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Saudi Journal of Kidney Diseases and Transplantation
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EDITORIAL Table of Contents   
Year : 2004  |  Volume : 15  |  Issue : 1  |  Page : 1-6
PPAR: Receptors that Regulate Inflammation


37 Princess Road, Camden, London NW1 8JS, United Kingdom

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   Abstract 

The pharmacology of the perioxisome proliferators activated receptor PRAR ligands is summarized. The alpha, delta (beta) and gamma receptors occur in vascular walls and on macrophages suggesting that their ligands can be used to modify atherosclerosis and other forms of vascular disease. Furthermore, gamma-ligands exert an anti-inflammatory effect on macrophages. Troglitazone has been used to protect against glomerulosclerosis in rats. The thiazolidinediones (TZDs) could be important adjunct therapy for lupus glomerulonephritis.

Keywords: Perioxisome proliferators, Receptors, Lupus, Glomerulonephritis, Glomerulosclerosis.

How to cite this article:
Wardle E N. PPAR: Receptors that Regulate Inflammation. Saudi J Kidney Dis Transpl 2004;15:1-6

How to cite this URL:
Wardle E N. PPAR: Receptors that Regulate Inflammation. Saudi J Kidney Dis Transpl [serial online] 2004 [cited 2019 Sep 21];15:1-6. Available from: http://www.sjkdt.org/text.asp?2004/15/1/1/32958

   Introduction Top


Perioxisome proliferator activated receptors (PPARs) are transcription factors and members of the nuclear receptor superfamily. [1],[2] In mammalian cells there are PPARα which play a critical role in cellular uptake and β-oxidation of fatty acids, [2],[3] PPARδ/β [4] and PPARγ , which modify inflammatory res­ponses. [1],[2] Leukotriene B4 (LTB4), polyun­saturated fatty acids and the hypolipidaemic agents, the fibrates, are selective PPARα agonists. Carbaprostacyclin is reported to selectively activate PPARδ. The cyclo­pentenone prostaglandin that is derived from PGD2 and called 15dPGJ2 and thiazolidinedione antidiabetic compounds are PPARγ ligands. The relevance of these receptors to inflammation was appreciated when PPARα was found to respond to LTB4. Activation of PPARα inhibits the inflammatory action of eicosanoids by augmenting the hepatic enzymes required for their metabolism. Treatment of activated macrophages with PPARα and γ agonists causes apoptosis b1 interfering with NF-kB survival pathway.

Details of how PPAR heterodimerises with the retinoic acid receptor (RAR) to bind the perioxisome proliferator response elements (PPREs) upstream of genes that are activated or inhibited is in reviews. [1],[2],[3] PPARα are expressed in tissues with a high rate of fatty acid catabolism like liver, heart, muscle and kidneys. PPARγ are sited in adipose tissue, the mammary glands and the gut. They also occur in immune cell types like macrophages, mesangial cells, synoviocytes and chondro­cytes, T and B lymphocytes. Stimulation of PPARγ leads to inhibition of iNOS and Cox-2 and inhibition of release of cytokines IL-1, IL-2, IL-6 and TNFa. Hence such ligands can control chronic inflammation like that of rheumatoid arthritis. [6]

What might the PPARs contribute to Nephrology?

Vascular Disease/Atherosclerosis

The presence of PPARα, PPARδ [4] and PPARD in cells of the vessel wall, such as endothelial cells, smooth muscle cells and macrophages suggests that their ligands will have anti-atherosclerotic potential. [1],[7] [Table - 1] summarizes the available therapeutic ligands.

PPARα is involved in the regulation of endothelial cell inflammatory responses.[8] Ligands for PPARα and PPARγ modulate the recruitment of leucocytes and their adhesion to endothelial cells, regulate production of cytokines and endothelial and vascular smooth muscle cells, and affect lipid homeostasis of monocyte-macrophages that would be involved in vasculitis or atheroma. The pro­inflammatory adhesion molecules that appear on endothelial cells are downregulated by PPARγ ligands, [9] as well as PPARα. [8] Their action is via repression of the transcription factors NF-kB and AP-1 [10] and so ICAM-1 and VCAM-1 are not expressed. PPARα inhibit thrombin induced expression of endothelin-1, and PPARα inhibit expression of I1-6 and tissue factor on endothelial cells, smooth muscle cells and macrophages. PPARγ ligands like glitazones inhibit for­mation of monocyte recruiting chemokine MCP-1, and inhibit expression of CCR2 on monocytes so that recruitment is thwarted.[11]

PPARγ promote cholesterol accumulation in macrophages by upregulation of genes for cholesterol accumulation like scavenger receptors A and CD36, and yet they induce the ABC.1 transporter cholesterol efflux pump. [12] Hence the overall action could be complex. Fortunately rosiglitazone improved atherosclerosis in LDL receptor knock-out mice, and troglitazone reduced development of atherosclerosis in Watanabe heritable hyperlipidemic rabbits. [2] PPARγ increases CD36 expression, a promoter of lipid accumulation, but it decreases scavenger receptors-A and the net effect is no foam cell formation. PPARγ will inhibit T cells that might contribute to atherosclerosis and certainly to vasculitis. [7]

The hypolipidaemic fibrates activate PPARα across species. Treatment of patients lowers their triglycerides and induces moderate elevation of HDL. The PPARγ ligands like the TZDs help to regulate glucose and lipid homeostasis. Mutation in the ligand binding domains of PPARγ causes a syndrome of insulin resistance, diabetes and hypertension.

Monocyte-Macrophages

Macrophages derived from monocytes are important in glomerular inflammation, for­mation of crescents and glomerulosclerosis, and in the induction of tubulointerstitial fibrosis of the kidneys. Monocytes do not express PPARγ but it is induced by ligation with ICAM-3, which occurs on other leuco­cytes. Activated monocytes display PPARγ and in them it helps induction of Cox-2. [13] As indicated, PPARγ regulates the scavenger receptor CD36 which helps lipid accumulation in macrophages, and, as readers will know parallels between atherosclerosis and glome­rulosclerosis have proved to be valid.[14] PPARα is present in undifferentiated mono­cytes and in macrophages. Ligands for PPARγ cause apoptosis of activated macrophages. [5] Clearly there ought to be therapeutic potential here. Also PPARγ ligands inhibit macrophage inflammatory responses, [15] espe­cially in a murine system, [16] but one must note that the presence of IFNγ might prevent PPARγ ligands from completely suppressing macrophage proinflammatory cytokines! [16] Moreover the latter study revealed that there were differences in potency of the PPARγ ligands attributable to differences in their PPARγ binding site affinities, and the effectiveness of the ligands did depend on the nature of the inciting stimulus. One will note furthermore that nitric oxide donors can switch monocyte-macrophages from a pro- to an anti-inflammatory phenotype by activation of PPAR as shown by EMSAs. [17] In particular a PPARγ responsive gene product attenuates the respiratory burst of macrophages. [17]

The anti-inflammatory effect of PPARγ ligands directed at macrophages is impre­ssive, [18] albeit one must be aware that all publications do not concur. [19] PPARγ ligands (i) decrease the output of vital cytokines like I1-1β , I1-6, TNFa and I1-12, (ii) decrease the expression of iNOS by macrophages, (iii) decrease the formation of metalloproteinases. [20] There can be induction of macrophage apoptosis.

PPAR Ligands and Renal Pathology

In view of these actions one will not be surprised that the PPARγ agonist troglita­zone confers protection against glomerulo­sclerosis in rats with 5/6 nephrectomy. [21] There was reduction of glomerular cell proliferation associated with a reduction of glomerular macrophages which would mean decreased ROS related injury. TGFβ was decreased in glomerular and tubular epithelial cells. So was the expression of PAI-1 which could reflect the suppressive action of PPARγ on NF-kB and AP-I. [21] We know too that PPARα and γ repress TNFa induced expression of selections required for the recruitment of leucocytes. [22]

In addition to the TZDs, various NSAIDs are PPARγ ligands, and 15dPGJ2 and 13HODE and 15HETE [Table - 1]. [23] The cyclopentenone 15dPGJ2 might seem desi­rable as a therapeutic agent, for it is an NFkB inhibitor [24] and it can prevent macrophage activation. [25] Actually at low micromolar concentrations it is proinflammatory [26] and larger concentrations must be sustained for beneficial effect! One can assume that an elevated expression of PPARD on renal tubular epithelial cells and on mesangial cells will service to restrict tissue damage, as can be demonstrated with unilateral renal obstruction in rats. [27] However under normal circumstances these receptors have restricted tissue distribution. [2] PPARα species that play a major role in fatty acid utilization co­localize with P450 4A enzymes in the proximal tubules and thick limbs. PPARγ are predominantly in the collecting ducts, but present also on mesangial cells. The distribution suggests functions related to water and sodium balance and control of blood pressure that are not yet fully elucidated. [2] Using the mesangial cells of diabetic mice Zheng et al [28] used transfection with PPARγ expression construct and application of troglitazone to show induced suppression of TGFβ1 and production of type I collagen and mRNA. This confirms the ability of PPARγ to lessen glomerulosclerosis in non­diabetic and diabetic context.


   PPAR and Immune Reactions Top


Since NFkB promotes iNOS, one might expect PPARγ or PGJ2 to reduce iNOS activity as was shown in mesangial cells. [29] Yet in spite of NFkB inhibition some PPAR agonists act via independent mechanisms to promote iNOS expression in mesangial cells. [30] Generally NO is anti-inflammatory and will downregulate cytokine formation.

There are big differences between murine and human dendritic cells (DCs) and eluci­dation of some problems is slow. Using human monocyte derived DCs Gosset et al [31] found that PPARγ activation inhibited secretion of I1-12 which could indicate that they become DC-2 which will impair for­mation of Th-1 lymphocytes. Now Nencioni et al [32] report that activation of PPARγ during DC differentiation so alters costimula­tory molecules that there is then impaired ability to activate lymphocytes and to prime cytotoxic T cells. So the TZDs might create more profound immunosuppression than anticipated in some persons.

Troglitazone and 15dPGJ2 inhibit production of I1-2 and PHA induced T lymphocyte proliferation in proportion to dosage [33] and PPARγ agonists can induce apoptosis of human B lineage cells. [34] Add to these facts the information that PPARγ activators inhibit IFNγ induced expression of chemokines for T cells like IP-10, [35] and TNFa induction of the selectins [22] and one has a very good case for suggesting that PPARγ agonists could be important adjunct therapy for conditions like lupus glomerulonephritis. Clearly the TZDs will be advantageous in persons who might be subject to compli­cations of corticosteroid therapy, but they can cause weight gain and fluid retention in proportion to dosage.

 
   References Top

1.Berger J, Moller DE. The mechanisms of action of PPARs. Ann Rev Med 2002;53: 409-35.  Back to cited text no. 1  [PUBMED]  [FULLTEXT]
2.Guan Y, Breyer MD. Peroxisome proliferator activated receptors (PPARs): novel therapeutic targets in renal disease. Kid Int 2001;60:14-30.  Back to cited text no. 2    
3.Vamecq J, Latruffe N. Medical significance of perioxisome proliferator activated receptors. Lancet 1999;354:141-8.  Back to cited text no. 3  [PUBMED]  [FULLTEXT]
4.Zhang J, Fu M, Zhu X, et al. Peroxisome proliferator activated receptor delta is up­regulated during vascular lesion formation and promotes post-confluent cell proli­feration in vascular smooth muscle cells. J Biol Chem 2002;277:11505-12.  Back to cited text no. 4  [PUBMED]  [FULLTEXT]
5.Chinetti C, Griglio S, Antonucci M, et al. Activation of proliferator-activated receptors delta and gamma induces apoptosis of human monocyte derived macrophages. J Biol Chem 1998;273: 25573-80.  Back to cited text no. 5    
6.Oates J C, Reilly C M, Crosby MB, Gilkeson GS. Peroxisome proliferator activated receptor gamma agonists: potential use for treating chronic inflammatory diseases. Arthritis Rheum 2002;46:598-605.  Back to cited text no. 6    
7.Duval C, Chinetti G, Trottein F, Fruchart JC, Staels B. The role of PPARs in atherosclerosis. Trends Mol Med 2002;8: 422-30.  Back to cited text no. 7  [PUBMED]  [FULLTEXT]
8.Marx N, Sukhovra GK, Collins T, Libby P, Plutzky J. PPAR alpha activators inhibit cytokine induced vascular cell adhesion molecule-1 expression in human endothelial cells. Circulation 1999;99:3125-31.  Back to cited text no. 8    
9.Wang N, Verna L, Chen NG, et al. Constitutive activation of Peroxisome proli­ferator activated receptor gamma suppresses pro-inflammatory adhesion molecules in human vascular endothelial cells. J Biol Chem 2002;277:34176-81.  Back to cited text no. 9  [PUBMED]  [FULLTEXT]
10.Delerive P, DeBosscher K, Besnard S, et al. Peroxisome proliferator activated receptor gamma negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors: NF­Kappa Band AP-1. J Biol Chem 1994;274: 32048-54.  Back to cited text no. 10    
11.Jiang C, Ting AT, Seed B. PPAR gamma agonists inhibit production of monocyte inflammatory cytokines. Nature 1998;391: 82-6.  Back to cited text no. 11  [PUBMED]  [FULLTEXT]
12.Chinetti G, Lestavels, Bocher V, et al. PPAR alpha and PPAR gamma activators induce cholesterol removal from human macro­phage foam cells through stimulation of the ABC A1 pathway. Nat Med 2001;7: 53-8.  Back to cited text no. 12    
13.Pontsler AV, St Hilaire A, Mamathe GK, Zimmerman GA, McIntyre TM. Cyclo­oxygenase-2 is induced in monocytes by Peroxisome proliferator activated receptor gamma and oxidised alkyl phospholipids from oxidised low density lipoprotion. J Biol Chem 2002;277:13029-36.  Back to cited text no. 13    
14.Chawla A, Barak Y, Nagy L, et al. PPAR gamma dependent and independent effects on macrophage gene expression in lipid metabolism and inflammation. Nat Med 2001;7:48-52.  Back to cited text no. 14  [PUBMED]  [FULLTEXT]
15.Ricote M, Huang J T, Welch J S, Glass CK. The Peroxisome proliferator activated receptor gamma as a regulator of monocyte/ macro­phage function. J Leukoc Biol 1999; 66:733-9.  Back to cited text no. 15    
16.Alleva DG, Johnson E B, Lio FM. Boehme SA, Conlon PJ, Crowe PD, et al. Regulation of murine macrophage proinflammatory and anti-inflammatory cytokines by ligands for Peroxisome proliferator activated receptor gamma: counter-regulatory activity by IFN gamma. J Leukoc Biol 2002;71:677-85.  Back to cited text no. 16    
17.Von Knethen A, Brune B. Activation of Peroxisome proliferator activated receptor gamma by nitric oxide in monocyte/ macrophages down-regulates p47phox and attenuates the respiratory burst. J Immunol 2002;169:2619-26.  Back to cited text no. 17    
18.Clark RB. The role of PPARs in inflammation and immunity. J Leukoc Biol 2002;71:388-400.  Back to cited text no. 18  [PUBMED]  [FULLTEXT]
19.Thieringer R, Fenyk-Melody JE, Le Grand C, et al. Activation of Peroxisome proliferator activated receptor gamma does not inhibit IL-6 or TNF alpha responses of macrophages to lipopoly­saccharide in vitro or in vivo. J Immunol 2000;164:1046-54.  Back to cited text no. 19    
20.Shu H, Wong B, Zhou G, et al. Activation of PPAR alpha or gamma reduces secretion of matrix metalloproteinase 9 but not interleukin 8 from human monocytic THP-1 cells. Biochem Biophys Res Common 2000; 267:345-9.  Back to cited text no. 20    
21.Ma LJ, Marcantoni C, Linton MF Fazio S, Fogo AB. Peroxisome proliferator activated receptor gamma agonist troglitazone protects against nondiabetic glomerulo­sclerosis in rats. Kidney Int 2001;59:1899-­910.  Back to cited text no. 21    
22.Nawa T, Nawa MT, Cai Y, et al. Repression of TNF alpha induced E-selectin expression by PPAR activators. Biochem Biophys Res Common 2000;275:406-11.  Back to cited text no. 22    
23.Huang J T, Welch J S, Ricote M, et al. Interleukin-4-dependent production of PPAR gamma ligands in macrophages by 12/15 lipoxygenase. Nature 1999;400:378-82.  Back to cited text no. 23    
24.Straus D S, Pascual G, Li M, et al. 15­deoxy delta 12,14-prostaglandin J2 inhibits multiple steps in the NF-KappaB signaling pathway. Proc Natl Acad Sci USA 2000; 97:4844-9.  Back to cited text no. 24    
25.Guyton K, Bond R, Reilly C, et al. Differential effects of 15-deoxy delta (12,14) prostaglandin J2 and Peroxisome proliferator activated receptor gamma agonist on macrophage activation. J Leukoc Biol 2001;69:631-8.  Back to cited text no. 25  [PUBMED]  [FULLTEXT]
26.Bureau F, Desmet C, Melotte D, et al. A proinflammatory role for the cyclopentenone prostaglandins at low micromolar concen­trations. J Immunol 2002;168:5318-25.  Back to cited text no. 26    
27.Sommer M, Eismann U, Gerth J, Stein G. Upregulation of PPAR11and GSK311during the development of renal interstitial fibrosis in rats with unilateral ureteral obstruction. In press.  Back to cited text no. 27    
28.Zheng F, Fornoni A, Elliott SJ, et al. Upregulation of type I collagen by TGF­beta in mesangial cells is blocked by PPAR gamma activation. Am J Physiol Renal Physiol. 2002;282:F639-48.  Back to cited text no. 28    
29.Reilly CM, Oates JC, Sudian J, et al. Prostaglandin J (2) inhibition of mesangial cell iNOS expression. Clin Immunol 2001;98:337-45.  Back to cited text no. 29  [PUBMED]  [FULLTEXT]
30.Cernuda-Morollon E, Rodriguez-Pascual F, Klatt P, Lamas S, Perez-Sala D. PPAR agonists amplify iNOS expression while inhibiting NF-kappaB: implications for mesangial cell activation by cytokines. J Am Soc Nephrol 2002;13:2223-31.  Back to cited text no. 30    
31.Gosset P, Charbonnier AS, Delerive P, et al. Peroxisome proliferator activated receptor gamma activators affect the maturation of human monocyte derived dendritic cells. Eur J Immunol 2001;21:2857-62.  Back to cited text no. 31    
32.Nencioni A, Grunebach F, Zobywlaski A, et al. Dendritic cell immunogenicity is regulated by Peroxisome proliferator activated receptor gamma. J Immunol 2002;169:1228-35.  Back to cited text no. 32    
33.Yang X Y, Wang L H, Chen T, et al. Activation of human T lymphocytes is inhibited by PPARD agonists. J Biol Chem 2000;275:4541-4.  Back to cited text no. 33    
34.Padilla J, Leung E, Phipps RP. Human B lymphocytes and B lymphomas express PPAR gamma and are killed by PPAR gamma agonists. Clin Immunol 2002;103:22-33.  Back to cited text no. 34  [PUBMED]  [FULLTEXT]
35.Marx N, Mach F, Sauty A, et al. Peroxisome proliferator activated receptor gamma activators inhibit IFN gamma induced expression of the T cell active CXC chemokines IP-10, Mig and I-TAC in human endothelial cells. J Immunol 2000;164: 6503-8.  Back to cited text no. 35  [PUBMED]  [FULLTEXT]

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Correspondence Address:
E Nigel Wardle
37 Princess Road, Camden, London NW1 8JS
United Kingdom
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