Self-regulation of the inflammatory response by peroxisome proliferator-activated receptors

Self-regulation of the inflammatory response by peroxisome proliferator-activated receptors The peroxisome proliferator-activated receptor (PPAR) family includes three transcription factors: PPARα, PPARβ/δ, and PPARγ. PPAR are nuclear receptors activated by oxidised and nitrated fatty acid derivatives as well as by cyclopentenone prostaglandins (PGA and 15d-PGJ ) during the inflammatory response. This results in the modulation of the pro-inflam- 2 2 matory response, preventing it from being excessively activated. Other activators of these receptors are nonsteroidal anti- inflammatory drug (NSAID) and fatty acids, especially polyunsaturated fatty acid (PUFA) (arachidonic acid, ALA, EPA, and DHA). The main function of PPAR during the inflammatory reaction is to promote the inactivation of NF-κB. Possible mechanisms of inactivation include direct binding and thus inactivation of p65 NF-κB or ubiquitination leading to proteolytic degradation of p65 NF-κB. PPAR also exert indirect effects on NF-κB. They promote the expression of antioxidant enzymes, such as catalase, superoxide dismutase, or heme oxygenase-1, resulting in a reduction in the concentration of reactive oxygen species (ROS), i.e., secondary transmitters in inflammatory reactions. PPAR also cause an increase in the expression of IκBα, SIRT1, and PTEN, which interferes with the activation and function of NF-κB in inflammatory reactions. Keywords Inflammation · Peroxisome proliferator-activated receptor · Cyclooxygenase-2 · NF-κB · Signaling pathway AbbreviationsEPA Eicosapentaenoic acid 5(S)-HETE (S)-hydroxyeicosatetraenoic acidEET Epoxyeicosatrienoic acid 12,14 15d-PGJ 15-Deoxy-Δ-prostaglandin J ERK Extracellular signal-regulated kinase 2 2 AF1 Activation function 1γ-LA γ-Linolenic acid AMPK AMP-activated protein kinaseHO-1 Heme oxygenase-1 ARE Antioxidant response element H O Hydrogen peroxide 2 2 AA Arachidonic acid IKKβ IκB kinase β subunit CO Carbon monoxideLBD Ligand-binding domain JNK c-Jun N-terminal kinaseLOX Lipoxygenases COX-2 Cyclooxygenase-2 MAPK Mitogen-activated protein kinase CYP Cytochromes P450NO Nitric oxide DHA Docosahexaenoic acid NSAID N onsteroidal anti-inflammatory drug EP Prostaglandin E receptors NF-κB Nuclear factor κB NCoR Nuclear receptor corepressor PPAR Peroxisome proliferator-activated receptors PPRE PPAR response element Responsible Editor: John Di Battista. ONOO Peroxynitrite * Jan Korbecki PTEN Phosphatase and tensin homolog jan.korbecki@onet.eu PI3K Phosphoinositide 3-kinase PUFA Polyunsaturated fatty acid Department of Molecular Biology, School of Medicine in Katowice, Medical University of Silesia, Medyków 18 PG Prostaglandin Str., 40-752 Katowice, Poland PGE Prostaglandin E 2 2 Department of Biochemistry and Molecular Biology, Faculty PKA Protein kinase A of Health Sciences, University of Bielsko-Biala, Willowa 2 ROS Reactive oxygen species Str., 43-309 Bielsko-Biała, Poland Vol.:(0123456789) 1 3 444 J. Korbecki et al. SMRT Silencing mediator of retinoid and thyroid hormone receptors SIRT1 Sirtuin 1 SOD Superoxide dismutase •− O Superoxide radical Background The prostaglandin synthesis pathway is an important ele- ment of inflammatory responses. The pathway is induced by cytokines [1, 2], LPS [3, 4], or xenobiotics, including metal compounds [5–7] and fluoride [8 –10]. At the begin- ning of the pathway, PLA releases arachidonic acid (AA) from the cell membranes [11]. Next, AA is enzymatically converted, at first by lipoxygenases (LOX) or cytochromes P450 (CYP), or by the best known COX, into a large group of compounds called eicosanoids [12, 13]. Like any bio- chemical response, increasing synthesis of various eicosa- noids in the COX pathway is subject to strict regulation. There are numerous regulatory mechanisms in this pathway which cause both an increase and decrease in synthesis and in activity of particular eicosanoids [14, 15]. Regulation relating to modification of activity of prostaglandins and Fig. 1 Self-regulation of NF-κB activity and COX-2 expression. In thromboxanes receptors is an example of the above [16]. inflammatory reactions, NF-κB is activated and, partly as a result of The activity of COX-2 is also enhanced by the product of this, an increase in expression and activity of enzymes of the pros- taglandin synthesis pathway takes place. Released AA is converted its pathway, i.e., by PGE in an autocrine manner [17, 18]. into PGD or PGE . In inflammatory reactions, the production and 2 2 Activation of prostaglandin E receptors (EPs) causes an concentration of NO also increase. With time, all of the compounds increase in the level of cAMP and activation of the cAMP react together or undergo further non-enzymatic transformation. AA response element-binding protein (CREB) which leads in reaction with NO is subject to nitration. PGD and PGE convert 2 2 to 15d-PGJ and PG A respectively. Compounds with anti-inflamma- to increased COX-2 expression [19, 20]. The increase in 2 2, tory properties are formed, which activate PPARα and PPARγ. Acti- COX-2 expression may also depend on the activation of vated PPARα and PPARγ inhibit the activity of NF-κB, which leads mitogen-activated protein kinase (MAPK) cascades [21] to inhibition of inflammatory reactions by the products of these reac- and phosphoinositide 3-kinase (PI3K) [18, 22]. Apart from tions the effect of individual products of the COX pathway, LOX products also increase COX-2 expression [23]. Despite this, AA, regardless of COX, LOX, and CYP activity, is itself capable of causing oxidative stress and, in particular, gene for PPARα causes an increase in the intensity of inflam- of activating NADPH oxidase [24, 25]. This results in an matory responses to IL-1 or LPS [28, 30]. increase in the level of reactive oxygen species (ROS) and activation of c-Jun N-terminal kinase (JNK) MAPK and NF-κB, which increases COX-2 expression. Ligands of peroxisome proliferator‑activated Nonetheless, self-regulation of the COX pathway does receptors not consist solely of positive feedback. The pathway also involves mechanisms which inhibit a too strong inflamma- PPAR are nuclear receptors and transcription factors. tory response. In the center of the COX auto-inhibition path- They include PPARα, PPARβ/δ, and PPARγ. These tran- way, peroxisome proliferator-activated receptors (PPAR) are scription factors control genes responsible for the oxida- found (Fig. 1). Activation of inflammatory responses by LPS tion of lipids [31, 32]. PPARα is a transcription factor or other pro-inflammatory particles causes an increase in the that increases gene expression of acyl-CoA oxidase and expression of PPARα and a decrease in the expression of carnitine palmitoyltransferase I, i.e., enzymes involved PPARγ [26–29]. Blocking the mechanism with a knock-out 1 3 Self-regulation of the inflammatory response by peroxisome proliferator -activated receptors 445 in β-oxidation. PPARγ increases adiponectin concentra-of IC equal to 1.2 ± 0.2 μM and 1.6 ± 0.2 μM for PPARα tion and expression of transporters GLUT1 and GLUT4. and PPARγ, respectively [33, 41]. Eicosapentaenoic acid PPARβ/δ increases the expression of pyruvate dehydro- (EPA) and docosahexaenoic acid (DHA) have similar genase kinase-4 and carnitine palmitoyltransferase 1A, properties. However, at a much higher concentration, which increases the intensity of fatty acid oxidation. 100 μM, inhibition of PPARα activity by AA, EPA, and All of PPAR have a similar structure—ligand-binding DHA takes place [38]. domain (LBD). LBD is in the shape of the letter Y and is Hydrophilic residue is also present in LBD, which ena- of polar character [33–36]. In the first arm, hydrophilic bles activation of PPAR by derivatives of fatty acids aris- amino acid residue can be found, which is responsible for ing from enzymatic and non-enzymatic oxidation [35, 42]. ligand binding. This part also contains helix12, which is Owing to self-regulation of inflammatory responses, AA stabilized during ligand binding and PPAR activation. The metabolites fulfill special roles as activators. An example remaining two arms of the ligand-binding domain consist of the above is the products of the 5-LOX pathway, 5(S)- of hydrophobic amino acid residue with far less hydro- hydroxyeicosatetraenoic acid (5(S)-HETE), and leukot- philic residue. These two parts of LBD are responsible for riene B (LTB ), which also activate PPARα [37, 40, 43]. 4 4 the specificity of ligand binding when activating PPAR. Nonetheless, this effect is less significant compared to the This LBD structure enables the activation of PPAR impact of free AA—fatty acids from which they arise. Other by polar structure ligands, and, in particular, by a fatty important activators of PPAR are 8(S)-HETE and hydroper- acids and derivatives of fatty acids (Table  1). Nonethe- oxyeicosatetraenoic acid (8S-HPETE)—products of murine less, not all fatty acids equally activate PPAR. The arms 8-LOX [37, 40, 44, 45]. Yet, another important activator with hydrophobic residue in LBD stabilize ligand [33]. of PPARγ and PPARβ/δ is the 15-LOX product: 15-HETE Therefore, only fatty acids with 14 and more carbon atoms [46, 47]. Among natural activators of PPARα and PPARγ are capable of activating PPAR [33, 37, 38]. However, are AA metabolites, products of many CYP isoforms with saturated fatty acids with 20 and more carbon atoms do anti-inflammatory properties are also found. They include: not fit in the LBD and thus are not activators of PPAR. 5,6-epoxyeicosatrienoic acid (EET), 8,9-EET, 11,12-EET, Double bonds also play an important role in the structure 14,15-EET, and 20-HETE (with its metabolite 20-COOH- of a fatty acid as a potential ligand. Monounsaturated fatty AA) [13, 48–51]. acids in cis configuration have a favorable conformation to Prostaglandins produced in the COX pathway have better match LBD than saturated fatty acids and fatty acids impact on activating PPARγ. Cyclopentenone prostaglandins in trans configuration of the same length. Fatty acids in activate PPARγ [37, 44, 52]. This group includes prostaglan- trans configuration have similar conformation as unsatu- din (PG)A, PGC, PGJ , Δ -PGJ and the most thoroughly 2 2 2 2, 12,14 rated fatty acids [33]. Long-chain polyunsaturated fatty studied 15-deoxy-Δ-prostaglandin J (15d-PGJ ). All 2 2 acid (PUFA) is also ligands for PPAR [33, 37, 39, 40]. prostaglandins in this group arise from pro-inflammatory For example, AA connects with LBD at a concentration prostaglandins. PGA is formed as a result of non-enzymatic Table 1 Examples of PPAR agonist Agonist PPARα PPARβ/δ PPARγ Bibliography Saturated fatty acids Palmitic acid, stearic acid Palmitic acid, stearic acid – [33, 37] Monounsaturated fatty acids Palmitoleic acid, oleic acid Palmitoleic acid, oleic acid Palmitoleic acid, oleic acid [33] Polyunsaturated fatty acid γ-LA, AA, EPA, DHA γ-LA, AA, EPA, DHA γ-LA, AA, EPA, DHA [33, 37, 40] Arachidonic acid metabolites LTB , 8(S)-HETE, EET, 8(S)-HETE, 15-HETE 8(S)-HETE, 15-HETE, EET, [37, 40, 44, 46–49, 51] 20-COOH-AA20-COOH-AA, PGA , 15d-PGJ Other derivatives of fatty Nitrated derivatives of – Nitrated derivatives of [65, 66] acids unsaturated fatty acids unsaturated fatty acids Synthetic agonist Wy 14,643 Bezafibrate, ETYA Ciprofibrate, clofibrate, [37, 40, 109–111] Ciprofibrate, clofibrate, BRL 49653, NSAID bezafibrate, ETYA (diclofenac, flufenamic acid, flurbiprofen, indo- methacin, NS-398) 12,14 15d-PGJ : 15-deoxy-Δ-prostaglandin J ; AA: arachidonic acid; γ-LA: γ-linolenic acid; DHA: docosahexaenoic acid; EET: epoxyeicosa- 2 2 trienoic acid; EPA: eicosapentaenoic acid; ETYA: 5,8,11,14-eicosatetraynoic acid; HETE: hydroxyeicosatetraenoic acid; L TB : leukotriene B ; 2 4 NSAID: nonsteroidal anti-inflammatory drug; PGA : prostaglandin A 2 2 1 3 446 J. Korbecki et al. dehydration of PGE . Subsequently, PGA may be isomer- anti-inflammatory nature. One of their functions is bind- 2 2 ized to PGB and PGC , whereas PGD may be subject to ing-free thiol (–SH) groups in cysteine [62, 63]. Owing to 2 2 2 12 62 non-enzymatic dehydration and isomerisation to PGJ , Δ - this, they may cause nitroalkylation of Cy s p50 NF-κB PGJ and, finally, to 15d-PGJ . All of the cyclopentenone and Cys p65 NF-κB, which, as a consequence, inactivates 2 2 prostaglandins contain an electrophilic carbon atom in their these transcription factor subunits. A nitrated derivative of cyclopentenone ring [53, 54]. Owing to this, they can be AA replaces heme in COX, which impacts the intensity of subject to Michael addition to free thiol (–SH) groups in inflammatory responses. This results in irreversible inhibi- cysteine. If such residue is present in the catalytic center tion of the enzymes K for COX-1, equal to 1.02 μM, and K i i or in an important domain in the function of a given pro- for COX-2, equal to 1.76 μM [64]. Another anti-inflamma- tein, such enzymes and transcription factors become inac- tory characteristic of nitrated derivatives of fatty acids, in tive. IκB kinase β subunit (IKKβ) and nuclear factor κB very low concentrations, is activation of PPARα and PPARγ (NF-κB) are examples of such proteins [52, 55]. Cysteine [65, 66]. In PPARγ, meanwhile, there are residues of Ar g 285 343 is also present in LBD PPARγ in position 285 (Cy s ), and Glu which stabilize, respectively, the nitrated deriva- which is specifically susceptible to reactions and covalent tives of fatty acids on 10 and 12 carbon [67]. The above- 288 343 15d-PGJ connection (Fig. 2) [40, 54, 56]. As a result of mentioned residues of Ar g and Glu are not conserva- alkylation of this residue, a change in PPARγ conforma- tive and hence do not occur in other PPAR. Owing to such tion takes place and the protein is activated [37, 39, 40, 44]. structure, PPARγ is activated by the nitrated derivatives of The cyclopentenone prostaglandins constitute negative feed- unsaturated fatty acids even at a concentration of 100 nM back to inflammatory responses. During the inflammatory [65, 66]. Meanwhile, concentration of PPARα deprived of responses, an increase in the production of PGE and PGD such residues occurs at a concentration of 300 nM [65]. For 2 2 is observed [57]. With time, in a non-enzymatic way, further higher concentrations of about 4 μM, nitrated derivatives of transformation of the prostaglandins into anti-inflammatory fatty acids, and of AA in particular, unbalance the assembly compounds takes place in PG A and 15d-PGJ respectively. of the NADPH oxidase complex [68]. This causes distur- 2 2, As a consequence, the inflammatory response is reduced by bance in ROS generation and, as a result, suppresses inflam- transformed products of the responses [3, 58]. matory reactions. In the course of inflammatory reactions, an increased synthesis occurs of nitric oxide (NO) and ROS generation, •− among others superoxide radical (O ), and hydrogen per- •− oxide (H O ) [59, 60]. NO may react with O creating per- Activation of peroxisome 2 2 2 − − oxynitrite (ONOO ). Both compounds, NO and ON OO , proliferator‑activated receptors lead to nitration of double bonds in unsaturated fatty acids [42, 61]. As a result, nitrated derivatives of fatty acids are PPARγ is a transcription factor, whose activity is subject formed. These compounds have biological properties of an to regulation by SUMOylation and an assembly of com- plexes with various proteins, especially with nuclear recep- tor corepressor (NCoR) and silencing mediator of retinoid and thyroid hormone receptors (SMRT) [69–73]. Activa- tion of PPARγ with ligand causes changes in SUMOyla- tion of this protein. In particular, a decrease takes place in SUMOylation of L ys PPARγ1 in the domain of activation function 1 (AF1) [74]. This allows LBD to interact with the AF1 domain, whereas SUMOylation of the Lys in LBD PPARγ1 allows for full activation of PPARγ1 by ligand. PPARγ activation also causes suppression of proteolytic degradation of NCoR and dissociation of the complex of PPARγ with NCoR and SMRT [69, 72]. As a result, expres- sion of genes is suppressed by these corepressors, especially of the genes dependent on NF-κB and AP-1, such as PTGS2 and NOS2 [75–77]. A similar mechanism is present in PPARα. The transcrip- tion factor in its inactive form is subject to SUMOylation and it is also in complex with NCoR [78, 79]. The process Fig. 2 15d-PGJ as an agonist of PPARγ. Modeled (as purple) 15d- of SUMOylation is governed by enzymes Ubc9 and PIASy, PGJ in LBD PPARγ. Amino acid residues interacting with this ligand and covalently bound Cy s are shown. PDB:2zk1 [54] which modify the L ys PPARα. Activation of PPARα by 1 3 Self-regulation of the inflammatory response by peroxisome proliferator -activated receptors 447 ligand leads to a decrease in SUMOylation and, as a conse- dysregulation of MuRF2 activity in diabetes has an impact on quence, to release of NCoR. NCoR is a corepressor which the development of cardiomyopathy [90]. connects exclusively to SUMOylated receptors. Dissociation of the complex of PPARα with NCoR leads to activation of both proteins; PPARα increases expression of particular Phosphorylation changing the activity genes and NCoR is a corepressor suppressing the expression of peroxisome proliferator‑activated of other genes, including PTGS2 and NOS2 [77]. receptors Activated PPAR may also be subject to phosphorylation, Changes in the stability of peroxisome which modifies the activity of these nuclear receptors. PPARγ proliferator‑activated receptors as a result is subject to phosphorylation into the N-terminus A/B domain of activation by ligand by such kinases as protein kinase A (PKA) [91], extracel- lular signal-regulated kinase (ERK) MAPK [92–94] or JNK PPAR are transcription factors which are also subject to MAPK [92, 95]. This results in a change of character of the regulation by proteolytic degradation. Nonetheless, dif- PPARγ. As a result of phosphorylation at the N-terminus, ferent PPAR are subject to different mechanisms of this PPARγ ceases to be a transcription factor and begins to physi- regulation. Activating PPARα by ligand causes inhibition cally bind the activated NF-κB. This mechanism may consti- of ubiquitination, which leads to suppression of proteolytic tute regulation of inflammatory responses in which activation degradation of this protein [80]. Ubiquitination of L ys , of the above-mentioned kinases takes place and ligands for 310 388 Lys , and Lys PPARα by muscle ring finger-(MuRF)1 PPARγ are present. results in export from the nucleus of this transcription factor PPARα is also subject to phosphorylation by such kinases and subsequently in proteolytic degradation of PPARα [81]. as PKA [96], p38 MAPK [97] or ERK MAPK [98]. This A similar mechanism occurs in regulation of the activity causes enhanced ligand-dependent activation. Phosphoryla- of PPARβ/δ by ligand. Activation by ligand causes inhibition tion by p38 MAPK can also inhibit the activity of PPARα [99]. of ubiquitination and inhibition of proteolytic degradation of PPARβ/δ [82]. Interaction between various peroxisome Contrary to PPARα and PPARβ/δ, activation of PPARγ by proliferator‑activated receptors ligand leads to ubiquitination and proteolytic degradation of this protein in proteasomes [83, 84]. In adipocytes, drosophila All three PPAR have a similar LBD structure. This ena- seven-in-absentia homolog 2 (Siah2) is responsible for this bles their simultaneous activation by the same ligand, for process [85]. Ubiquitination in this PPARγ mechanism causes example, a given PUFA [33]. This results in interactions changes in the structure of the activation function 2 (AF-2) between different PPAR. As yet, unfortunately, not much domain, and as a consequence, the protein is directed to the research has been done into the interactions between vari- proteolytic degradation pathway [86]. Nonetheless, PPARγ may ous PPAR. also be subject to ubiquitination independently of ligand, which Activation of PPARγ leads to an increase in the expres- causes degradation or increase in the stability of the protein sion of genes dependent on this transcription factor and depending on the place of ubiquitination. Tripartite motif pro- on COX-2 in particular. This is associated with increased tein 23 (TRIM23) catalyzes polyubiquitination, owing to which expression of PPARβ/δ [100]. However, sole activation of PPARγ stability increases [87]. Meanwhile, F-box only protein PPARβ/δ by ligand does not cause changes in COX-2 expres- 9 (FBXO9) [88] or makorin ring finger protein 1 (MKRN1) sion. It only cooperates with the activated PPARγ. Depend- [89] has been identified as specific E3 ligase of PPARγ in ing on the model, activation of PPARβ/δ inhibits [101] or adipocytes, which leads to ubiquitination and proteasome- increases [100] transcription activity of PPARγ. Activation dependent degradation of PPARγ. The regulation mechanism of of PPARβ/δ also increases expression of PPARα, whereas PPARγ expression through proteolytic degradation is important activation of PPARα decreases expression of PPARβ/δ [100]. in adipocyte differentiation, as this transcription factor impacts Thus, simultaneous activation of PPARα and PPARγ leads expression of genes responsible for lipogenesis of adipocytes. to mutual abolishing of activity of both the PPAR through Meanwhile, MuRF2, which is present in cardiomiocytes, causes changes in expression of PPARβ/δ. However, the specific ubiquitination of PPARγ and thus leads to an increase in stabil- tissue expression of various PPAR should not be ignored, as ity of the protein [90]. However, overactivity of MuRF2 causes it may modify the response to the activation of these nuclear polyubiquitination of PPARγ and, as a consequence, proteo- receptors. lytic degradation of the protein. It has been demonstrated that 1 3 448 J. Korbecki et al. Activation of peroxisome Peroxisome proliferator‑activated receptor proliferator‑activated receptor‑γ as a protein with anti‑inflammatory as an inducer of cyclooxygenase‑2 properties: effect on NF‑κB expression Activation of all PPAR, PPARα [4, 118–121], PPARβ/δ Activating PPAR reduces inflammatory reactions. How - [122, 123] and PPARγ [124–127] causes inhibition of ever, when pro-inflammatory factors are absent, activation NF-κB activation (Table 2). Nonetheless, the mechanism of PPARγ induces the expression of COX-2 [100]. In the of anti-inflammatory properties is a very complex one and promoter of gene PTGS2, a PPAR response (PPRE) element takes different forms. is found [102, 103]. Thus, when pro-inflammatory factors PPAR are transcription factors, but they also have are absent, activation of PPARγ causes induction of COX-2 properties which are not associated with the expression of protein expression. Inducers of COX-2 expression, which genes. They are capable of binding different proteins, by are commonly known, as compounds decrease expression which means they inactivate them. It is predominantly the of COX-2 in inflammatory reactions, are PUFA [γ-linolenic binding of PPARα [30, 128], PPARβ/δ [129], or PPARγ acid (γ-LA), AA, EPA, and DHA] [102, 104–106] as well as with p65 NF-κB that is responsible for anti-inflammatory 15d-PGJ [107–109]. Nonsteroidal anti-inflammatory drug properties [94, 130] with p65 NF-κB which reduces the (NSAID) is also agonists for PPARγ [110, 111]. This is why pro-inflammatory response. such compounds as diclofenac, flufenamic acid, flurbiprofen, The direct impact of PPARγ on NF-κB may be associ- indomethacin, or NS-398, despite inhibiting the activity of ated with its enzymatic properties. PPARγ is E3 ubiquitin COX-2, induce expression of that enzyme [107–109, 112]. ligase, which cooperates with E2 UBCH3. PPARγ causes AA  and EPA (both PUFA) are processed into 2- and ubiquitination of the L ys p65 NF-κB, which leads to 3-series prostanoids [113–115], respectively. Prostanoids proteolytic degradation of this NF-κB subunit [131]. The serve a very important biological function, unrelated to intensity of NF-κB degradation is increased by PPARγ inflammatory reactions; they are crucial for proper function- ligand activation. However, it is not only NF-κB that is ing of the kidneys [116] and blood vessels [117]. Therefore, subject to such regulation by PPARγ. It is possible to PUFA must influence the expression and activity of COX-2 reduce the stability of the MUC1-C by PPARγ, which has differently than in inflammatory reactions. In metabolism, anticancer properties [132]. very often, the substrate of a given enzymatic pathway stim- Inactivated PPARβ/δ occurs in the complex with p65 ulates an increase in the activity of enzymes participating NF-κB [133, 134]. During induction of inflammatory in its processing. That is a likely explanation as to why AA responses, the inactivated PPARβ/δ is involved in activa- and EPA, by activating PPARγ increase the expression of tion of NF-κB p65. PPARβ/δ, in particular, takes part in COX-2. That is, they increase the expression and activity of assembly of the complex from TAK1, TAB1, and HSP27 the enzyme which uses them as substrates. This effect is not [135]. Activation by ligand PPARβ/δ results in lack of this related to inflammation, but more likely to the functions of cooperation, and consequently, activation of PPARβ/δ inter- AA and EPA as substrates for the production of prostanoids. feres with the function of NF-κB p65. As a result, inflamma- tory responses caused by a high concentration of glucose, Table 2 Presentation of mechanisms which involve inhibition of NF-κB activity by PPAR PPAR isoform The mechanism of the anti-inflammatory properties Bibliography PPARα, PPARβ/δ, PPARγ Direct binding of p65 NF-κB [30, 94, 128–130] PPARγ Activity of the E3 ubiquitin ligase, proteolytic degradation of p65 NF-κB [131] PPARβ/δ Disruption in the assembly of the complex with TAK1, TAB1, and HSP27, disrup- [135–137] tion in the activation of NF-κB PPARα, PPARγ Binding of p300, inhibition of acetylation of p65 NF-κB [30, 140, 141] PPARα, PPARγ Increase in the activity of SIRT1, decrease in acetylation of p65 NF-κB [144–147, 150] PPARα, PPARγ Increase in expression of IκBα, inhibition of NF-κB activation [154–156] PPARβ/δ, PPARγ Increase in expression and activity of PTEN, inhibition of NF-κB activation [125, 157–161] PPARα, PPARβ/δ, PPARγ Increase in the expression and activity of HO-1, decrease in the level of ROS [180–185] PPARα, PPARγ Increase in the expression and activity of SOD, decrease in the level of ROS [71, 185, 197–200] PPARα, PPARγ Increase in the expression and activity of catalase, decrease in the level of ROS [176, 177, 199, 204–206] 1 3 Self-regulation of the inflammatory response by peroxisome proliferator -activated receptors 449 activation of the receptor for TNFα, IL-1β, or activation of expression and activity of PTEN leads to inhibition of TLR4 are reduced [136, 137]. NF-κB activation by PI3K. PPARα and PPARγ can also inhibit acetylation of p65 NF-κB, which inhibits activation of this pro-inflammatory transcription factor. After degradation of the IκB, p65 Peroxisome proliferator‑activated NF-κB is subject to acetylation of the L ys p65 NF-κB receptor as protein with anti‑inflammatory by p300. This modification is very important with respect properties: effect on other signaling to the proper functioning of p65 NF-κB [138, 139]. PPARα pathways [30, 140] and PPARγ [141] bind p300. Assembly of these complexes leads to loss of enzymatic properties of p300 and, PPAR cause inhibition of inflammatory reactions not only as a consequence, to inhibition of activation of p65 NF-κB by their effect on NF-κB. What is more, c-Jun is bound by through reduced of acetylation of this NF-κB subunit. PPARα or PPARγ. As a result of this reaction, inhibition of Besides this pathway, PPARα and PPARγ also cause AP-1 activation and inhibition of AP-1 DNA-binding activ- deacetylation of p65 NF-κB. The process of deacetylation, ity by activated PPARα occur [30, 50, 165], and PPARγ which leads to inactivation of NF-κB, is catalyzed by sir- occurs [124, 141, 166]. AP-1-binding site occurs in pro- tuin 1 (SIRT1) [142–144]. Activation of PPARα increases moters of many genes important in inflammatory reactions, expression and activity of SIRT1, which inhibits the p65 including PTGS2 [167]. As a result of this mechanism, NF-κB function [144–147]. The impact of PPARα on SIRT1 PPARα and PPARγ inhibit COX-2 protein expression. is dependent on AMP-activated protein kinase (AMPK) PPAR disrupt activation of STATs. In particular, PPARγ [145, 146]. Activation of AMPK leads to phosphorylation causes an increase in the expression of the suppressor of of p300, which decreases activity of the latter enzyme [123]. cytokine signaling 3 (SOCS3) [168, 169]. This protein Nevertheless, SIRT1 and AMPK are enzymes which activate inhibits activation of JAK2/STAT3. The activity of STAT1 one another [148, 149]. Hence, no accurate data are available is disrupted by the activated PPARα [170]. STAT5b is also on whether PPARα activates SIRT1 directly or activation of disrupted by the activated PPARα or PPARγ [171, 172]. SIRT1 is caused directly by activation of AMPK. Activation Nonetheless, the exact mechanism of such activity of PPARα of PPARγ causes deacetylation of p65 NF-κB depending on and PPARγ is not fully understood. PPARα and PPARγ SIRT1 [150]. Nonetheless, the SIRT1 protein itself forms a probably compete with STATs for coactivators [171]. It is complex with NCoR, SMRT, and PPARγ [149, 151, 152]. also possible that they have an effect on membrane receptors. The process inactivates PPARγ. The expression of β-defensin 1 is increased, especially by PPARα and PPARγ indirectly impact the pro-inflamma- PPARα. This signaling element leads to decreased expres- tory transcription factor. In particular, the promoter of the sion of TLR4 in J774 macrophages [173]. gene-coding IκBα is controlled by PPAR [153]. Owing to this, PPARα [154, 155] and PPARγ [156] increase expres- sion of IκBα—protein binding NF-κB. As a result, inactive The effect on antioxidant enzymes NF-κB bound with its inhibitor, IκBα, occurs in the cell. During inflammatory reactions, phosphorylation and pro- Besides the direct impact of the activated PPAR on NF-κB, teolytic degradation of IκBα takes place, which activates an indirect effect on inflammatory reactions is also possi- NF-κB. Increased expression of IκBα by PPARα and PPARγ ble. PPAR reduce concentration of ROS by increasing the prevents activation of NF-κB. expression of antioxidant enzymes. Due to the fact that ROS Activation of PPARγ [125, 157–160] or PPARβ/δ [161] fulfill a very important role as a second messenger in inflam- causes an increase in expression and activity of phosphatase matory reactions, the increase in the activity of antioxidant and tensin homolog (PTEN). This effect, however, may be enzymes has an anti-inflammatory character [174, 175]. dependent on the research model. In, A549 line lung carci- This leads to decreased activation of NF-κB, and thus to noma, H23 line adenocarcinoma, and squamous H157 cell decreased expression of COX-2 [176, 177]. line carcinoma activation of PPARβ/δ decrease expression One of such ways is increased expression and activity of of PTEN for a few hours [162]. He et al. [163] shows that heme oxygenase-1 (HO-1) [2, 178]. In the HO-1 promoter, after a day of being exposed to ligand, expression returns two PPAR responsive elements are present [179]. Owing to to its control level. PTEN is phosphatase what catalyzes this, all the three isoforms of activated PPAR increase the the dephosphorylation of phosphate from position 3′ in expression of HO-1 [180–185]. An increase in HO-1 expres- phosphatidylinositol-3,4,5-trisphosphate. This enzyme cat- sion may also take place by other means. PPARγ forms a alyzes a reaction reverse to PI3K. In the transmission of pro- complex with Nrf2 and binds in antioxidant response ele- inflammatory factor signals, activation of the PI3K/PKB/ ment (ARE) on the HO-1 promoter, causing an increase in IKK/NF-κB pathway takes place [164]. Thus, increased expression of this antioxidant enzyme [184]. PPARγ also 1 3 450 J. Korbecki et al. leads to stabilization of mRNA HO-1, which prolongs the solution in therapy is interference with the signaling path- half-life of this transcript, thus increasing the expression of ways of the inflammatory reactions. In particular, PPAR the HO-1 protein [186]. However, it must be remembered activators can be used, such as naturally occurring n-3 PUFA that activators of PPAR may also increase expression of (EPA and DHA), or artificial pharmacological compounds HO-1 regardless of the transcription factor and depending (ciprofibrate). Activating PPAR reduces inflammatory reac- on induction of oxidative stress [187]. tions and, as a result, decreases the expression and activity HO-1 is an enzyme engaged in heme degradation to bili- of COX-2. This allows for cancer prevention or for combin- verdin and carbon monoxide (CO). These compounds have ing PPAR activators with the current anticancer treatment antioxidant properties. Biliverdin is converted to bilirubin, [215–224]. In addition to the effect on inflammatory reac- which is an antioxidant [188]. The second product of HO-1 tions, medications that activate PPAR also regulate metabo- activity, CO, decreases the activity of NADPH oxidase, lism, which has a therapeutic effect in diabetics [225]. which decreases the level of ROS in cells activated by pro- It should be remembered, however, that the activation of inflammatory factors [189, 190]. This also disrupts the acti- PPARγ may induce the expression of COX-2 and an increase vation of TLR4, which inhibits the pro-inflammatory effect in synthesis of PGE [102, 105, 107–112]. This may lead to of fatty acids and LPS [191]. In addition, CO, depending on counterproductive side effects of preventive treatment. ROS, causes S-glutathionylation of STAT3 and p65 NF-κB, which leads to deregulation of the function of these proteins [192, 193]. Owing to all of those properties, HO-1 is an Conclusion antioxidant and anti-inflammatory enzyme [2 , 194]. Activating PPAR causes induction of expression of Inflammatory reactions, such as all processes occur in liv - other antioxidant enzymes, such as catalase, Mn-superox- ing organisms, are strictly regulated. One group of such ide dismutase (SOD), and CuZn-SOD. In the promoter of regulators are PPAR, receptors activated by nitrated fatty gene Mn-SOD, a sequence of PPRE is present [195]. This acid derivatives and cyclopentenone prostaglandins, prod- allows PPARγ to increase the expression of this enzyme. ucts formed in the late stages of the inflammatory reaction. The expression of CuZn-SOD is also increased after acti- Activation of PPAR then results in the inhibition of core vation of PPARα [196–199] and PPARγ [185, 198, 200]. elements of the inflammatory reaction. Detailed knowledge Consequently, an increase in SOD activity is followed by of the regulatory mechanisms governing a given biological •− a decrease in O concentration, produced by NADPH process facilitates interference with the functioning of cells oxidase. and tissues, allowing for the development of therapeutic In the promoter of the catalase gene, the PPRE is also approaches for the treatment of diseases based on disorders present [201–203]. Owing to this, activation of PPARα or in these processes. PPARγ causes an increase in expression of this antioxidant enzyme [176, 177, 199, 204–206]. As a consequence of the increase in the activity of catalase, the H O level decreases 2 2 Authors’ contributions JK: manuscript concept, literature search and and inflammatory reactions are reduced. review, and writing the manuscript, MD: participated in writing the manuscript, RB: participated in writing the manuscript and translation In this not fully understood mechanism, which is probably the manuscript. All authors read and approved the final manuscript. independent on ROS, an increase in catalase expression may lead to increased expression of COX-2 [207–209]. Funding This study was supported by the statutory budget of the Fac- ulty of Health Sciences, University of Bielsko-Biala. Mechanisms inhibiting inflammatory Compliance with ethical standards reactions as the aim of the therapy Conflict of interest The authors declare that they have no conflict of interest. Inflammatory reactions, and the expression of COX-2 as well as synthesis of PGE in particular, constitute an impor- Open Access This article is distributed under the terms of the Crea- tant element in pathogenesis of many illnesses, such as Par- tive Commons Attribution 4.0 International License (http://creat iveco kinson’s disease [210, 211], type II diabetes and concomitant mmons.or g/licenses/b y/4.0/), which permits unrestricted use, distribu- diseases [212] and cancer [213, 214]. Therefore, the use of tion, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the specific COX-2 inhibitors has a preventive effect and may Creative Commons license, and indicate if changes were made. facilitate the process of curing the diseases. Nonetheless, COX-2 is only an enzyme, whose expression and activ- ity depends on intracellular signal transduction pathways induced in the course of many diseases. 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Self-regulation of the inflammatory response by peroxisome proliferator-activated receptors

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Abstract

The peroxisome proliferator-activated receptor (PPAR) family includes three transcription factors: PPARα, PPARβ/δ, and PPARγ. PPAR are nuclear receptors activated by oxidised and nitrated fatty acid derivatives as well as by cyclopentenone prostaglandins (PGA and 15d-PGJ ) during the inflammatory response. This results in the modulation of the pro-inflam- 2 2 matory response, preventing it from being excessively activated. Other activators of these receptors are nonsteroidal anti- inflammatory drug (NSAID) and fatty acids, especially polyunsaturated fatty acid (PUFA) (arachidonic acid, ALA, EPA, and DHA). The main function of PPAR during the inflammatory reaction is to promote the inactivation of NF-κB. Possible mechanisms of inactivation include direct binding and thus inactivation of p65 NF-κB or ubiquitination leading to proteolytic degradation of p65 NF-κB. PPAR also exert indirect effects on NF-κB. They promote the expression of antioxidant enzymes, such as catalase, superoxide dismutase, or heme oxygenase-1, resulting in a reduction in the concentration of reactive oxygen species (ROS), i.e., secondary transmitters in inflammatory reactions. PPAR also cause an increase in the expression of IκBα, SIRT1, and PTEN, which interferes with the activation and function of NF-κB in inflammatory reactions. Keywords Inflammation · Peroxisome proliferator-activated receptor · Cyclooxygenase-2 · NF-κB · Signaling pathway AbbreviationsEPA Eicosapentaenoic acid 5(S)-HETE (S)-hydroxyeicosatetraenoic acidEET Epoxyeicosatrienoic acid 12,14 15d-PGJ 15-Deoxy-Δ-prostaglandin J ERK Extracellular signal-regulated kinase 2 2 AF1 Activation function 1γ-LA γ-Linolenic acid AMPK AMP-activated protein kinaseHO-1 Heme oxygenase-1 ARE Antioxidant response element H O Hydrogen peroxide 2 2 AA Arachidonic acid IKKβ IκB kinase β subunit CO Carbon monoxideLBD Ligand-binding domain JNK c-Jun N-terminal kinaseLOX Lipoxygenases COX-2 Cyclooxygenase-2 MAPK Mitogen-activated protein kinase CYP Cytochromes P450NO Nitric oxide DHA Docosahexaenoic acid NSAID N onsteroidal anti-inflammatory drug EP Prostaglandin E receptors NF-κB Nuclear factor κB NCoR Nuclear receptor corepressor PPAR Peroxisome proliferator-activated receptors PPRE PPAR response element Responsible Editor: John Di Battista. ONOO Peroxynitrite * Jan Korbecki PTEN Phosphatase and tensin homolog jan.korbecki@onet.eu PI3K Phosphoinositide 3-kinase PUFA Polyunsaturated fatty acid Department of Molecular Biology, School of Medicine in Katowice, Medical University of Silesia, Medyków 18 PG Prostaglandin Str., 40-752 Katowice, Poland PGE Prostaglandin E 2 2 Department of Biochemistry and Molecular Biology, Faculty PKA Protein kinase A of Health Sciences, University of Bielsko-Biala, Willowa 2 ROS Reactive oxygen species Str., 43-309 Bielsko-Biała, Poland Vol.:(0123456789) 1 3 444 J. Korbecki et al. SMRT Silencing mediator of retinoid and thyroid hormone receptors SIRT1 Sirtuin 1 SOD Superoxide dismutase •− O Superoxide radical Background The prostaglandin synthesis pathway is an important ele- ment of inflammatory responses. The pathway is induced by cytokines [1, 2], LPS [3, 4], or xenobiotics, including metal compounds [5–7] and fluoride [8 –10]. At the begin- ning of the pathway, PLA releases arachidonic acid (AA) from the cell membranes [11]. Next, AA is enzymatically converted, at first by lipoxygenases (LOX) or cytochromes P450 (CYP), or by the best known COX, into a large group of compounds called eicosanoids [12, 13]. Like any bio- chemical response, increasing synthesis of various eicosa- noids in the COX pathway is subject to strict regulation. There are numerous regulatory mechanisms in this pathway which cause both an increase and decrease in synthesis and in activity of particular eicosanoids [14, 15]. Regulation relating to modification of activity of prostaglandins and Fig. 1 Self-regulation of NF-κB activity and COX-2 expression. In thromboxanes receptors is an example of the above [16]. inflammatory reactions, NF-κB is activated and, partly as a result of The activity of COX-2 is also enhanced by the product of this, an increase in expression and activity of enzymes of the pros- taglandin synthesis pathway takes place. Released AA is converted its pathway, i.e., by PGE in an autocrine manner [17, 18]. into PGD or PGE . In inflammatory reactions, the production and 2 2 Activation of prostaglandin E receptors (EPs) causes an concentration of NO also increase. With time, all of the compounds increase in the level of cAMP and activation of the cAMP react together or undergo further non-enzymatic transformation. AA response element-binding protein (CREB) which leads in reaction with NO is subject to nitration. PGD and PGE convert 2 2 to 15d-PGJ and PG A respectively. Compounds with anti-inflamma- to increased COX-2 expression [19, 20]. The increase in 2 2, tory properties are formed, which activate PPARα and PPARγ. Acti- COX-2 expression may also depend on the activation of vated PPARα and PPARγ inhibit the activity of NF-κB, which leads mitogen-activated protein kinase (MAPK) cascades [21] to inhibition of inflammatory reactions by the products of these reac- and phosphoinositide 3-kinase (PI3K) [18, 22]. Apart from tions the effect of individual products of the COX pathway, LOX products also increase COX-2 expression [23]. Despite this, AA, regardless of COX, LOX, and CYP activity, is itself capable of causing oxidative stress and, in particular, gene for PPARα causes an increase in the intensity of inflam- of activating NADPH oxidase [24, 25]. This results in an matory responses to IL-1 or LPS [28, 30]. increase in the level of reactive oxygen species (ROS) and activation of c-Jun N-terminal kinase (JNK) MAPK and NF-κB, which increases COX-2 expression. Ligands of peroxisome proliferator‑activated Nonetheless, self-regulation of the COX pathway does receptors not consist solely of positive feedback. The pathway also involves mechanisms which inhibit a too strong inflamma- PPAR are nuclear receptors and transcription factors. tory response. In the center of the COX auto-inhibition path- They include PPARα, PPARβ/δ, and PPARγ. These tran- way, peroxisome proliferator-activated receptors (PPAR) are scription factors control genes responsible for the oxida- found (Fig. 1). Activation of inflammatory responses by LPS tion of lipids [31, 32]. PPARα is a transcription factor or other pro-inflammatory particles causes an increase in the that increases gene expression of acyl-CoA oxidase and expression of PPARα and a decrease in the expression of carnitine palmitoyltransferase I, i.e., enzymes involved PPARγ [26–29]. Blocking the mechanism with a knock-out 1 3 Self-regulation of the inflammatory response by peroxisome proliferator -activated receptors 445 in β-oxidation. PPARγ increases adiponectin concentra-of IC equal to 1.2 ± 0.2 μM and 1.6 ± 0.2 μM for PPARα tion and expression of transporters GLUT1 and GLUT4. and PPARγ, respectively [33, 41]. Eicosapentaenoic acid PPARβ/δ increases the expression of pyruvate dehydro- (EPA) and docosahexaenoic acid (DHA) have similar genase kinase-4 and carnitine palmitoyltransferase 1A, properties. However, at a much higher concentration, which increases the intensity of fatty acid oxidation. 100 μM, inhibition of PPARα activity by AA, EPA, and All of PPAR have a similar structure—ligand-binding DHA takes place [38]. domain (LBD). LBD is in the shape of the letter Y and is Hydrophilic residue is also present in LBD, which ena- of polar character [33–36]. In the first arm, hydrophilic bles activation of PPAR by derivatives of fatty acids aris- amino acid residue can be found, which is responsible for ing from enzymatic and non-enzymatic oxidation [35, 42]. ligand binding. This part also contains helix12, which is Owing to self-regulation of inflammatory responses, AA stabilized during ligand binding and PPAR activation. The metabolites fulfill special roles as activators. An example remaining two arms of the ligand-binding domain consist of the above is the products of the 5-LOX pathway, 5(S)- of hydrophobic amino acid residue with far less hydro- hydroxyeicosatetraenoic acid (5(S)-HETE), and leukot- philic residue. These two parts of LBD are responsible for riene B (LTB ), which also activate PPARα [37, 40, 43]. 4 4 the specificity of ligand binding when activating PPAR. Nonetheless, this effect is less significant compared to the This LBD structure enables the activation of PPAR impact of free AA—fatty acids from which they arise. Other by polar structure ligands, and, in particular, by a fatty important activators of PPAR are 8(S)-HETE and hydroper- acids and derivatives of fatty acids (Table  1). Nonethe- oxyeicosatetraenoic acid (8S-HPETE)—products of murine less, not all fatty acids equally activate PPAR. The arms 8-LOX [37, 40, 44, 45]. Yet, another important activator with hydrophobic residue in LBD stabilize ligand [33]. of PPARγ and PPARβ/δ is the 15-LOX product: 15-HETE Therefore, only fatty acids with 14 and more carbon atoms [46, 47]. Among natural activators of PPARα and PPARγ are capable of activating PPAR [33, 37, 38]. However, are AA metabolites, products of many CYP isoforms with saturated fatty acids with 20 and more carbon atoms do anti-inflammatory properties are also found. They include: not fit in the LBD and thus are not activators of PPAR. 5,6-epoxyeicosatrienoic acid (EET), 8,9-EET, 11,12-EET, Double bonds also play an important role in the structure 14,15-EET, and 20-HETE (with its metabolite 20-COOH- of a fatty acid as a potential ligand. Monounsaturated fatty AA) [13, 48–51]. acids in cis configuration have a favorable conformation to Prostaglandins produced in the COX pathway have better match LBD than saturated fatty acids and fatty acids impact on activating PPARγ. Cyclopentenone prostaglandins in trans configuration of the same length. Fatty acids in activate PPARγ [37, 44, 52]. This group includes prostaglan- trans configuration have similar conformation as unsatu- din (PG)A, PGC, PGJ , Δ -PGJ and the most thoroughly 2 2 2 2, 12,14 rated fatty acids [33]. Long-chain polyunsaturated fatty studied 15-deoxy-Δ-prostaglandin J (15d-PGJ ). All 2 2 acid (PUFA) is also ligands for PPAR [33, 37, 39, 40]. prostaglandins in this group arise from pro-inflammatory For example, AA connects with LBD at a concentration prostaglandins. PGA is formed as a result of non-enzymatic Table 1 Examples of PPAR agonist Agonist PPARα PPARβ/δ PPARγ Bibliography Saturated fatty acids Palmitic acid, stearic acid Palmitic acid, stearic acid – [33, 37] Monounsaturated fatty acids Palmitoleic acid, oleic acid Palmitoleic acid, oleic acid Palmitoleic acid, oleic acid [33] Polyunsaturated fatty acid γ-LA, AA, EPA, DHA γ-LA, AA, EPA, DHA γ-LA, AA, EPA, DHA [33, 37, 40] Arachidonic acid metabolites LTB , 8(S)-HETE, EET, 8(S)-HETE, 15-HETE 8(S)-HETE, 15-HETE, EET, [37, 40, 44, 46–49, 51] 20-COOH-AA20-COOH-AA, PGA , 15d-PGJ Other derivatives of fatty Nitrated derivatives of – Nitrated derivatives of [65, 66] acids unsaturated fatty acids unsaturated fatty acids Synthetic agonist Wy 14,643 Bezafibrate, ETYA Ciprofibrate, clofibrate, [37, 40, 109–111] Ciprofibrate, clofibrate, BRL 49653, NSAID bezafibrate, ETYA (diclofenac, flufenamic acid, flurbiprofen, indo- methacin, NS-398) 12,14 15d-PGJ : 15-deoxy-Δ-prostaglandin J ; AA: arachidonic acid; γ-LA: γ-linolenic acid; DHA: docosahexaenoic acid; EET: epoxyeicosa- 2 2 trienoic acid; EPA: eicosapentaenoic acid; ETYA: 5,8,11,14-eicosatetraynoic acid; HETE: hydroxyeicosatetraenoic acid; L TB : leukotriene B ; 2 4 NSAID: nonsteroidal anti-inflammatory drug; PGA : prostaglandin A 2 2 1 3 446 J. Korbecki et al. dehydration of PGE . Subsequently, PGA may be isomer- anti-inflammatory nature. One of their functions is bind- 2 2 ized to PGB and PGC , whereas PGD may be subject to ing-free thiol (–SH) groups in cysteine [62, 63]. Owing to 2 2 2 12 62 non-enzymatic dehydration and isomerisation to PGJ , Δ - this, they may cause nitroalkylation of Cy s p50 NF-κB PGJ and, finally, to 15d-PGJ . All of the cyclopentenone and Cys p65 NF-κB, which, as a consequence, inactivates 2 2 prostaglandins contain an electrophilic carbon atom in their these transcription factor subunits. A nitrated derivative of cyclopentenone ring [53, 54]. Owing to this, they can be AA replaces heme in COX, which impacts the intensity of subject to Michael addition to free thiol (–SH) groups in inflammatory responses. This results in irreversible inhibi- cysteine. If such residue is present in the catalytic center tion of the enzymes K for COX-1, equal to 1.02 μM, and K i i or in an important domain in the function of a given pro- for COX-2, equal to 1.76 μM [64]. Another anti-inflamma- tein, such enzymes and transcription factors become inac- tory characteristic of nitrated derivatives of fatty acids, in tive. IκB kinase β subunit (IKKβ) and nuclear factor κB very low concentrations, is activation of PPARα and PPARγ (NF-κB) are examples of such proteins [52, 55]. Cysteine [65, 66]. In PPARγ, meanwhile, there are residues of Ar g 285 343 is also present in LBD PPARγ in position 285 (Cy s ), and Glu which stabilize, respectively, the nitrated deriva- which is specifically susceptible to reactions and covalent tives of fatty acids on 10 and 12 carbon [67]. The above- 288 343 15d-PGJ connection (Fig. 2) [40, 54, 56]. As a result of mentioned residues of Ar g and Glu are not conserva- alkylation of this residue, a change in PPARγ conforma- tive and hence do not occur in other PPAR. Owing to such tion takes place and the protein is activated [37, 39, 40, 44]. structure, PPARγ is activated by the nitrated derivatives of The cyclopentenone prostaglandins constitute negative feed- unsaturated fatty acids even at a concentration of 100 nM back to inflammatory responses. During the inflammatory [65, 66]. Meanwhile, concentration of PPARα deprived of responses, an increase in the production of PGE and PGD such residues occurs at a concentration of 300 nM [65]. For 2 2 is observed [57]. With time, in a non-enzymatic way, further higher concentrations of about 4 μM, nitrated derivatives of transformation of the prostaglandins into anti-inflammatory fatty acids, and of AA in particular, unbalance the assembly compounds takes place in PG A and 15d-PGJ respectively. of the NADPH oxidase complex [68]. This causes distur- 2 2, As a consequence, the inflammatory response is reduced by bance in ROS generation and, as a result, suppresses inflam- transformed products of the responses [3, 58]. matory reactions. In the course of inflammatory reactions, an increased synthesis occurs of nitric oxide (NO) and ROS generation, •− among others superoxide radical (O ), and hydrogen per- •− oxide (H O ) [59, 60]. NO may react with O creating per- Activation of peroxisome 2 2 2 − − oxynitrite (ONOO ). Both compounds, NO and ON OO , proliferator‑activated receptors lead to nitration of double bonds in unsaturated fatty acids [42, 61]. As a result, nitrated derivatives of fatty acids are PPARγ is a transcription factor, whose activity is subject formed. These compounds have biological properties of an to regulation by SUMOylation and an assembly of com- plexes with various proteins, especially with nuclear recep- tor corepressor (NCoR) and silencing mediator of retinoid and thyroid hormone receptors (SMRT) [69–73]. Activa- tion of PPARγ with ligand causes changes in SUMOyla- tion of this protein. In particular, a decrease takes place in SUMOylation of L ys PPARγ1 in the domain of activation function 1 (AF1) [74]. This allows LBD to interact with the AF1 domain, whereas SUMOylation of the Lys in LBD PPARγ1 allows for full activation of PPARγ1 by ligand. PPARγ activation also causes suppression of proteolytic degradation of NCoR and dissociation of the complex of PPARγ with NCoR and SMRT [69, 72]. As a result, expres- sion of genes is suppressed by these corepressors, especially of the genes dependent on NF-κB and AP-1, such as PTGS2 and NOS2 [75–77]. A similar mechanism is present in PPARα. The transcrip- tion factor in its inactive form is subject to SUMOylation and it is also in complex with NCoR [78, 79]. The process Fig. 2 15d-PGJ as an agonist of PPARγ. Modeled (as purple) 15d- of SUMOylation is governed by enzymes Ubc9 and PIASy, PGJ in LBD PPARγ. Amino acid residues interacting with this ligand and covalently bound Cy s are shown. PDB:2zk1 [54] which modify the L ys PPARα. Activation of PPARα by 1 3 Self-regulation of the inflammatory response by peroxisome proliferator -activated receptors 447 ligand leads to a decrease in SUMOylation and, as a conse- dysregulation of MuRF2 activity in diabetes has an impact on quence, to release of NCoR. NCoR is a corepressor which the development of cardiomyopathy [90]. connects exclusively to SUMOylated receptors. Dissociation of the complex of PPARα with NCoR leads to activation of both proteins; PPARα increases expression of particular Phosphorylation changing the activity genes and NCoR is a corepressor suppressing the expression of peroxisome proliferator‑activated of other genes, including PTGS2 and NOS2 [77]. receptors Activated PPAR may also be subject to phosphorylation, Changes in the stability of peroxisome which modifies the activity of these nuclear receptors. PPARγ proliferator‑activated receptors as a result is subject to phosphorylation into the N-terminus A/B domain of activation by ligand by such kinases as protein kinase A (PKA) [91], extracel- lular signal-regulated kinase (ERK) MAPK [92–94] or JNK PPAR are transcription factors which are also subject to MAPK [92, 95]. This results in a change of character of the regulation by proteolytic degradation. Nonetheless, dif- PPARγ. As a result of phosphorylation at the N-terminus, ferent PPAR are subject to different mechanisms of this PPARγ ceases to be a transcription factor and begins to physi- regulation. Activating PPARα by ligand causes inhibition cally bind the activated NF-κB. This mechanism may consti- of ubiquitination, which leads to suppression of proteolytic tute regulation of inflammatory responses in which activation degradation of this protein [80]. Ubiquitination of L ys , of the above-mentioned kinases takes place and ligands for 310 388 Lys , and Lys PPARα by muscle ring finger-(MuRF)1 PPARγ are present. results in export from the nucleus of this transcription factor PPARα is also subject to phosphorylation by such kinases and subsequently in proteolytic degradation of PPARα [81]. as PKA [96], p38 MAPK [97] or ERK MAPK [98]. This A similar mechanism occurs in regulation of the activity causes enhanced ligand-dependent activation. Phosphoryla- of PPARβ/δ by ligand. Activation by ligand causes inhibition tion by p38 MAPK can also inhibit the activity of PPARα [99]. of ubiquitination and inhibition of proteolytic degradation of PPARβ/δ [82]. Interaction between various peroxisome Contrary to PPARα and PPARβ/δ, activation of PPARγ by proliferator‑activated receptors ligand leads to ubiquitination and proteolytic degradation of this protein in proteasomes [83, 84]. In adipocytes, drosophila All three PPAR have a similar LBD structure. This ena- seven-in-absentia homolog 2 (Siah2) is responsible for this bles their simultaneous activation by the same ligand, for process [85]. Ubiquitination in this PPARγ mechanism causes example, a given PUFA [33]. This results in interactions changes in the structure of the activation function 2 (AF-2) between different PPAR. As yet, unfortunately, not much domain, and as a consequence, the protein is directed to the research has been done into the interactions between vari- proteolytic degradation pathway [86]. Nonetheless, PPARγ may ous PPAR. also be subject to ubiquitination independently of ligand, which Activation of PPARγ leads to an increase in the expres- causes degradation or increase in the stability of the protein sion of genes dependent on this transcription factor and depending on the place of ubiquitination. Tripartite motif pro- on COX-2 in particular. This is associated with increased tein 23 (TRIM23) catalyzes polyubiquitination, owing to which expression of PPARβ/δ [100]. However, sole activation of PPARγ stability increases [87]. Meanwhile, F-box only protein PPARβ/δ by ligand does not cause changes in COX-2 expres- 9 (FBXO9) [88] or makorin ring finger protein 1 (MKRN1) sion. It only cooperates with the activated PPARγ. Depend- [89] has been identified as specific E3 ligase of PPARγ in ing on the model, activation of PPARβ/δ inhibits [101] or adipocytes, which leads to ubiquitination and proteasome- increases [100] transcription activity of PPARγ. Activation dependent degradation of PPARγ. The regulation mechanism of of PPARβ/δ also increases expression of PPARα, whereas PPARγ expression through proteolytic degradation is important activation of PPARα decreases expression of PPARβ/δ [100]. in adipocyte differentiation, as this transcription factor impacts Thus, simultaneous activation of PPARα and PPARγ leads expression of genes responsible for lipogenesis of adipocytes. to mutual abolishing of activity of both the PPAR through Meanwhile, MuRF2, which is present in cardiomiocytes, causes changes in expression of PPARβ/δ. However, the specific ubiquitination of PPARγ and thus leads to an increase in stabil- tissue expression of various PPAR should not be ignored, as ity of the protein [90]. However, overactivity of MuRF2 causes it may modify the response to the activation of these nuclear polyubiquitination of PPARγ and, as a consequence, proteo- receptors. lytic degradation of the protein. It has been demonstrated that 1 3 448 J. Korbecki et al. Activation of peroxisome Peroxisome proliferator‑activated receptor proliferator‑activated receptor‑γ as a protein with anti‑inflammatory as an inducer of cyclooxygenase‑2 properties: effect on NF‑κB expression Activation of all PPAR, PPARα [4, 118–121], PPARβ/δ Activating PPAR reduces inflammatory reactions. How - [122, 123] and PPARγ [124–127] causes inhibition of ever, when pro-inflammatory factors are absent, activation NF-κB activation (Table 2). Nonetheless, the mechanism of PPARγ induces the expression of COX-2 [100]. In the of anti-inflammatory properties is a very complex one and promoter of gene PTGS2, a PPAR response (PPRE) element takes different forms. is found [102, 103]. Thus, when pro-inflammatory factors PPAR are transcription factors, but they also have are absent, activation of PPARγ causes induction of COX-2 properties which are not associated with the expression of protein expression. Inducers of COX-2 expression, which genes. They are capable of binding different proteins, by are commonly known, as compounds decrease expression which means they inactivate them. It is predominantly the of COX-2 in inflammatory reactions, are PUFA [γ-linolenic binding of PPARα [30, 128], PPARβ/δ [129], or PPARγ acid (γ-LA), AA, EPA, and DHA] [102, 104–106] as well as with p65 NF-κB that is responsible for anti-inflammatory 15d-PGJ [107–109]. Nonsteroidal anti-inflammatory drug properties [94, 130] with p65 NF-κB which reduces the (NSAID) is also agonists for PPARγ [110, 111]. This is why pro-inflammatory response. such compounds as diclofenac, flufenamic acid, flurbiprofen, The direct impact of PPARγ on NF-κB may be associ- indomethacin, or NS-398, despite inhibiting the activity of ated with its enzymatic properties. PPARγ is E3 ubiquitin COX-2, induce expression of that enzyme [107–109, 112]. ligase, which cooperates with E2 UBCH3. PPARγ causes AA  and EPA (both PUFA) are processed into 2- and ubiquitination of the L ys p65 NF-κB, which leads to 3-series prostanoids [113–115], respectively. Prostanoids proteolytic degradation of this NF-κB subunit [131]. The serve a very important biological function, unrelated to intensity of NF-κB degradation is increased by PPARγ inflammatory reactions; they are crucial for proper function- ligand activation. However, it is not only NF-κB that is ing of the kidneys [116] and blood vessels [117]. Therefore, subject to such regulation by PPARγ. It is possible to PUFA must influence the expression and activity of COX-2 reduce the stability of the MUC1-C by PPARγ, which has differently than in inflammatory reactions. In metabolism, anticancer properties [132]. very often, the substrate of a given enzymatic pathway stim- Inactivated PPARβ/δ occurs in the complex with p65 ulates an increase in the activity of enzymes participating NF-κB [133, 134]. During induction of inflammatory in its processing. That is a likely explanation as to why AA responses, the inactivated PPARβ/δ is involved in activa- and EPA, by activating PPARγ increase the expression of tion of NF-κB p65. PPARβ/δ, in particular, takes part in COX-2. That is, they increase the expression and activity of assembly of the complex from TAK1, TAB1, and HSP27 the enzyme which uses them as substrates. This effect is not [135]. Activation by ligand PPARβ/δ results in lack of this related to inflammation, but more likely to the functions of cooperation, and consequently, activation of PPARβ/δ inter- AA and EPA as substrates for the production of prostanoids. feres with the function of NF-κB p65. As a result, inflamma- tory responses caused by a high concentration of glucose, Table 2 Presentation of mechanisms which involve inhibition of NF-κB activity by PPAR PPAR isoform The mechanism of the anti-inflammatory properties Bibliography PPARα, PPARβ/δ, PPARγ Direct binding of p65 NF-κB [30, 94, 128–130] PPARγ Activity of the E3 ubiquitin ligase, proteolytic degradation of p65 NF-κB [131] PPARβ/δ Disruption in the assembly of the complex with TAK1, TAB1, and HSP27, disrup- [135–137] tion in the activation of NF-κB PPARα, PPARγ Binding of p300, inhibition of acetylation of p65 NF-κB [30, 140, 141] PPARα, PPARγ Increase in the activity of SIRT1, decrease in acetylation of p65 NF-κB [144–147, 150] PPARα, PPARγ Increase in expression of IκBα, inhibition of NF-κB activation [154–156] PPARβ/δ, PPARγ Increase in expression and activity of PTEN, inhibition of NF-κB activation [125, 157–161] PPARα, PPARβ/δ, PPARγ Increase in the expression and activity of HO-1, decrease in the level of ROS [180–185] PPARα, PPARγ Increase in the expression and activity of SOD, decrease in the level of ROS [71, 185, 197–200] PPARα, PPARγ Increase in the expression and activity of catalase, decrease in the level of ROS [176, 177, 199, 204–206] 1 3 Self-regulation of the inflammatory response by peroxisome proliferator -activated receptors 449 activation of the receptor for TNFα, IL-1β, or activation of expression and activity of PTEN leads to inhibition of TLR4 are reduced [136, 137]. NF-κB activation by PI3K. PPARα and PPARγ can also inhibit acetylation of p65 NF-κB, which inhibits activation of this pro-inflammatory transcription factor. After degradation of the IκB, p65 Peroxisome proliferator‑activated NF-κB is subject to acetylation of the L ys p65 NF-κB receptor as protein with anti‑inflammatory by p300. This modification is very important with respect properties: effect on other signaling to the proper functioning of p65 NF-κB [138, 139]. PPARα pathways [30, 140] and PPARγ [141] bind p300. Assembly of these complexes leads to loss of enzymatic properties of p300 and, PPAR cause inhibition of inflammatory reactions not only as a consequence, to inhibition of activation of p65 NF-κB by their effect on NF-κB. What is more, c-Jun is bound by through reduced of acetylation of this NF-κB subunit. PPARα or PPARγ. As a result of this reaction, inhibition of Besides this pathway, PPARα and PPARγ also cause AP-1 activation and inhibition of AP-1 DNA-binding activ- deacetylation of p65 NF-κB. The process of deacetylation, ity by activated PPARα occur [30, 50, 165], and PPARγ which leads to inactivation of NF-κB, is catalyzed by sir- occurs [124, 141, 166]. AP-1-binding site occurs in pro- tuin 1 (SIRT1) [142–144]. Activation of PPARα increases moters of many genes important in inflammatory reactions, expression and activity of SIRT1, which inhibits the p65 including PTGS2 [167]. As a result of this mechanism, NF-κB function [144–147]. The impact of PPARα on SIRT1 PPARα and PPARγ inhibit COX-2 protein expression. is dependent on AMP-activated protein kinase (AMPK) PPAR disrupt activation of STATs. In particular, PPARγ [145, 146]. Activation of AMPK leads to phosphorylation causes an increase in the expression of the suppressor of of p300, which decreases activity of the latter enzyme [123]. cytokine signaling 3 (SOCS3) [168, 169]. This protein Nevertheless, SIRT1 and AMPK are enzymes which activate inhibits activation of JAK2/STAT3. The activity of STAT1 one another [148, 149]. Hence, no accurate data are available is disrupted by the activated PPARα [170]. STAT5b is also on whether PPARα activates SIRT1 directly or activation of disrupted by the activated PPARα or PPARγ [171, 172]. SIRT1 is caused directly by activation of AMPK. Activation Nonetheless, the exact mechanism of such activity of PPARα of PPARγ causes deacetylation of p65 NF-κB depending on and PPARγ is not fully understood. PPARα and PPARγ SIRT1 [150]. Nonetheless, the SIRT1 protein itself forms a probably compete with STATs for coactivators [171]. It is complex with NCoR, SMRT, and PPARγ [149, 151, 152]. also possible that they have an effect on membrane receptors. The process inactivates PPARγ. The expression of β-defensin 1 is increased, especially by PPARα and PPARγ indirectly impact the pro-inflamma- PPARα. This signaling element leads to decreased expres- tory transcription factor. In particular, the promoter of the sion of TLR4 in J774 macrophages [173]. gene-coding IκBα is controlled by PPAR [153]. Owing to this, PPARα [154, 155] and PPARγ [156] increase expres- sion of IκBα—protein binding NF-κB. As a result, inactive The effect on antioxidant enzymes NF-κB bound with its inhibitor, IκBα, occurs in the cell. During inflammatory reactions, phosphorylation and pro- Besides the direct impact of the activated PPAR on NF-κB, teolytic degradation of IκBα takes place, which activates an indirect effect on inflammatory reactions is also possi- NF-κB. Increased expression of IκBα by PPARα and PPARγ ble. PPAR reduce concentration of ROS by increasing the prevents activation of NF-κB. expression of antioxidant enzymes. Due to the fact that ROS Activation of PPARγ [125, 157–160] or PPARβ/δ [161] fulfill a very important role as a second messenger in inflam- causes an increase in expression and activity of phosphatase matory reactions, the increase in the activity of antioxidant and tensin homolog (PTEN). This effect, however, may be enzymes has an anti-inflammatory character [174, 175]. dependent on the research model. In, A549 line lung carci- This leads to decreased activation of NF-κB, and thus to noma, H23 line adenocarcinoma, and squamous H157 cell decreased expression of COX-2 [176, 177]. line carcinoma activation of PPARβ/δ decrease expression One of such ways is increased expression and activity of of PTEN for a few hours [162]. He et al. [163] shows that heme oxygenase-1 (HO-1) [2, 178]. In the HO-1 promoter, after a day of being exposed to ligand, expression returns two PPAR responsive elements are present [179]. Owing to to its control level. PTEN is phosphatase what catalyzes this, all the three isoforms of activated PPAR increase the the dephosphorylation of phosphate from position 3′ in expression of HO-1 [180–185]. An increase in HO-1 expres- phosphatidylinositol-3,4,5-trisphosphate. This enzyme cat- sion may also take place by other means. PPARγ forms a alyzes a reaction reverse to PI3K. In the transmission of pro- complex with Nrf2 and binds in antioxidant response ele- inflammatory factor signals, activation of the PI3K/PKB/ ment (ARE) on the HO-1 promoter, causing an increase in IKK/NF-κB pathway takes place [164]. Thus, increased expression of this antioxidant enzyme [184]. PPARγ also 1 3 450 J. Korbecki et al. leads to stabilization of mRNA HO-1, which prolongs the solution in therapy is interference with the signaling path- half-life of this transcript, thus increasing the expression of ways of the inflammatory reactions. In particular, PPAR the HO-1 protein [186]. However, it must be remembered activators can be used, such as naturally occurring n-3 PUFA that activators of PPAR may also increase expression of (EPA and DHA), or artificial pharmacological compounds HO-1 regardless of the transcription factor and depending (ciprofibrate). Activating PPAR reduces inflammatory reac- on induction of oxidative stress [187]. tions and, as a result, decreases the expression and activity HO-1 is an enzyme engaged in heme degradation to bili- of COX-2. This allows for cancer prevention or for combin- verdin and carbon monoxide (CO). These compounds have ing PPAR activators with the current anticancer treatment antioxidant properties. Biliverdin is converted to bilirubin, [215–224]. In addition to the effect on inflammatory reac- which is an antioxidant [188]. The second product of HO-1 tions, medications that activate PPAR also regulate metabo- activity, CO, decreases the activity of NADPH oxidase, lism, which has a therapeutic effect in diabetics [225]. which decreases the level of ROS in cells activated by pro- It should be remembered, however, that the activation of inflammatory factors [189, 190]. This also disrupts the acti- PPARγ may induce the expression of COX-2 and an increase vation of TLR4, which inhibits the pro-inflammatory effect in synthesis of PGE [102, 105, 107–112]. This may lead to of fatty acids and LPS [191]. In addition, CO, depending on counterproductive side effects of preventive treatment. ROS, causes S-glutathionylation of STAT3 and p65 NF-κB, which leads to deregulation of the function of these proteins [192, 193]. Owing to all of those properties, HO-1 is an Conclusion antioxidant and anti-inflammatory enzyme [2 , 194]. Activating PPAR causes induction of expression of Inflammatory reactions, such as all processes occur in liv - other antioxidant enzymes, such as catalase, Mn-superox- ing organisms, are strictly regulated. One group of such ide dismutase (SOD), and CuZn-SOD. In the promoter of regulators are PPAR, receptors activated by nitrated fatty gene Mn-SOD, a sequence of PPRE is present [195]. This acid derivatives and cyclopentenone prostaglandins, prod- allows PPARγ to increase the expression of this enzyme. ucts formed in the late stages of the inflammatory reaction. The expression of CuZn-SOD is also increased after acti- Activation of PPAR then results in the inhibition of core vation of PPARα [196–199] and PPARγ [185, 198, 200]. elements of the inflammatory reaction. Detailed knowledge Consequently, an increase in SOD activity is followed by of the regulatory mechanisms governing a given biological •− a decrease in O concentration, produced by NADPH process facilitates interference with the functioning of cells oxidase. and tissues, allowing for the development of therapeutic In the promoter of the catalase gene, the PPRE is also approaches for the treatment of diseases based on disorders present [201–203]. Owing to this, activation of PPARα or in these processes. PPARγ causes an increase in expression of this antioxidant enzyme [176, 177, 199, 204–206]. As a consequence of the increase in the activity of catalase, the H O level decreases 2 2 Authors’ contributions JK: manuscript concept, literature search and and inflammatory reactions are reduced. review, and writing the manuscript, MD: participated in writing the manuscript, RB: participated in writing the manuscript and translation In this not fully understood mechanism, which is probably the manuscript. All authors read and approved the final manuscript. independent on ROS, an increase in catalase expression may lead to increased expression of COX-2 [207–209]. Funding This study was supported by the statutory budget of the Fac- ulty of Health Sciences, University of Bielsko-Biala. Mechanisms inhibiting inflammatory Compliance with ethical standards reactions as the aim of the therapy Conflict of interest The authors declare that they have no conflict of interest. Inflammatory reactions, and the expression of COX-2 as well as synthesis of PGE in particular, constitute an impor- Open Access This article is distributed under the terms of the Crea- tant element in pathogenesis of many illnesses, such as Par- tive Commons Attribution 4.0 International License (http://creat iveco kinson’s disease [210, 211], type II diabetes and concomitant mmons.or g/licenses/b y/4.0/), which permits unrestricted use, distribu- diseases [212] and cancer [213, 214]. Therefore, the use of tion, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the specific COX-2 inhibitors has a preventive effect and may Creative Commons license, and indicate if changes were made. facilitate the process of curing the diseases. Nonetheless, COX-2 is only an enzyme, whose expression and activ- ity depends on intracellular signal transduction pathways induced in the course of many diseases. 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Inflammation ResearchSpringer Journals

Published: Mar 29, 2019

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