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Interleukin 18 in the CNS

Interleukin 18 in the CNS Interleukin (IL)-18 is a cytokine isolated as an important modulator of immune responses and subsequently shown to be pleiotropic. IL-18 and its receptors are expressed in the central nervous system (CNS) where they participate in neuroinflammatory/neurodegenerative processes but also influence homeostasis and behavior. Work on IL-18 null mice, the localization of the IL-18 receptor complex in neurons and the neuronal expression of decoy isoforms of the receptor subunits are beginning to reveal the complexity and the significance of the IL-18 system in the CNS. This review summarizes current knowledge on the central role of IL-18 in health and disease. Introduction soon found that IL-18 could be synthesized centrally Interleukin (IL)-18 was isolated in 1995 as a co-factor and its receptor subunits were now demonstrated to be that, in synergism with IL-12, stimulated the production broadly expressed in neurons. When recombinant inter- of gamma interferon (INF-g) in Th1 cells [1]. Since then leukin 18 became available it also became clear that IL- extensive in vitro and in vivo studies have identified IL- 18 was active centrally. Work on mice null for IL-18 or 18 as an important link between innate and adaptive its receptor subunit alpha is helping to decipher the immune responses and a regulator of both cellular and action of this cytokine in the brain. Finally, the recent humoral immunity [2-4]. Constitutively produced as an discovery of novel IL-18 receptor subunits in the brain inactive precursor by several cell types IL-18 is secreted has revealed the complexity of the IL-18 system and in its active form following maturation by caspase 1 in may lead to better understanding of both the similarities response to inflammatory and infectious stimuli. In and opposing actions of IL-1 and IL-18. This review addition to its effects on Th1 cells, IL-18 is a strong sti- summarizes more than a decade of work aimed at mulator of the activity of natural killer cells alone or in understanding how the IL-18 system contributes to local combination with IL-15, and of CD8 lymphocytes. central inflammatory processes or can influence neuro- Together with IL-2, IL-18 can also stimulate the pro- nal function and behavior. A summary of the literature duction of IL-13 and of other Th2 cytokines. Thus, it is supporting the involvement of IL-18 in neurophysiologi- perhaps not surprising that IL-18 was found to be asso- cal and neuropathological conditions is presented in ciated with or demonstrated to contribute to numerous Table 1. inflammatory-associated disorders. These include infec- Components of the IL-18 system tions, autoimmune diseases, rheumatoid arthritis, can- IL-18 is synthesized as an inactive 24-kDa precursor cer, as well as metabolic syndrome and atherosclerosis protein that is subsequently processed by caspase-1 into [5-11]. itsmaturesecretableform, whichhas amolecular IL-18 had not originally been expected to cross an weight of 18 kDa [4,12-16]. Pro-IL-18 can also be pro- intact blood brain barrier and its immunological effector cessed into its active form by various extracellular cells are not normally found in the healthy brain. Yet, enzymes including protease 3 (PR-3), serine protease, studies on the possible role of IL-18 in the central ner- elastase and cathepsin G [17-19]. Only the mature pep- vous system (CNS), initiated soon after its cloning, were tide is reported to be biologically active. prompted primarily by its similarities with IL-1, which The existence of a putative short isoform of IL-18 was already demonstrated to have central action. It was resulting from alternative splicing removing 57 bp/19 aa was first described in rat adrenal glands (IL-18a)[20] and subsequently in mouse spleens (IL-18s) [21]. Recom- * Correspondence: [email protected] † Contributed equally binant IL-18s did not display IL-18-like activity in stimu- Molecular and Integrative Neurosciences Department, The Scripps Research lating INF-g production when tested alone but appeared Institute, CA, USA © 2010 Alboni et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Alboni et al. Journal of Neuroinflammation 2010, 7:9 Page 2 of 12 http://www.jneuroinflammation.com/content/7/1/9 Table 1 Representative neurophisiological and immunoglobuling-like domains and one intracellular neurophatological conditions involving IL-18 Toll/IL-1 receptor (TIR) domain [22,23]. IL-18 is Condition Species Citation believed to bind directly only to IL-18Ra with signal Behavior transduction occurring after recruitment of IL-18Rb to Sleep Rat/Rabbit [72] form a high-affinity heterotrimeric complex with IL- Fever Mouse [73,162] 18Ra/IL-18 [23-25]. Feeding Mouse [10,11] Isoforms of both IL-18Ra and IL-18Rb were recently Learning and memory Mouse [77] described in vivo in the CNS. They include a short tran- Rat [48,74,75] script for IL-18Ra encoding for a receptor subunit lack- Human [108,111,163] ing the TIR domain arbitrarily named IL-18Ra type II Stress and HPA axis [26]. Since the TIR domain is required for signaling, IL- 18Ra type II was proposed to be a decoy receptor, simi- Rat [56,57,81] lar to the type II IL-1R [27]. In addition, a truncated Rat/Mouse [62] form of IL-18Rb comprising only one of the three Holstein cattle [80] immunoglobulin domains was described in rat and Pig [54,55] human tissues including the brain [28,29]. This form Human [136] was proposed to act as a soluble negative regulator of Neuroinflammation IL-18 action by stabilizing IL-18 binding to IL-18Ra yet Brain injury preventing signaling. Hypoxia-ischemia Mouse [67,84,164-167] Another negative regulator of IL-18 action is the IL-18 Rat [67,168] binding protein (IL-18BP). Isolated as cytokine-binding Thromboembolic stroke Mouse [83] molecules, this 38-kDa soluble protein displays some Spinal cord injury Rat [87] sequence homology with IL-18Ra [30-32]. IL-18BP Focal brain ischemia Rat [86] binds selectively and with high affinity to mature IL-18, Stroke Mouse [59,85] but not to pro-IL-18, preventing its interaction with IL- Human [169] 18Ra. Four human (18BPa-d) and two murine (IL- Nerve injury Rat [47] 18BPc and d) IL-18BP isoforms have been described Viral infection Chicken [170] [33]. Of these human IL-18BPb and d lack the structural Human [59,171] requirement to inhibit IL-18 action and their role Autoimmune neurodegenerative disease remains to be determined [5]. Multiple Sclerosis Human [95-99,101] A different member of the IL-1 family, IL-1F7, is also EAE Mouse [91,93,100] a negative regulator of IL-18 action. IL-1F7 is able to Rat [89,90,92,94] bind IL-18BP and the IL-18BP/IL-1F7 complex can Neurodegenerative disease interact with the IL-18Rb chain preventing the forma- Alzheimer’s disease Human [50,106-109,111-114] tion of the funtional IL-18R complex [34]. Several Parkinson’s disease Mouse [117] human IL-1F7 splice variants (IL-1F7a-e) have been Neuropsychiatric disorders described [35-39] whereas no murine homologue of IL- Depression Rat [133] 1F7 has yet been found. Of these, IL-1F7b (also known Human [136,137,139] as IL-1H, IL-1H4 and IL-1RP1) matured by caspase-1 is Schizophrenia Human [134,135] capable of binding IL-18Ra [37,40]. Yet, the IL-1F7/IL- Other central actions 18Ra complex failed to recruit IL-8Rb and no direct Excitotoxic damage agonistic nor antagonistic activity of IL-1F7b for IL-18R Ataxia Mouse [53] was described [37,40]. Neurodegeneration Mouse [150] IL-18 signaling Glioma Rat [156,157] Canonical IL-18 action occurs via recruitment of the Mouse [152-155] adaptor myeloid differentiation factor (MyD88). This event allows activation of the IL-1R-associated kinase to have a modest synergistic action with IL-18. To this (IRAK)/tumor necrosis factor receptor-associated fac- date this isoform has not been reported in the CNS. tor 6 (TRAF6) pathway leading to nuclear transloca- The IL-18 receptor (IL-18R) belongs to the interleukin tion of the nuclear factor kappa beta (NF-B) and 1 receptor/Toll like receptor superfamily. It is comprised subsequent modulation of gene transcription of two subunits, IL-18Ra (also known as IL-1Rrp1, IL- [4,5,41,42] (Fig 1). 18R1 or IL-1R5) and IL-18Rb (also termed IL-18RacP, IL-18 has also been reported to signal via the activa- IL-18RII or IL-1R7) both with three extracellular tion of the transcription factor tyk-2 [43], STAT3 [44] Alboni et al. Journal of Neuroinflammation 2010, 7:9 Page 3 of 12 http://www.jneuroinflammation.com/content/7/1/9 and NFATc4 [45]. In addition, a role for mitogen-acti- prior application of c-jun-n-terminal kinase (JNK) path- vated protein kinases (MAPK) (i.e., extracellular signal- way, cyclooxygenase-2 (COX-2) and inducible nitric regulated kinase, ERK1/2 and p38), and phosphatidyli- oxide synthase (iNOS) inhibitors, and a role for p38 nositol-3 kinase (Pi3K) in IL-18 signalling has been sug- MAPK was also suggested [48,49]. Moreover, human gested [4,44-46]. neuron-like differentiated SH-SY5Y neuroblastomas While these data on peripheral cells were consolidated exhibited an IL-18-dependent increase in the levels of over a decade of work with the immune system, knowl- several kinases including p35, Cdk5, GSK-3beta, and edge of the IL-18-dependent signaling in the CNS is Ser15-phosphorylated p53 [50]. only beginning to emerge. Activation of the IL-18R IL-18 system in the CNS increased NF-B phosphorylation and induced hypertro- IL-18 transcript was demonstrated by RT-PCR in a vari- phy in astrocytes [47]. In the rat dentate gyrus, the func- ety of brain regions including the hippocampus, the tional effects of IL-18 were significantly attenuated by hypothalamus and the cerebral cortex [51,52]. In in vivo Figure 1 The IL-18 system. Active IL-18 is produced and secreted after proteolitic cleavage of the biological inactive precursor Pro-IL-18 by caspase-1. IL-18 action can be regulated by the IL-18 binding protein (IL18-BP) that binds IL-18 with high affinity and inhibits its function. Free IL-18 binds to a specific heterodimeric cell surface receptor, a member of the IL-1 receptor/Toll like receptor superfamily comprised of two subunits, IL-18Ra (here referred to as IL-18RaI) and IL-18Rb, both with three extracellular Ig-like domains and one intracellular portion containing the Toll/IL-1R domain (TIR). Interaction of IL-18 with the IL-18Ra stabilizes its interaction with IL-18Rb and with the adaptor protein MyD88 via the TIR domain. This initiates signal transduction by recruitment of the IL-1 receptor activating kinase (IRAK). IRAK autophosphorylates and dissociates from the receptor complex subsequently interacting with the TNFR-associated factor-6 (TRAF6) eventually leading to nuclear translocation of the nuclear factor B (NF-B). Engagement of the IL-18R complex can also activate STAT3 and the mitogen-activated protein kinase (MAPK) p38, JNK and ERK. One truncated variant of IL-18Ra (IL-18RaII) lacking the intracellular TIR domain, and one soluble isoform of the IL-18Rb (sIL-18Rb) were demonstrated in vivo in the mouse brain and in the rat and human brain, respectively. These isoforms originating from differential splicing are proposed to be decoy receptors and possible negative regulators of IL-18 fuction. IL-1F7 is another proposed regulator of IL-18 action (see text for details). Alboni et al. Journal of Neuroinflammation 2010, 7:9 Page 4 of 12 http://www.jneuroinflammation.com/content/7/1/9 studies, IL-18 protein was demonstrated in the pituitary It was demonstrated that central intracerebroventricular gland, ependymal cells, the neurons of the medial habe- (i.c.v.) injection of IL-18 in rabbits and rats increased non- nula (where its synthesis was elevated by stress), in Pur- rapid eye movement sleep as well as brain temperature kinje cells, and in astrocytes in the cerebellum [53-57]. [72]. The lethargic effects of IL-18 were also observed fol- In addition, it was demonstrated in vitro that microglia lowing intraperitoneal injection of IL-18, whereas, unlike and astrocytes can produce IL-18 [58-61] and its level IL-1b, peripheral administration did not induce fever can be up-regulated following LPS stimulation [62] or [72,73]. Instead, pre-treatment with IL-18 reduced the treatment with INF-g [63]. pyrogenic effects of IL-1 suggesting the possibility of an In the CNS, Northern blot analysis failed to detect antagonizing effect of these cytokines on fever [73]. thepresenceofIL-Ra [64] and IL-Rb [65] soon after Work on IL-18 null, and on IL-18BP overexpressing their cloning. The first evidence that IL-18R compo- mice indicated that IL-18 is anorexigenic and can mod- nents are expressed in brain tissue was obtained by ulate feeding, but also energy homeostasis, influencing Wheeler and colleagues [52] which reported the con- obesity and insulin resistance [10,11]. The mechanisms stitutive expression of IL-18Ra, IL-18Rb in the rat through which IL-18 exerts these effects are largely hypothalamus by RT-PCR. Subsequently, the mRNA unknown but central action was proposed following the expression of IL-18Ra, IL-18Rb and the soluble form observation that i.c.v. injections of exogenous IL-18 of the IL-18Rb were detected in the hypothalamus, induces sleep [72] and anorexia [11]. The recent demon- hippocampus, striatum and cortex and in cultured stration that IL-18 functional and regulatory subunits of astrocytes, microglia and neurons [28]. More recently the IL-18R are expressed in several brain regions includ- in vivo analysis showed that IL-18Ra mRNA and pro- ing the hippocampus, the hypothalamus and the cortex tein are constitutively expresseed in neurons through- provided a molecular and cellular basis for the central out the brain [26,53,60,66]. Similar neuronal action of IL-18 in modulating these functions [26]. localization and distribution was found for IL-18Rb Evidence for the role of IL-18 as modulator of neuro- (Alboni et al., unpublished data). At the same time it nal functions includes studies on the hippocampal sys- was demonstrated that the truncated decoy form of tem, a structure that plays a major role in memory and the IL-18Ra was expressed in neuronal cells with a in cognition. For instance, IL-18 reduces long term pattern similar to that of its active counterpart [26]. potentiation (LTP) in the rat dentate gyrus, possibly Overall, IL-18R subunits had broad distribution across through the involvement of metabotropic glutamate the brain with the highest level in the hypothalamus, receptors [48,49,74,75]. In particular, IL-18 had no effect hippocampus and amygdala. Finally, both IL-18 and on baseline synaptic transmission or paired pulse IL-18R subunits are inducible and their CNS levels can depression, but significantly depressed the amplitude of be regulated. For instance, in the mouse hippocampus NMDA receptor-mediated field excitatory post synaptic the levels of IL-18 and IL-18Ra increased after kainic potentials [75] providing evidence of a direct neuromo- acid (KA)-induced excitotoxicity, [60] whereas dulatory role for IL-18 in synaptic plasticity. It is possi- hypoxic-ischemic brain injurymarkedlyincreased IL- ble that IL-18 may act directly on the neurons of the 18 expression in mouse microglia [67]. In addition dentate gyrus, moreover, its action may be regulated by nerve injury induced IL-18 upregulation in rat spinal the relative level of IL-18Ra type I and type II, both cord microglia possibly via p38 activation [47]. highly expressed in these cells [26]. Work on CA1 pyra- IL-18BP has been investigated and demonstrated in midal neurons of mouse hippocampal slices demon- rodent brains, mixed glia and microglia by only one strated that IL-18 stimulated synaptically released group using RT-PCR. Its distribution and action in the glutamate and enhanced postsynaptic AMPA receptor CNS remain to be investigated [52,68]. responses, thereby facilitating basal hippocampal synap- Information on central IL-1F7 is also limited to one tic transmission without affecting LTP [76]. study that demonstrated its presence in the human Recently an ex vivo study found that LPS-induced IL- brain [37]. Investigating IL-1F7 in the CNS is also ham- 18 elevation in the brain was unable to affect LTP in pered by the fact that a mouse homologue has not been the CA1 hippocampal subregion [77]. However, when identified. comparing wild-type and IL-18 KO mice, the same Behavior study demonstrated that IL-18 regulates fear memory The similarities between the IL-1 and the IL-18 systems and spatial learning. In particular, assessment of spatial suggested the possibility that like IL-1b,IL-18 maybe learning and memory with the water maze test showed one mediator of the behavior symptoms of sickness. that compared to wild-type mice IL-18 KO mice exhibit These include fever, lethargy, hypophagia and cognitive prolonged acquisition latency and that this phenotype alterations [69-71]. was rescued by i.c.v. injection of IL-18. Alboni et al. Journal of Neuroinflammation 2010, 7:9 Page 5 of 12 http://www.jneuroinflammation.com/content/7/1/9 Stress and the hypothalamic-pituitary-adrenal axis binding of IL-18 occurs in several neuroinflammatory IL-18 occupies a peculiar role in stress response both associated pathological conditions including microbial centrally and peripherally. This subject was recently infections, focal cerebral ischemia, Wallerian degenera- extensively reviewed and we briefly refer to it here only tion and hypoxic-ischemic, hyperoxic and traumatic for those aspects relevant to understanding of the cen- brain injuries (e.g., stroke). Further evidence comes from tral actions of this cytokine [78]. recent papers reporting an activation of IL-18 in the In response to restraint stress, IL-18 null mice showed brain of mice that underwent thromboembolic stroke a markedly reduced morphological microglial activation [83] or an increase of IL-18 levels after hypoxia-ischemia in the thalamus, hypothalamus, hippocampus, substantia in the juvenile hippocampus of mice [84]. nigra and central gray area [62]. In addition, IL-18 During CNS inflammation, the IL-18 system may have expression was elevated by restraint stress in the neu- an important role in the activation and response of rons of the medial habenula [56]. Since the habenula is microglia and possibly infiltrating cells. As mentioned a potential site for the interaction of neuro-endocrine above, microglia cells can synthesize and respond to IL- and immune functions, the possibility exists that IL-18 18 [20,59-61]. IL-18 KO mice had impaired microglia 2+- might mediate the communication between the CNS activation with reduced expression of Ca binding pro- and the periphery. Indeed, there is a general agreement tein regulating phagocytic functions that resulted in that IL-18 may regulate hypothalamic-pituitary axis reduced clearance of neurovirulent influenza A virus activity, possibly mediating the stress response of the [85]. In the absence of infection IL-18 deficient mice adrenal gland [20,78,79]. In this respect, stress has been also showed diminished stress-induced morphological shown to induce transient IL-18 mRNA elevation in rat microglial hypertrophy [62]. pituitary cells where increase of the IL-18 mRNA level Interestingly, IL-1b is upregulated within 4 h of focal was observed also after adrenalectomy [57]. ischemia in rat brain, but IL-18 is upregulated much IL-18 is also produced in the neurohypophysis [20] as later, at time points associated with infiltration of per- well as in the adenohypophysis where in situ hybridiza- ipheral immune cells, thus suggesting different roles for tion combined with immunohistochemistry demon- these interleukins in the regulation of glial functions strated its expression in corticotrope cells [57]. In [86]. In this respect, it was shown that mice infected addition, bovine somatotropes have been shown to pro- with Japanese Encephalitis produce IL-18 and IL-1b duce IL-18 and IL-18Ra was co-localized with IL-18, or from microglia and astroglia [59]. Both interleukins are growth hormone, suggesting the possibility that IL-18 capable of inducing pro-inflammatory cytokines and acts on somatotropes through the autocrine pathway chemokines from human microglia and astroglia, [80]. However, IL-18 seems to also act at the hypothala- although IL-18 seems to be more potent than IL-1b. mic level. Indeed, the application of IL-18 in rat In the spinal cord, IL-18 seems to play a role in the hypothalamic explants decreases basal and KCl-stimu- innate inflammatory response. Indeed, moderate cervical lated corticotropin-releasing hormones (CRH), as well as contusive spinal cord injury induced processing of IL-18 CRH gene expression [81]. In particular, the cytokine in neurons of the rat spinal cord [87]. In addition, nerve did not modify basal PGE2 production but abolished injury induced a striking increase in IL-18 and IL-18R production stimulated by IL-1b demonstrating that IL- expression in the dorsal horn, and IL-18 and IL-18R 18 possesses a profile of in vitro neuroendocrine activ- were upregulated in hyperactive microglia and astro- ities opposed to, and even antagonizing, those of IL-1b. cytes, respectively [47,88]. Intrathecal injection of IL-18 Recently, IL-18 was localized in the marginal cell layer induced behavioral, morphological, and biochemical of thebovineand porcineRathke ’spouch,thatis changes similar to those observed after nerve injury assumed to embody a stem/progenitor cell compartment [47], suggesting that IL-18-mediated microglia/astrocyte of the postnatal pituitary gland [54,55]. Interestingly, sti- interactions in the spinal cord have a substantial role in mulation of a cloned anterior pituitary-derived cell line the generation of tactile allodynia. (from the bovine anterior pituitary gland) with IL-18 Autoimmune neurodegenerative disease increased expression of mRNAs of a different cytokine A pivotal role for IL-18, in the pathogenesis of autoim- suggesting the possibility that IL-18 may modulate not mune neurodegenerative disease has been proposed. only the immuno-endocrine function of the pituitary High levels of IL-18 mRNA were found in the brain and cells but also their development [55]. the spinal cord of rats with experimental autoimmune Microglia and neuroinflammation encephalomyelitis (EAE), an animal model of multiple Functional maturation and activation of IL-18 can occur sclerosis (MS) [89,90]. Elevated IL-18 transcript was in the brain under inflammatory conditions. Indeed, as found at the onset and throughout the course of the dis- extensively reviewed by Felderhoff-Mueser and collea- ease. A different study showed that IL-18 increases gues [82], experimental and clinical studies suggest that severity of EAE [91]. Moreover, it has been Alboni et al. Journal of Neuroinflammation 2010, 7:9 Page 6 of 12 http://www.jneuroinflammation.com/content/7/1/9 demonstrated that anti-IL-18 antibodies or targeted tau phosphorylation as a part of the amyloid-associated overexpression of IL-18BP in the CNS had preventive inflammatory reaction. Additionally, IL-18 can enhance effects on the induction of EAE[90,92]. These observa- protein levels of Cdk5/p35 and GSK-3b kinases, tau tionssuggested arolefor IL-18inMS, IL-18KOmice phosphorylation and cell cycle activators in neuron- were susceptible to EAE, whereas IL-18Ra KO mice or like differentiated human SH-SY5Y neuroblastoma IL-18 KO mice treated with anti-IL-18Ra antibodies cells [50]. Thus, on a pathway leading to AD, IL-18 were not [93]. Thus, alternative IL-18Ra ligands with may have an impact on the hyperphosphorylation of encephalitogenic properties may exist [93]. In EAE-sus- tau but also on cell cycle related mechanisms. In the ceptible Dark Agouti rats, the basal and post-immuniza- plasma, the levels of IL-18 were significantly elevated tion (day 5, 7 and 12) levels of IL-18Ra in lymph node in patients with AD, vascular dementia, and mild cog- cells were significantly higher than in the EAE-resistant nitive impairment compared to the control group Piebald Virol Glaxo rats [94]. [107,108]. Interestingly, IL-18 levels were higher in In human, serum and cerebrospinal fluid levels of IL- AD-mild patients, were slightly lower in AD-moderate 18 are elevated in patients with MS [95-98] and IL-18 patients, whereas no significant difference was positive cells have been detected in demyelinating brain observed between AD-severe patients and non-demen- lesions from MS patients [99]. ted age-matched subjects [109], suggesting a gradual The pathological role of IL-18 in EAE is also sup- decline of immune responsiveness in AD. Although ported by the up-regulation of caspase-1 (required to other studies showed no differences in circulating IL- convert IL-18 precursor protein into its biologically 18 levels measured between AD patients (both mild active mature form) mRNA in the spinal cord of rats cognitive impairment and severe AD patients) and with EAE [89], and decreased disease severity in cas- controls [106,110,111], a significant increased produc- pase-1 KO mice [100]. Finally, peripheral blood mono- tion of IL-18 was obtained from stimulated blood nuclear cells from patients with MS have elevated mononuclear cells or macrophages of peripheral blood caspase-1 mRNA levels [95,101]. of AD patients [111,112]. Furthermore, a significant In addition to a role in MS there is also evidence to correlation between IL-18 peripheral production and support a function for IL-18 in the onset and progres- cognitive decline was observed in AD patients. Overall, sion of autoimmune CNS disease. For instance, infection these data indicate that IL-18-related inflammatory of microglia lines with Theiler’s murine encephalomyeli- pathways, are exacerbated in the peripheral blood of tis virus (which causes the development of a chronic- AD patients, and that this cytokine may indeed partici- progressive autoimmune demyelinating disease) signifi- pate in pathogenic processes leading to dementia. cantly upregulates the expression of cytokines involved Genetic association studies reported that two func- in innate immunity, including IL-18 [102]. tional polymorphisms (137G/C and -607C/A) in IL-18 Neurodegenerative disorders promoter may increase the risk of developing sporadic Alzheimer’s Disease (AD) is the most common type of late onset AD in the Han Chinese population [113]. An human dementia. It is characterized clinically by a gra- association between 137G/C and -607C/A polymorph- dual but progressive decline in memory and pathologi- isms and the susceptibility/clinical outcome of AD was cally by neuritic plaques, neuro-fibrillary tangles, and also suggested in an Italian population [114], although thelossofsynapsesand neurons[103].Inflammatory these correlations remain controversial. Indeed, in processes were proposed to contribute to neurodegen- another Italian population a lack of association between eration in AD and extensive studies indicated that IL-1 IL-18 gene promoter polymorphisms and onset of AD is a pivotal cytokine in mediating direct neuronal loss was reported, indicating that the association of IL-18 and sustaining microglia activation leading to further promoter polymorphisms with AD is not so strong, AD cellular damage in AD [104]. Microglia-derived inflam- being a multifactorial disease [115]. Importantly, IL-18 matory cytokines can initiate nerve cell degeneration promoter remains poorly characterized. and enhance the plaque production typically found in Finally, it has been hypothesized that increased pro- AD [105]. Increasing evidence indicates that IL-18 may duction of IL-18 in the brain may lead to motor and have aroleinthisscenario. cognitive dysfunctions, leading to the development of For instance, the levels of IL-18 transcript and pro- HIV-associated dementia. Thus, IL-18 concentrations in tein were increased in the frontal lobe of AD patients HIV-infected persons are likely to play an important compared to healthy age-matched controls. In these role in the development and progression of the infection brains IL-18 was found in microglia, astrocytes and in toward AIDS and associated clinical conditions [116]. neurons that co-localize with amyloid-b-plaques and In Parkinsonism, there is evidence of chronic inflam- with tau [106], suggesting that amyloid-b may induce mation in the substantia nigra and striatum. Activated the synthesis of IL-18, and IL-18 kinases involved in microglia, producing proinflammatory cytokines, Alboni et al. Journal of Neuroinflammation 2010, 7:9 Page 7 of 12 http://www.jneuroinflammation.com/content/7/1/9 surround the degenerating dopaminergic neurons and The significance of these correlations with respect to may contribute to dopaminergic neuron loss. In an the role of the IL-18 system to neurophsychiatric disease experimental model of Parkinson’s disease that utilized pathophysiology or manifestation remains to be deter- injection of the dopaminergic specific neurotoxin MPTP mined. Caution should be taken particularly since per- the number of activated microglial cells in the substantia ipheral IL-18 can be subject to neurogenic stimulation nigra pars compacta of IL-18 KO mice was reduced or stress [20,78,141-143]. It is thus difficult to determine compared to wild-type [117], indicating the possibility whether IL-18 elevation contributes to these pathologies that IL-18 may participate in microglial activation and or whether it is a consequence of the disorders. Indeed, dopaminergic neurodegeneration. Kokai and colleagues suggest that IL-18 can be consid- Neuropsychiatric disorders ered a psychologic stress-associated marker since they Several groups found that depressed and schizophrenic demonstrated that exposure to stressful events (i.e., patients have high circulating levels of pro-inflammatory panic attack in human, restraint stress in mice), the cytokines [118-123]. Others reported that psychotic epi- most important precipitating factor in depression, sodes often occur in conditions characterized by ele- induces a prompt increase in the level of circulating IL- vated levels of pro-inflammatory cytokines, for instance 18 [136]. during inflammation or in patients suffering from Regardless, elevated IL-18 levels have the potential to immune diseases [124-127]. contribute to several of the symptoms associated with Other studies suggested that the correlation between neuropsychiatric disorders. For instance, like other inflammatory markers and psychiatric disorders may be pro-inflammatory cytokines, IL-18 may participate in more that merely associative, with inflammation actually the control of the activity of the HPA axis reported to contributing to mental disorders. Improvement in psy- be dysregulated in depression [78,144-146]. IL-18 may chiatric symptoms has been recently reported in patients antagonize glucocorticoid signalling via activation of treated with anti-inflammatory drugs for other indica- NF-B and p38 MAPK possibly disrupting glucocorti- tions [128] and functional allelic variants of genes codi- coid-dependent negative feedback on the HPA axis fying for pro-inflammatory cytokines were associated [147-149]. Finally, IL-18 can affect other hallmarks of with reduced responsiveness to antidepressant therapy depression impairing learning and memory by acting [129,130]. It was also recently demonstrated that IL-6 as an attenuator of long-term potentiation, and indu- plays a pivotal role in the pharmacological ketamine cing lethargy and loss of appetite [11,72,74]. model of schizophrenia by modulating the NADPH-oxi- Other central actions of IL-18 dase increase of superoxide affecting parvalbumin inter- Three groups investigated the action of IL-18 in neurons [131]. An interesting line of research is rodents following administration of KA, an agonist of exploring the possibility that these actions may be devel- the kainate receptors inducing seizure, cerebellar ataxia opmental, with cytokines influencing early-life program- and exitotoxic mediated neuronal loss [53,60,150]. In ming of brain functions [132]. mouse hippocampus KA elevated IL-18 and IL-18R At present evidence linking IL-18 and psychiatric dis- expression on microglial cells progressively 3 days after orders are primarily associative. IL-18 mRNA expression treatment [60]. The authors hypothesized that similar is elevated in subordinate rat models with depression to what was observed peripherally in studies of the with respect to dominant rats [133]. A significant eleva- immune system, IL-18 may contribute to cellular tion of circulating plasma levels of IL-18 has been damage. This hypothesis was partially supported by reported in subjects affected by schizophrenia and were another group showing that the KA-induced hippo- normalized by pharmacological treatment with risperi- campal neurodegeneration was shown to be more done, a dopamine antagonist with antipsychotic activity severe in IL-18 KO mice compared to wild-type litter- [134,135]. Normalization was demonstrated also within mates [150]. Yet, in recombinant mice with the same 6 month of treatment with the antipsychotic clozepine pre-treatment, IL-18 aggravated both the clinical and [134] although the possibility that these effects could be pathological signs of neurodegeneration in a dose- due to clozepine’s effects on leukocyte numbers cannot dependent manner. be excluded. The serum levels of IL-18 were also signifi- In the cerebellum, where KA was demonstrate to cantly higher in moderate-severe depression patients, induce ataxia partially via elevation of IL-1b,exogen- further suggesting that the pathophysiology of depres- ous IL-18 was protective and played a positive role in sion is associated with an inflammatory response invol- the recovery from kainate-induced ataxia [53]. Consis- ving IL-18 [136,137]. Coincidentally, IL-18 is also tently, IL-18 KO and IL-18Ra KO mice show delay in elevated after stroke, a condition followed by emotional recovery from kainate-induced ataxia. The antagoniz- disorders [138-140]. ing effects of IL-18 and IL-1b also observed in the per- ipheral effects of IL-1b on fever, [73] are intriguing Alboni et al. Journal of Neuroinflammation 2010, 7:9 Page 8 of 12 http://www.jneuroinflammation.com/content/7/1/9 particularly since these cytokines share many similari- physiological conditions IL-18 is not easily found in the ties including their signalling. Preliminary observations CNS. Interestingly, the genes encoding for IL-18 and its suggest that these effects may be explained by IL-1b receptors are subject to differential promoter usage and and IL-18 targeting different cells or activating distinct their transcription to differential splicing indicating that signalling [53]. these molecules have the potential of being produced in Some groups have investigated the possibility that a tissue/cell specific way in response to different stimuli IL-18 could be used against glioma, a common and [26,78]. It will be important to determine which physio- highly aggressive type of brain tumor with poor long- logical or pathological conditions modulate these term prognosis [151]. In this respect, IL-18 was inves- molecules. tigated alone or in synergism with IL-12 or Fas, for its Also unexplored is the investigation of the possible ability to induce INFg and NO inducing a cytotoxic role of IL-18 in CNS development suggested by work response against glioma cells [152]. Systemic or intra- on microglial cultures from newborn mice and brain cerebral administration of IL-18 inhibited the growth homogenates where IL-18 was preferentially expressed of inoculated glioma cells and prolonged the survival during early postnatal stages and subsequently downre- of mice with subcutaneous or brain tumors, respec- gulated, being virtually absent in the brains of adult tively [153]. Antitumor activity against glioma was also mice [61]. Additionally, the activated microglia-derived found in mice treated with IL-18 and IL-12 via Semliki cytokines, including IL-18, may either inhibit the neu- Forest virus [154,155] or with a combination of IL-18 ronal differentiation or induce neuronal cell death in and Fas [156]. Finally, encouraging data were also the rat neural progenitor cell culture, which are cells reported by overexpressing IL-18 in mesenchymal cells capable of giving rise to various neuronal and glial cell of rats [157]. populations in the developing and adult CNS [160]. Finally, in adult rodents IL-18 is produced in ependy- Conclusions mal cells [56] considered a primary source of neural Investigation on the presence of IL-18 in the CNS began stem cells in response to injury [161]. The possible soon after its discovery as a co-stimulator of INF-g pro- role of IL-18 in their differentiation has also not been duction in the immune system [1,20,158,159]. Initially investigated. IL-18 was investigated for its similarities with IL-1b as a Work on existing IL-18 and IL-18R null mice as well possible mediator of sickness behavior and of local as the development of new experimental models includ- inflammatory reactions associated with neuronal ing CNS specific null or overexpressor mice and the damage. These actions were both demonstrated and IL- identification of suitable in vitro systems will determine 18 was shown to promote loss of appetite, sleep and the specificity of the central effects of IL-18 in health inhibition of LTP, as well as to be produced by and and disease. active in microglial cells, and to possibly contribute to neurodegenerative diseases. Acknowledgements Yet, two observations suggest that IL-18 has a central Supported by The Ellison Medical Foundation and NIH HL088083 and grant- role and function that may be unique and distinct from in-aid for Science Research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (20500359). those of IL-1b or other cytokines. The first being the recognition that Il-18 and Il-1b, when their combined Author details action was tested, may have antagonizing effects such as Department of Biomedical Sciences, University of Modena and Reggio Emilia, Italy. Department of Environmental Sciences, University of Tuscia, those occurring in fever and in kainate-induced cerebel- Viterbo, Italy. Department of Physiology, Nippon Medical School, 1-1-5 lar ataxia. The second was the finding that IL-18R is 4 Sendagi Bunkyo-ku, Tokyo 113-8602, Japan. Molecular and Integrative constitutively and broadly expressed in neuronal cells Neurosciences Department, The Scripps Research Institute, CA, USA. throughout the rodent brain. This finding opened the Authors’ contributions possibility of a direct action of IL-18 on neuronal func- SA and DC wrote the initial draft of the manuscript, SS and BC contributed tions particularly in all of the CNS disorders showed to to its final version. All authors read and approved the final manuscript. be correlated to elevated cytokine levels. Competing interests Thus, the investigation of the central action of IL-18 The authors declare that they have no competing interests. may be considered in its infancy and the significance of Received: 10 December 2009 the neuronal IL-18R complex and of its isoforms Accepted: 29 January 2010 Published: 29 January 2010 remains to be determined. 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Abdul-Careem MF, Hunter BD, Sarson AJ, Mayameei A, Zhou H, Sharif S: deficiency aggravates kainic acid-induced hippocampal Marek’s disease virus-induced transient paralysis is associated with neurodegeneration in C57BL/6 mice due to an overcompensation by IL- cytokine gene expression in the nervous system. Viral Immunol 2006, 12. Exp Neurol 2007, 205:64-73. 19:167-176. 151. Sarin H: Recent progress towards development of effective systemic 171. von Giesen HJ, Jander S, Koller H, Arendt G: Serum and cerebrospinal fluid chemotherapy for the treatment of malignant brain tumors. J Transl Med levels of interleukin-18 in human immunodeficiency virus type 1- 2009, 7:77. associated central nervous system disease. J Neurovirol 2004, 10:383-386. 152. Kito T, Kuroda E, Yokota A, Yamashita U: Cytotoxicity in glioma cells due doi:10.1186/1742-2094-7-9 to interleukin-12 and interleukin-18-stimulated macrophages mediated Cite this article as: Alboni et al.: Interleukin 18 in the CNS. Journal of by interferon-gamma-regulated nitric oxide. J Neurosurg 2003, 98:385-392. Neuroinflammation 2010 7:9. 153. Kikuchi T, Akasaki Y, Joki T, Abe T, Kurimoto M, Ohno T: Antitumor activity of interleukin-18 on mouse glioma cells. J Immunother 2000, 23:184-189. 154. Yamanaka R, Tsuchiya N, Yajima N, Honma J, Hasegawa H, Tanaka R, Ramsey J, Blaese RM, Xanthopoulos KG: Induction of an antitumor immunological response by an intratumoral injection of dendritic cells pulsed with genetically engineered Semliki Forest virus to produce interleukin-18 combined with the systemic administration of interleukin- 12. J Neurosurg 2003, 99:746-753. 155. Yamanaka R, Yajima N, Tsuchiya N, Honma J, Tanaka R, Ramsey J, Blaese M, Xanthopoulos KG: Administration of interleukin-12 and -18 enhancing the antitumor immunity of genetically modified dendritic cells that had http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Neuroinflammation Springer Journals

Interleukin 18 in the CNS

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Copyright © 2010 by Alboni et al; licensee BioMed Central Ltd.
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Biomedicine; Neurosciences; Neurology; Neurobiology; Immunology
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Abstract

Interleukin (IL)-18 is a cytokine isolated as an important modulator of immune responses and subsequently shown to be pleiotropic. IL-18 and its receptors are expressed in the central nervous system (CNS) where they participate in neuroinflammatory/neurodegenerative processes but also influence homeostasis and behavior. Work on IL-18 null mice, the localization of the IL-18 receptor complex in neurons and the neuronal expression of decoy isoforms of the receptor subunits are beginning to reveal the complexity and the significance of the IL-18 system in the CNS. This review summarizes current knowledge on the central role of IL-18 in health and disease. Introduction soon found that IL-18 could be synthesized centrally Interleukin (IL)-18 was isolated in 1995 as a co-factor and its receptor subunits were now demonstrated to be that, in synergism with IL-12, stimulated the production broadly expressed in neurons. When recombinant inter- of gamma interferon (INF-g) in Th1 cells [1]. Since then leukin 18 became available it also became clear that IL- extensive in vitro and in vivo studies have identified IL- 18 was active centrally. Work on mice null for IL-18 or 18 as an important link between innate and adaptive its receptor subunit alpha is helping to decipher the immune responses and a regulator of both cellular and action of this cytokine in the brain. Finally, the recent humoral immunity [2-4]. Constitutively produced as an discovery of novel IL-18 receptor subunits in the brain inactive precursor by several cell types IL-18 is secreted has revealed the complexity of the IL-18 system and in its active form following maturation by caspase 1 in may lead to better understanding of both the similarities response to inflammatory and infectious stimuli. In and opposing actions of IL-1 and IL-18. This review addition to its effects on Th1 cells, IL-18 is a strong sti- summarizes more than a decade of work aimed at mulator of the activity of natural killer cells alone or in understanding how the IL-18 system contributes to local combination with IL-15, and of CD8 lymphocytes. central inflammatory processes or can influence neuro- Together with IL-2, IL-18 can also stimulate the pro- nal function and behavior. A summary of the literature duction of IL-13 and of other Th2 cytokines. Thus, it is supporting the involvement of IL-18 in neurophysiologi- perhaps not surprising that IL-18 was found to be asso- cal and neuropathological conditions is presented in ciated with or demonstrated to contribute to numerous Table 1. inflammatory-associated disorders. These include infec- Components of the IL-18 system tions, autoimmune diseases, rheumatoid arthritis, can- IL-18 is synthesized as an inactive 24-kDa precursor cer, as well as metabolic syndrome and atherosclerosis protein that is subsequently processed by caspase-1 into [5-11]. itsmaturesecretableform, whichhas amolecular IL-18 had not originally been expected to cross an weight of 18 kDa [4,12-16]. Pro-IL-18 can also be pro- intact blood brain barrier and its immunological effector cessed into its active form by various extracellular cells are not normally found in the healthy brain. Yet, enzymes including protease 3 (PR-3), serine protease, studies on the possible role of IL-18 in the central ner- elastase and cathepsin G [17-19]. Only the mature pep- vous system (CNS), initiated soon after its cloning, were tide is reported to be biologically active. prompted primarily by its similarities with IL-1, which The existence of a putative short isoform of IL-18 was already demonstrated to have central action. It was resulting from alternative splicing removing 57 bp/19 aa was first described in rat adrenal glands (IL-18a)[20] and subsequently in mouse spleens (IL-18s) [21]. Recom- * Correspondence: [email protected] † Contributed equally binant IL-18s did not display IL-18-like activity in stimu- Molecular and Integrative Neurosciences Department, The Scripps Research lating INF-g production when tested alone but appeared Institute, CA, USA © 2010 Alboni et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Alboni et al. Journal of Neuroinflammation 2010, 7:9 Page 2 of 12 http://www.jneuroinflammation.com/content/7/1/9 Table 1 Representative neurophisiological and immunoglobuling-like domains and one intracellular neurophatological conditions involving IL-18 Toll/IL-1 receptor (TIR) domain [22,23]. IL-18 is Condition Species Citation believed to bind directly only to IL-18Ra with signal Behavior transduction occurring after recruitment of IL-18Rb to Sleep Rat/Rabbit [72] form a high-affinity heterotrimeric complex with IL- Fever Mouse [73,162] 18Ra/IL-18 [23-25]. Feeding Mouse [10,11] Isoforms of both IL-18Ra and IL-18Rb were recently Learning and memory Mouse [77] described in vivo in the CNS. They include a short tran- Rat [48,74,75] script for IL-18Ra encoding for a receptor subunit lack- Human [108,111,163] ing the TIR domain arbitrarily named IL-18Ra type II Stress and HPA axis [26]. Since the TIR domain is required for signaling, IL- 18Ra type II was proposed to be a decoy receptor, simi- Rat [56,57,81] lar to the type II IL-1R [27]. In addition, a truncated Rat/Mouse [62] form of IL-18Rb comprising only one of the three Holstein cattle [80] immunoglobulin domains was described in rat and Pig [54,55] human tissues including the brain [28,29]. This form Human [136] was proposed to act as a soluble negative regulator of Neuroinflammation IL-18 action by stabilizing IL-18 binding to IL-18Ra yet Brain injury preventing signaling. Hypoxia-ischemia Mouse [67,84,164-167] Another negative regulator of IL-18 action is the IL-18 Rat [67,168] binding protein (IL-18BP). Isolated as cytokine-binding Thromboembolic stroke Mouse [83] molecules, this 38-kDa soluble protein displays some Spinal cord injury Rat [87] sequence homology with IL-18Ra [30-32]. IL-18BP Focal brain ischemia Rat [86] binds selectively and with high affinity to mature IL-18, Stroke Mouse [59,85] but not to pro-IL-18, preventing its interaction with IL- Human [169] 18Ra. Four human (18BPa-d) and two murine (IL- Nerve injury Rat [47] 18BPc and d) IL-18BP isoforms have been described Viral infection Chicken [170] [33]. Of these human IL-18BPb and d lack the structural Human [59,171] requirement to inhibit IL-18 action and their role Autoimmune neurodegenerative disease remains to be determined [5]. Multiple Sclerosis Human [95-99,101] A different member of the IL-1 family, IL-1F7, is also EAE Mouse [91,93,100] a negative regulator of IL-18 action. IL-1F7 is able to Rat [89,90,92,94] bind IL-18BP and the IL-18BP/IL-1F7 complex can Neurodegenerative disease interact with the IL-18Rb chain preventing the forma- Alzheimer’s disease Human [50,106-109,111-114] tion of the funtional IL-18R complex [34]. Several Parkinson’s disease Mouse [117] human IL-1F7 splice variants (IL-1F7a-e) have been Neuropsychiatric disorders described [35-39] whereas no murine homologue of IL- Depression Rat [133] 1F7 has yet been found. Of these, IL-1F7b (also known Human [136,137,139] as IL-1H, IL-1H4 and IL-1RP1) matured by caspase-1 is Schizophrenia Human [134,135] capable of binding IL-18Ra [37,40]. Yet, the IL-1F7/IL- Other central actions 18Ra complex failed to recruit IL-8Rb and no direct Excitotoxic damage agonistic nor antagonistic activity of IL-1F7b for IL-18R Ataxia Mouse [53] was described [37,40]. Neurodegeneration Mouse [150] IL-18 signaling Glioma Rat [156,157] Canonical IL-18 action occurs via recruitment of the Mouse [152-155] adaptor myeloid differentiation factor (MyD88). This event allows activation of the IL-1R-associated kinase to have a modest synergistic action with IL-18. To this (IRAK)/tumor necrosis factor receptor-associated fac- date this isoform has not been reported in the CNS. tor 6 (TRAF6) pathway leading to nuclear transloca- The IL-18 receptor (IL-18R) belongs to the interleukin tion of the nuclear factor kappa beta (NF-B) and 1 receptor/Toll like receptor superfamily. It is comprised subsequent modulation of gene transcription of two subunits, IL-18Ra (also known as IL-1Rrp1, IL- [4,5,41,42] (Fig 1). 18R1 or IL-1R5) and IL-18Rb (also termed IL-18RacP, IL-18 has also been reported to signal via the activa- IL-18RII or IL-1R7) both with three extracellular tion of the transcription factor tyk-2 [43], STAT3 [44] Alboni et al. Journal of Neuroinflammation 2010, 7:9 Page 3 of 12 http://www.jneuroinflammation.com/content/7/1/9 and NFATc4 [45]. In addition, a role for mitogen-acti- prior application of c-jun-n-terminal kinase (JNK) path- vated protein kinases (MAPK) (i.e., extracellular signal- way, cyclooxygenase-2 (COX-2) and inducible nitric regulated kinase, ERK1/2 and p38), and phosphatidyli- oxide synthase (iNOS) inhibitors, and a role for p38 nositol-3 kinase (Pi3K) in IL-18 signalling has been sug- MAPK was also suggested [48,49]. Moreover, human gested [4,44-46]. neuron-like differentiated SH-SY5Y neuroblastomas While these data on peripheral cells were consolidated exhibited an IL-18-dependent increase in the levels of over a decade of work with the immune system, knowl- several kinases including p35, Cdk5, GSK-3beta, and edge of the IL-18-dependent signaling in the CNS is Ser15-phosphorylated p53 [50]. only beginning to emerge. Activation of the IL-18R IL-18 system in the CNS increased NF-B phosphorylation and induced hypertro- IL-18 transcript was demonstrated by RT-PCR in a vari- phy in astrocytes [47]. In the rat dentate gyrus, the func- ety of brain regions including the hippocampus, the tional effects of IL-18 were significantly attenuated by hypothalamus and the cerebral cortex [51,52]. In in vivo Figure 1 The IL-18 system. Active IL-18 is produced and secreted after proteolitic cleavage of the biological inactive precursor Pro-IL-18 by caspase-1. IL-18 action can be regulated by the IL-18 binding protein (IL18-BP) that binds IL-18 with high affinity and inhibits its function. Free IL-18 binds to a specific heterodimeric cell surface receptor, a member of the IL-1 receptor/Toll like receptor superfamily comprised of two subunits, IL-18Ra (here referred to as IL-18RaI) and IL-18Rb, both with three extracellular Ig-like domains and one intracellular portion containing the Toll/IL-1R domain (TIR). Interaction of IL-18 with the IL-18Ra stabilizes its interaction with IL-18Rb and with the adaptor protein MyD88 via the TIR domain. This initiates signal transduction by recruitment of the IL-1 receptor activating kinase (IRAK). IRAK autophosphorylates and dissociates from the receptor complex subsequently interacting with the TNFR-associated factor-6 (TRAF6) eventually leading to nuclear translocation of the nuclear factor B (NF-B). Engagement of the IL-18R complex can also activate STAT3 and the mitogen-activated protein kinase (MAPK) p38, JNK and ERK. One truncated variant of IL-18Ra (IL-18RaII) lacking the intracellular TIR domain, and one soluble isoform of the IL-18Rb (sIL-18Rb) were demonstrated in vivo in the mouse brain and in the rat and human brain, respectively. These isoforms originating from differential splicing are proposed to be decoy receptors and possible negative regulators of IL-18 fuction. IL-1F7 is another proposed regulator of IL-18 action (see text for details). Alboni et al. Journal of Neuroinflammation 2010, 7:9 Page 4 of 12 http://www.jneuroinflammation.com/content/7/1/9 studies, IL-18 protein was demonstrated in the pituitary It was demonstrated that central intracerebroventricular gland, ependymal cells, the neurons of the medial habe- (i.c.v.) injection of IL-18 in rabbits and rats increased non- nula (where its synthesis was elevated by stress), in Pur- rapid eye movement sleep as well as brain temperature kinje cells, and in astrocytes in the cerebellum [53-57]. [72]. The lethargic effects of IL-18 were also observed fol- In addition, it was demonstrated in vitro that microglia lowing intraperitoneal injection of IL-18, whereas, unlike and astrocytes can produce IL-18 [58-61] and its level IL-1b, peripheral administration did not induce fever can be up-regulated following LPS stimulation [62] or [72,73]. Instead, pre-treatment with IL-18 reduced the treatment with INF-g [63]. pyrogenic effects of IL-1 suggesting the possibility of an In the CNS, Northern blot analysis failed to detect antagonizing effect of these cytokines on fever [73]. thepresenceofIL-Ra [64] and IL-Rb [65] soon after Work on IL-18 null, and on IL-18BP overexpressing their cloning. The first evidence that IL-18R compo- mice indicated that IL-18 is anorexigenic and can mod- nents are expressed in brain tissue was obtained by ulate feeding, but also energy homeostasis, influencing Wheeler and colleagues [52] which reported the con- obesity and insulin resistance [10,11]. The mechanisms stitutive expression of IL-18Ra, IL-18Rb in the rat through which IL-18 exerts these effects are largely hypothalamus by RT-PCR. Subsequently, the mRNA unknown but central action was proposed following the expression of IL-18Ra, IL-18Rb and the soluble form observation that i.c.v. injections of exogenous IL-18 of the IL-18Rb were detected in the hypothalamus, induces sleep [72] and anorexia [11]. The recent demon- hippocampus, striatum and cortex and in cultured stration that IL-18 functional and regulatory subunits of astrocytes, microglia and neurons [28]. More recently the IL-18R are expressed in several brain regions includ- in vivo analysis showed that IL-18Ra mRNA and pro- ing the hippocampus, the hypothalamus and the cortex tein are constitutively expresseed in neurons through- provided a molecular and cellular basis for the central out the brain [26,53,60,66]. Similar neuronal action of IL-18 in modulating these functions [26]. localization and distribution was found for IL-18Rb Evidence for the role of IL-18 as modulator of neuro- (Alboni et al., unpublished data). At the same time it nal functions includes studies on the hippocampal sys- was demonstrated that the truncated decoy form of tem, a structure that plays a major role in memory and the IL-18Ra was expressed in neuronal cells with a in cognition. For instance, IL-18 reduces long term pattern similar to that of its active counterpart [26]. potentiation (LTP) in the rat dentate gyrus, possibly Overall, IL-18R subunits had broad distribution across through the involvement of metabotropic glutamate the brain with the highest level in the hypothalamus, receptors [48,49,74,75]. In particular, IL-18 had no effect hippocampus and amygdala. Finally, both IL-18 and on baseline synaptic transmission or paired pulse IL-18R subunits are inducible and their CNS levels can depression, but significantly depressed the amplitude of be regulated. For instance, in the mouse hippocampus NMDA receptor-mediated field excitatory post synaptic the levels of IL-18 and IL-18Ra increased after kainic potentials [75] providing evidence of a direct neuromo- acid (KA)-induced excitotoxicity, [60] whereas dulatory role for IL-18 in synaptic plasticity. It is possi- hypoxic-ischemic brain injurymarkedlyincreased IL- ble that IL-18 may act directly on the neurons of the 18 expression in mouse microglia [67]. In addition dentate gyrus, moreover, its action may be regulated by nerve injury induced IL-18 upregulation in rat spinal the relative level of IL-18Ra type I and type II, both cord microglia possibly via p38 activation [47]. highly expressed in these cells [26]. Work on CA1 pyra- IL-18BP has been investigated and demonstrated in midal neurons of mouse hippocampal slices demon- rodent brains, mixed glia and microglia by only one strated that IL-18 stimulated synaptically released group using RT-PCR. Its distribution and action in the glutamate and enhanced postsynaptic AMPA receptor CNS remain to be investigated [52,68]. responses, thereby facilitating basal hippocampal synap- Information on central IL-1F7 is also limited to one tic transmission without affecting LTP [76]. study that demonstrated its presence in the human Recently an ex vivo study found that LPS-induced IL- brain [37]. Investigating IL-1F7 in the CNS is also ham- 18 elevation in the brain was unable to affect LTP in pered by the fact that a mouse homologue has not been the CA1 hippocampal subregion [77]. However, when identified. comparing wild-type and IL-18 KO mice, the same Behavior study demonstrated that IL-18 regulates fear memory The similarities between the IL-1 and the IL-18 systems and spatial learning. In particular, assessment of spatial suggested the possibility that like IL-1b,IL-18 maybe learning and memory with the water maze test showed one mediator of the behavior symptoms of sickness. that compared to wild-type mice IL-18 KO mice exhibit These include fever, lethargy, hypophagia and cognitive prolonged acquisition latency and that this phenotype alterations [69-71]. was rescued by i.c.v. injection of IL-18. Alboni et al. Journal of Neuroinflammation 2010, 7:9 Page 5 of 12 http://www.jneuroinflammation.com/content/7/1/9 Stress and the hypothalamic-pituitary-adrenal axis binding of IL-18 occurs in several neuroinflammatory IL-18 occupies a peculiar role in stress response both associated pathological conditions including microbial centrally and peripherally. This subject was recently infections, focal cerebral ischemia, Wallerian degenera- extensively reviewed and we briefly refer to it here only tion and hypoxic-ischemic, hyperoxic and traumatic for those aspects relevant to understanding of the cen- brain injuries (e.g., stroke). Further evidence comes from tral actions of this cytokine [78]. recent papers reporting an activation of IL-18 in the In response to restraint stress, IL-18 null mice showed brain of mice that underwent thromboembolic stroke a markedly reduced morphological microglial activation [83] or an increase of IL-18 levels after hypoxia-ischemia in the thalamus, hypothalamus, hippocampus, substantia in the juvenile hippocampus of mice [84]. nigra and central gray area [62]. In addition, IL-18 During CNS inflammation, the IL-18 system may have expression was elevated by restraint stress in the neu- an important role in the activation and response of rons of the medial habenula [56]. Since the habenula is microglia and possibly infiltrating cells. As mentioned a potential site for the interaction of neuro-endocrine above, microglia cells can synthesize and respond to IL- and immune functions, the possibility exists that IL-18 18 [20,59-61]. IL-18 KO mice had impaired microglia 2+- might mediate the communication between the CNS activation with reduced expression of Ca binding pro- and the periphery. Indeed, there is a general agreement tein regulating phagocytic functions that resulted in that IL-18 may regulate hypothalamic-pituitary axis reduced clearance of neurovirulent influenza A virus activity, possibly mediating the stress response of the [85]. In the absence of infection IL-18 deficient mice adrenal gland [20,78,79]. In this respect, stress has been also showed diminished stress-induced morphological shown to induce transient IL-18 mRNA elevation in rat microglial hypertrophy [62]. pituitary cells where increase of the IL-18 mRNA level Interestingly, IL-1b is upregulated within 4 h of focal was observed also after adrenalectomy [57]. ischemia in rat brain, but IL-18 is upregulated much IL-18 is also produced in the neurohypophysis [20] as later, at time points associated with infiltration of per- well as in the adenohypophysis where in situ hybridiza- ipheral immune cells, thus suggesting different roles for tion combined with immunohistochemistry demon- these interleukins in the regulation of glial functions strated its expression in corticotrope cells [57]. In [86]. In this respect, it was shown that mice infected addition, bovine somatotropes have been shown to pro- with Japanese Encephalitis produce IL-18 and IL-1b duce IL-18 and IL-18Ra was co-localized with IL-18, or from microglia and astroglia [59]. Both interleukins are growth hormone, suggesting the possibility that IL-18 capable of inducing pro-inflammatory cytokines and acts on somatotropes through the autocrine pathway chemokines from human microglia and astroglia, [80]. However, IL-18 seems to also act at the hypothala- although IL-18 seems to be more potent than IL-1b. mic level. Indeed, the application of IL-18 in rat In the spinal cord, IL-18 seems to play a role in the hypothalamic explants decreases basal and KCl-stimu- innate inflammatory response. Indeed, moderate cervical lated corticotropin-releasing hormones (CRH), as well as contusive spinal cord injury induced processing of IL-18 CRH gene expression [81]. In particular, the cytokine in neurons of the rat spinal cord [87]. In addition, nerve did not modify basal PGE2 production but abolished injury induced a striking increase in IL-18 and IL-18R production stimulated by IL-1b demonstrating that IL- expression in the dorsal horn, and IL-18 and IL-18R 18 possesses a profile of in vitro neuroendocrine activ- were upregulated in hyperactive microglia and astro- ities opposed to, and even antagonizing, those of IL-1b. cytes, respectively [47,88]. Intrathecal injection of IL-18 Recently, IL-18 was localized in the marginal cell layer induced behavioral, morphological, and biochemical of thebovineand porcineRathke ’spouch,thatis changes similar to those observed after nerve injury assumed to embody a stem/progenitor cell compartment [47], suggesting that IL-18-mediated microglia/astrocyte of the postnatal pituitary gland [54,55]. Interestingly, sti- interactions in the spinal cord have a substantial role in mulation of a cloned anterior pituitary-derived cell line the generation of tactile allodynia. (from the bovine anterior pituitary gland) with IL-18 Autoimmune neurodegenerative disease increased expression of mRNAs of a different cytokine A pivotal role for IL-18, in the pathogenesis of autoim- suggesting the possibility that IL-18 may modulate not mune neurodegenerative disease has been proposed. only the immuno-endocrine function of the pituitary High levels of IL-18 mRNA were found in the brain and cells but also their development [55]. the spinal cord of rats with experimental autoimmune Microglia and neuroinflammation encephalomyelitis (EAE), an animal model of multiple Functional maturation and activation of IL-18 can occur sclerosis (MS) [89,90]. Elevated IL-18 transcript was in the brain under inflammatory conditions. Indeed, as found at the onset and throughout the course of the dis- extensively reviewed by Felderhoff-Mueser and collea- ease. A different study showed that IL-18 increases gues [82], experimental and clinical studies suggest that severity of EAE [91]. Moreover, it has been Alboni et al. Journal of Neuroinflammation 2010, 7:9 Page 6 of 12 http://www.jneuroinflammation.com/content/7/1/9 demonstrated that anti-IL-18 antibodies or targeted tau phosphorylation as a part of the amyloid-associated overexpression of IL-18BP in the CNS had preventive inflammatory reaction. Additionally, IL-18 can enhance effects on the induction of EAE[90,92]. These observa- protein levels of Cdk5/p35 and GSK-3b kinases, tau tionssuggested arolefor IL-18inMS, IL-18KOmice phosphorylation and cell cycle activators in neuron- were susceptible to EAE, whereas IL-18Ra KO mice or like differentiated human SH-SY5Y neuroblastoma IL-18 KO mice treated with anti-IL-18Ra antibodies cells [50]. Thus, on a pathway leading to AD, IL-18 were not [93]. Thus, alternative IL-18Ra ligands with may have an impact on the hyperphosphorylation of encephalitogenic properties may exist [93]. In EAE-sus- tau but also on cell cycle related mechanisms. In the ceptible Dark Agouti rats, the basal and post-immuniza- plasma, the levels of IL-18 were significantly elevated tion (day 5, 7 and 12) levels of IL-18Ra in lymph node in patients with AD, vascular dementia, and mild cog- cells were significantly higher than in the EAE-resistant nitive impairment compared to the control group Piebald Virol Glaxo rats [94]. [107,108]. Interestingly, IL-18 levels were higher in In human, serum and cerebrospinal fluid levels of IL- AD-mild patients, were slightly lower in AD-moderate 18 are elevated in patients with MS [95-98] and IL-18 patients, whereas no significant difference was positive cells have been detected in demyelinating brain observed between AD-severe patients and non-demen- lesions from MS patients [99]. ted age-matched subjects [109], suggesting a gradual The pathological role of IL-18 in EAE is also sup- decline of immune responsiveness in AD. Although ported by the up-regulation of caspase-1 (required to other studies showed no differences in circulating IL- convert IL-18 precursor protein into its biologically 18 levels measured between AD patients (both mild active mature form) mRNA in the spinal cord of rats cognitive impairment and severe AD patients) and with EAE [89], and decreased disease severity in cas- controls [106,110,111], a significant increased produc- pase-1 KO mice [100]. Finally, peripheral blood mono- tion of IL-18 was obtained from stimulated blood nuclear cells from patients with MS have elevated mononuclear cells or macrophages of peripheral blood caspase-1 mRNA levels [95,101]. of AD patients [111,112]. Furthermore, a significant In addition to a role in MS there is also evidence to correlation between IL-18 peripheral production and support a function for IL-18 in the onset and progres- cognitive decline was observed in AD patients. Overall, sion of autoimmune CNS disease. For instance, infection these data indicate that IL-18-related inflammatory of microglia lines with Theiler’s murine encephalomyeli- pathways, are exacerbated in the peripheral blood of tis virus (which causes the development of a chronic- AD patients, and that this cytokine may indeed partici- progressive autoimmune demyelinating disease) signifi- pate in pathogenic processes leading to dementia. cantly upregulates the expression of cytokines involved Genetic association studies reported that two func- in innate immunity, including IL-18 [102]. tional polymorphisms (137G/C and -607C/A) in IL-18 Neurodegenerative disorders promoter may increase the risk of developing sporadic Alzheimer’s Disease (AD) is the most common type of late onset AD in the Han Chinese population [113]. An human dementia. It is characterized clinically by a gra- association between 137G/C and -607C/A polymorph- dual but progressive decline in memory and pathologi- isms and the susceptibility/clinical outcome of AD was cally by neuritic plaques, neuro-fibrillary tangles, and also suggested in an Italian population [114], although thelossofsynapsesand neurons[103].Inflammatory these correlations remain controversial. Indeed, in processes were proposed to contribute to neurodegen- another Italian population a lack of association between eration in AD and extensive studies indicated that IL-1 IL-18 gene promoter polymorphisms and onset of AD is a pivotal cytokine in mediating direct neuronal loss was reported, indicating that the association of IL-18 and sustaining microglia activation leading to further promoter polymorphisms with AD is not so strong, AD cellular damage in AD [104]. Microglia-derived inflam- being a multifactorial disease [115]. Importantly, IL-18 matory cytokines can initiate nerve cell degeneration promoter remains poorly characterized. and enhance the plaque production typically found in Finally, it has been hypothesized that increased pro- AD [105]. Increasing evidence indicates that IL-18 may duction of IL-18 in the brain may lead to motor and have aroleinthisscenario. cognitive dysfunctions, leading to the development of For instance, the levels of IL-18 transcript and pro- HIV-associated dementia. Thus, IL-18 concentrations in tein were increased in the frontal lobe of AD patients HIV-infected persons are likely to play an important compared to healthy age-matched controls. In these role in the development and progression of the infection brains IL-18 was found in microglia, astrocytes and in toward AIDS and associated clinical conditions [116]. neurons that co-localize with amyloid-b-plaques and In Parkinsonism, there is evidence of chronic inflam- with tau [106], suggesting that amyloid-b may induce mation in the substantia nigra and striatum. Activated the synthesis of IL-18, and IL-18 kinases involved in microglia, producing proinflammatory cytokines, Alboni et al. Journal of Neuroinflammation 2010, 7:9 Page 7 of 12 http://www.jneuroinflammation.com/content/7/1/9 surround the degenerating dopaminergic neurons and The significance of these correlations with respect to may contribute to dopaminergic neuron loss. In an the role of the IL-18 system to neurophsychiatric disease experimental model of Parkinson’s disease that utilized pathophysiology or manifestation remains to be deter- injection of the dopaminergic specific neurotoxin MPTP mined. Caution should be taken particularly since per- the number of activated microglial cells in the substantia ipheral IL-18 can be subject to neurogenic stimulation nigra pars compacta of IL-18 KO mice was reduced or stress [20,78,141-143]. It is thus difficult to determine compared to wild-type [117], indicating the possibility whether IL-18 elevation contributes to these pathologies that IL-18 may participate in microglial activation and or whether it is a consequence of the disorders. Indeed, dopaminergic neurodegeneration. Kokai and colleagues suggest that IL-18 can be consid- Neuropsychiatric disorders ered a psychologic stress-associated marker since they Several groups found that depressed and schizophrenic demonstrated that exposure to stressful events (i.e., patients have high circulating levels of pro-inflammatory panic attack in human, restraint stress in mice), the cytokines [118-123]. Others reported that psychotic epi- most important precipitating factor in depression, sodes often occur in conditions characterized by ele- induces a prompt increase in the level of circulating IL- vated levels of pro-inflammatory cytokines, for instance 18 [136]. during inflammation or in patients suffering from Regardless, elevated IL-18 levels have the potential to immune diseases [124-127]. contribute to several of the symptoms associated with Other studies suggested that the correlation between neuropsychiatric disorders. For instance, like other inflammatory markers and psychiatric disorders may be pro-inflammatory cytokines, IL-18 may participate in more that merely associative, with inflammation actually the control of the activity of the HPA axis reported to contributing to mental disorders. Improvement in psy- be dysregulated in depression [78,144-146]. IL-18 may chiatric symptoms has been recently reported in patients antagonize glucocorticoid signalling via activation of treated with anti-inflammatory drugs for other indica- NF-B and p38 MAPK possibly disrupting glucocorti- tions [128] and functional allelic variants of genes codi- coid-dependent negative feedback on the HPA axis fying for pro-inflammatory cytokines were associated [147-149]. Finally, IL-18 can affect other hallmarks of with reduced responsiveness to antidepressant therapy depression impairing learning and memory by acting [129,130]. It was also recently demonstrated that IL-6 as an attenuator of long-term potentiation, and indu- plays a pivotal role in the pharmacological ketamine cing lethargy and loss of appetite [11,72,74]. model of schizophrenia by modulating the NADPH-oxi- Other central actions of IL-18 dase increase of superoxide affecting parvalbumin inter- Three groups investigated the action of IL-18 in neurons [131]. An interesting line of research is rodents following administration of KA, an agonist of exploring the possibility that these actions may be devel- the kainate receptors inducing seizure, cerebellar ataxia opmental, with cytokines influencing early-life program- and exitotoxic mediated neuronal loss [53,60,150]. In ming of brain functions [132]. mouse hippocampus KA elevated IL-18 and IL-18R At present evidence linking IL-18 and psychiatric dis- expression on microglial cells progressively 3 days after orders are primarily associative. IL-18 mRNA expression treatment [60]. The authors hypothesized that similar is elevated in subordinate rat models with depression to what was observed peripherally in studies of the with respect to dominant rats [133]. A significant eleva- immune system, IL-18 may contribute to cellular tion of circulating plasma levels of IL-18 has been damage. This hypothesis was partially supported by reported in subjects affected by schizophrenia and were another group showing that the KA-induced hippo- normalized by pharmacological treatment with risperi- campal neurodegeneration was shown to be more done, a dopamine antagonist with antipsychotic activity severe in IL-18 KO mice compared to wild-type litter- [134,135]. Normalization was demonstrated also within mates [150]. Yet, in recombinant mice with the same 6 month of treatment with the antipsychotic clozepine pre-treatment, IL-18 aggravated both the clinical and [134] although the possibility that these effects could be pathological signs of neurodegeneration in a dose- due to clozepine’s effects on leukocyte numbers cannot dependent manner. be excluded. The serum levels of IL-18 were also signifi- In the cerebellum, where KA was demonstrate to cantly higher in moderate-severe depression patients, induce ataxia partially via elevation of IL-1b,exogen- further suggesting that the pathophysiology of depres- ous IL-18 was protective and played a positive role in sion is associated with an inflammatory response invol- the recovery from kainate-induced ataxia [53]. Consis- ving IL-18 [136,137]. Coincidentally, IL-18 is also tently, IL-18 KO and IL-18Ra KO mice show delay in elevated after stroke, a condition followed by emotional recovery from kainate-induced ataxia. The antagoniz- disorders [138-140]. ing effects of IL-18 and IL-1b also observed in the per- ipheral effects of IL-1b on fever, [73] are intriguing Alboni et al. Journal of Neuroinflammation 2010, 7:9 Page 8 of 12 http://www.jneuroinflammation.com/content/7/1/9 particularly since these cytokines share many similari- physiological conditions IL-18 is not easily found in the ties including their signalling. Preliminary observations CNS. Interestingly, the genes encoding for IL-18 and its suggest that these effects may be explained by IL-1b receptors are subject to differential promoter usage and and IL-18 targeting different cells or activating distinct their transcription to differential splicing indicating that signalling [53]. these molecules have the potential of being produced in Some groups have investigated the possibility that a tissue/cell specific way in response to different stimuli IL-18 could be used against glioma, a common and [26,78]. It will be important to determine which physio- highly aggressive type of brain tumor with poor long- logical or pathological conditions modulate these term prognosis [151]. In this respect, IL-18 was inves- molecules. tigated alone or in synergism with IL-12 or Fas, for its Also unexplored is the investigation of the possible ability to induce INFg and NO inducing a cytotoxic role of IL-18 in CNS development suggested by work response against glioma cells [152]. Systemic or intra- on microglial cultures from newborn mice and brain cerebral administration of IL-18 inhibited the growth homogenates where IL-18 was preferentially expressed of inoculated glioma cells and prolonged the survival during early postnatal stages and subsequently downre- of mice with subcutaneous or brain tumors, respec- gulated, being virtually absent in the brains of adult tively [153]. Antitumor activity against glioma was also mice [61]. Additionally, the activated microglia-derived found in mice treated with IL-18 and IL-12 via Semliki cytokines, including IL-18, may either inhibit the neu- Forest virus [154,155] or with a combination of IL-18 ronal differentiation or induce neuronal cell death in and Fas [156]. Finally, encouraging data were also the rat neural progenitor cell culture, which are cells reported by overexpressing IL-18 in mesenchymal cells capable of giving rise to various neuronal and glial cell of rats [157]. populations in the developing and adult CNS [160]. Finally, in adult rodents IL-18 is produced in ependy- Conclusions mal cells [56] considered a primary source of neural Investigation on the presence of IL-18 in the CNS began stem cells in response to injury [161]. The possible soon after its discovery as a co-stimulator of INF-g pro- role of IL-18 in their differentiation has also not been duction in the immune system [1,20,158,159]. Initially investigated. IL-18 was investigated for its similarities with IL-1b as a Work on existing IL-18 and IL-18R null mice as well possible mediator of sickness behavior and of local as the development of new experimental models includ- inflammatory reactions associated with neuronal ing CNS specific null or overexpressor mice and the damage. These actions were both demonstrated and IL- identification of suitable in vitro systems will determine 18 was shown to promote loss of appetite, sleep and the specificity of the central effects of IL-18 in health inhibition of LTP, as well as to be produced by and and disease. active in microglial cells, and to possibly contribute to neurodegenerative diseases. Acknowledgements Yet, two observations suggest that IL-18 has a central Supported by The Ellison Medical Foundation and NIH HL088083 and grant- role and function that may be unique and distinct from in-aid for Science Research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (20500359). those of IL-1b or other cytokines. The first being the recognition that Il-18 and Il-1b, when their combined Author details action was tested, may have antagonizing effects such as Department of Biomedical Sciences, University of Modena and Reggio Emilia, Italy. Department of Environmental Sciences, University of Tuscia, those occurring in fever and in kainate-induced cerebel- Viterbo, Italy. Department of Physiology, Nippon Medical School, 1-1-5 lar ataxia. The second was the finding that IL-18R is 4 Sendagi Bunkyo-ku, Tokyo 113-8602, Japan. Molecular and Integrative constitutively and broadly expressed in neuronal cells Neurosciences Department, The Scripps Research Institute, CA, USA. throughout the rodent brain. This finding opened the Authors’ contributions possibility of a direct action of IL-18 on neuronal func- SA and DC wrote the initial draft of the manuscript, SS and BC contributed tions particularly in all of the CNS disorders showed to to its final version. All authors read and approved the final manuscript. be correlated to elevated cytokine levels. Competing interests Thus, the investigation of the central action of IL-18 The authors declare that they have no competing interests. may be considered in its infancy and the significance of Received: 10 December 2009 the neuronal IL-18R complex and of its isoforms Accepted: 29 January 2010 Published: 29 January 2010 remains to be determined. 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Published: Jan 29, 2010

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