significance . Arterioscler Thromb Vasc Biol . 2015 ; 35 : 2638 – 46 . Google Scholar Crossref Search ADS PubMed WorldCat van de Veerdonk FL , Stoeckman AK, Wu G, Boeckermann AN, Azam T, Netea MG, et al. . IL-38 binds to the IL-36 receptor and has biological effects on immune cells similar to IL-36 receptor antagonist . Proc Natl Acad Sci USA . 2012 ; 109 : 3001 – 5 . Google Scholar Crossref Search ADS WorldCat Yuan X , Peng X, Li Y, Li M Role of IL-38 and its related cytokines in inflammation . Mediators Inflamm . 2015 ; 2015 :807976. Google Scholar OpenURL Placeholder Text WorldCat Takenaka S , Kaieda S, Kawayama T, Matsuoka M, Kaku Y, Kinoshita T, et al. . IL-38: a new factor in rheumatoid arthritis . Biochem Biophys Reports . 2015 ; 4 : 386 – 91 . Google Scholar Crossref Search ADS WorldCat Mora J , Schlemmer A, Wittig I, Richter F, Putyrski M, Frank AC, et al. . Interleukin-38 is released from apoptotic cells to limit inflammatory macrophage responses . J Mol Cell Biol . 2016 ; 8 : 426 – 438 . Google Scholar Crossref Search ADS PubMed WorldCat © 2017 Japan College of Rheumatology This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
TI - A review on interleukins: The key manipulators in rheumatoid arthritis
JF - Modern Rheumatology
DO - 10.1080/14397595.2016.1266071
DA - 2017-09-03
UR - https://www.deepdyve.com/lp/oxford-university-press/a-review-on-interleukins-the-key-manipulators-in-rheumatoid-arthritis-gIyX9pNLy4
SP - 723
EP - 746
VL - 27
IS - 5
DP - DeepDyve
ER -