Peroxisome Proliferator-Activated Receptors and Inflammation

Part of the The Receptors book series (REC, volume 24)


The peroxisome proliferator-activated receptors belong to the superfamily of nuclear receptors which produce their effects, in part, by regulation of gene transcription. There are three peroxisome proliferator-activated receptor (PPAR) isoforms; α, δ (also known as β), and γ, which are activated by a numerous ligands including endocannabinoids. Activation of these receptors has been shown to modulate inflammation, in a number of different animal models. This chapter discusses the evidence that PPAR activation modulates inflammation, inflammatory processes, and immune cell infiltration, as well as reports of adverse effects of PPAR activation, which may have an impact on the therapeutic potential of PPAR agonists as anti-inflammatory agents.


Chronic Constriction Injury Experimental Allergic Encephalomyelitis Fatty Acid Amide Hydrolase Glyceryl Ether Immune Cell Infiltration 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Interleukin 1 beta




Peroxisome proliferator-activated receptors alpha


Peroxisome proliferator-activated receptors beta


Peroxisome proliferator-activated receptors gamma


  1. Aoyama T, Peters J, Iritanii N, Nakajima T, Furihata K, Hashimoto T, and Gonzalez F (1998) Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor a (PPARa). J Biol Chem 273(10):5678–5684PubMedCrossRefGoogle Scholar
  2. Berger J, Moller DE (2002) The mechanisms of action of PPARs. Annu Rev Med 53:409–435PubMedCrossRefGoogle Scholar
  3. Bouaboula M, Hilairet S, Marchand J, Fajas L, Le Fur G, Casellas P (2005) Anandamide induced PPARgamma transcriptional activation and 3T3-L1 preadipocyte differentiation. Eur J Pharmacol 517(3):174–181PubMedCrossRefGoogle Scholar
  4. Brady PS, Marine KA, Brady LJ, Ramsay RR (1989) Co-ordinate induction of hepatic mitochondrial and peroxisomal carnitine acyltransferase synthesis by diet and drugs. Biochem J 260(1): 93–100PubMedGoogle Scholar
  5. Bright JJ, Kanakasabai S, Chearwae W, Chakraborty S (2008) PPAR regulation of inflammatory signaling in CNS diseases. PPAR Res 2008:658520PubMedCrossRefGoogle Scholar
  6. Carta AR, Frau L, Pisanu A, Wardas J, Spiga S, Carboni E (2011) Rosiglitazone decreases peroxisome proliferator receptor-gamma levels in microglia and inhibits TNF-alpha production: new evidences on neuroprotection in a progressive Parkinson’s disease model. Neuroscience 194:250–261PubMedCrossRefGoogle Scholar
  7. Chen JD, Evans RM (1995) A transcriptional co-repressor that interacts with nuclear hormone receptors. Nature 377(6548):454–457PubMedCrossRefGoogle Scholar
  8. Chinetti G, Griglio S, Antonucci M, Torra IP, Delerive P, Majd Z, Fruchart JC, Chapman J, Najib J, Staels B (1998) Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages. J Biol Chem 273(40):25573–25580PubMedCrossRefGoogle Scholar
  9. Clark R (2002) The role of PPARs in inflammation and immunity. J Leukoc Biol 71(3):388–400PubMedCrossRefGoogle Scholar
  10. Costa B, Comelli F, Bettoni I, Colleoni M, Giagnoni G (2008) The endogenous fatty acid amide, palmitoylethanolamide, has anti-allodynic and anti-hyperalgesic effects in a murine model of neuropathic pain: involvement of CB(1), TRPV1 and PPARgamma receptors and neurotrophic factors. Pain 139(3):541–550PubMedCrossRefGoogle Scholar
  11. Costa B, Russo D, Ronzulli D, Comelli F (2011) Experimental osteoarthritis in rats is attenuated by oral administration of palmitoylethanolamde. In: 21st annual symposium on the cannabinoids. International Cannabinoid Research Society, Research Triangle Park, NC, p 7Google Scholar
  12. Cunard R, DiCampli D, Archer DC, Stevenson JL, Ricote M, Glass CK, Kelly CJ (2002a) WY14,643, a PPAR alpha ligand, has profound effects on immune responses in vivo. J Immunol 169(12):6806–6812PubMedGoogle Scholar
  13. Cunard R, Ricote M, DiCampli D, Archer DC, Kahn DA, Glass CK, Kelly CJ (2002b) Regulation of cytokine expression by ligands of peroxisome proliferator activated receptors. J Immunol 168(6):2795–2802PubMedGoogle Scholar
  14. Defaux A, Zurich MG, Braissant O, Honegger P, Monnet-Tschudi F (2009) Effects of the PPAR-beta agonist GW501516 in an in vitro model of brain inflammation and antibody-induced demyelination. J Neuroinflammation 6:15PubMedCrossRefGoogle Scholar
  15. Delayre-Orthez C, Becker J, Guenon I, Lagente V, Auwerx J, Frossard N, Pons F (2005) PPARalpha downregulates airway inflammation induced by lipopolysaccharide in the mouse. Respir Res 6:91PubMedCrossRefGoogle Scholar
  16. Delerive P, Fruchart JC, Staels B (2001) Peroxisome proliferator-activated receptors in inflammation control. J Endocrinol 169(3):453–459PubMedCrossRefGoogle Scholar
  17. Devchand PR, Keller H, Peters JM, Vazquez M, Gonzalez FJ, Wahli W (1996) The PPARalpha-leukotriene B4 pathway to inflammation control. Nature 384(6604):39–43PubMedCrossRefGoogle Scholar
  18. Diab A, Deng C, Smith JD, Hussain RZ, Phanavanh B, Lovett-Racke AE, Drew PD, Racke MK (2002) Peroxisome proliferator-activated receptor-gamma agonist 15-deoxy-Delta(12,14)-prostaglandin J(2) ameliorates experimental autoimmune encephalomyelitis. J Immunol 168(5):2508–2515PubMedGoogle Scholar
  19. Frode TS, Buss Zda S, dos Reis GO, Medeiros YS (2009) Evidence of anti-inflammatory effects of pioglitazone in the murine pleurisy model induced by carrageenan. Int Immunopharmacol 9(12):1394–1400PubMedCrossRefGoogle Scholar
  20. Gasperi V, Fezza F, Pasquariello N, Bari M, Oddi S, Agro AF, Maccarrone M (2007) Endocannabinoids in adipocytes during differentiation and their role in glucose uptake. Cell Mol Life Sci 64(2):219–229PubMedCrossRefGoogle Scholar
  21. Genovese T, Mazzon E, Di Paola R, Muia C, Crisafulli C, Malleo G, Esposito E, Cuzzocrea S (2006) Role of peroxisome proliferator-activated receptor-alpha in acute pancreatitis induced by cerulein. Immunology 118(4):559–570PubMedGoogle Scholar
  22. Horlein AJ, Naar AM, Heinzel T, Torchia J, Gloss B, Kurokawa R, Ryan A, Kamei Y, Soderstrom M, Glass CK et al (1995) Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor. Nature 377(6548):397–404PubMedCrossRefGoogle Scholar
  23. Jhaveri MD, Richardson D, Robinson I, Garle MJ, Patel A, Sun Y, Sagar DR, Bennett AJ, Alexander SP, Kendall DA, Barrett DA, Chapman V (2008) Inhibition of fatty acid amide hydrolase and cyclooxygenase-2 increases levels of endocannabinoid related molecules and produces analgesia via peroxisome proliferator-activated receptor-alpha in a model of inflammatory pain. Neuropharmacology 55(1):85–93PubMedCrossRefGoogle Scholar
  24. Jiang H, Dhib-Jalbut S (1998) Differential induction of IL-12 by IFN-beta and IFN-gamma in human macrophages. J Interferon Cytokine Res 18(9):697–703PubMedCrossRefGoogle Scholar
  25. Kozak KR, Gupta RA, Moody JS, Ji C, Boeglin WE, DuBois RN, Brash AR, Marnett LJ (2002) 15-Lipoxygenase metabolism of 2-arachidonylglycerol. Generation of a peroxisome proliferator-activated receptor alpha agonist. J Biol Chem 277(26):23278–23286PubMedCrossRefGoogle Scholar
  26. Kumagai T, Matsukawa N, Kaneko Y, Kusumi Y, Mitsumata M, Uchida K (2004) A lipid peroxidation-derived inflammatory mediator: identification of 4-hydroxy-2-nonenal as a potential inducer of cyclooxygenase-2 in macrophages. J Biol Chem 279(46):48389–48396PubMedCrossRefGoogle Scholar
  27. LoVerme J, La Rana G, Russo R, Calignano A, Piomelli D (2005) The search for the palmitoylethanolamide receptor. Life Sci 77(14):1685–1698PubMedCrossRefGoogle Scholar
  28. Martin G, Schoonjans K, Lefebvre AM, Staels B, Auwerx J (1997) Coordinate regulation of the expression of the fatty acid transport protein and acyl-CoA synthetase genes by PPARalpha and PPARgamma activators. J Biol Chem 272(45):28210–28217PubMedCrossRefGoogle Scholar
  29. McTigue DM (2008) Potential therapeutic targets for PPARgamma after spinal cord injury. PPAR Res 2008:517162PubMedCrossRefGoogle Scholar
  30. Mendez M, LaPointe MC (2003) PPARgamma inhibition of cyclooxygenase-2, PGE2 synthase, and inducible nitric oxide synthase in cardiac myocytes. Hypertension 42(4):844–850PubMedCrossRefGoogle Scholar
  31. Motojima K, Passilly P, Peters JM, Gonzalez FJ, Latruffe N (1998) Expression of putative fatty acid transporter genes are regulated by peroxisome proliferator-activated receptor alpha and gamma activators in a tissue- and inducer-specific manner. J Biol Chem 273(27):16710–16714PubMedCrossRefGoogle Scholar
  32. Natarajan C, Bright JJ (2002) Peroxisome proliferator-activated receptor-gamma agonists inhibit experimental allergic encephalomyelitis by blocking IL-12 production, IL-12 signaling and Th1 differentiation. Genes Immun 3(2):59–70PubMedCrossRefGoogle Scholar
  33. Natarajan C, Muthian G, Barak Y, Evans RM, Bright JJ (2003) Peroxisome proliferator-activated receptor-gamma-deficient heterozygous mice develop an exacerbated neural antigen-induced Th1 response and experimental allergic encephalomyelitis. J Immunol 171(11):5743–5750PubMedGoogle Scholar
  34. Ohshima T, Koga H, Shimotohno K (2004) Transcriptional activity of peroxisome proliferator-activated receptor g Is modulated by SUMO-1 modification. J Biol Chem 279(28):29551–29557PubMedGoogle Scholar
  35. O’Sullivan SE, Kendall DA (2010) Cannabinoid activation of peroxisome proliferator-activated receptors: potential for modulation of inflammatory disease. Immunobiology 215(8):611–616PubMedCrossRefGoogle Scholar
  36. O’Sullivan SE, Tarling EJ, Bennett AJ, Kendall DA, Randall MD (2005) Novel time-dependent vascular actions of Delta9-tetrahydrocannabinol mediated by peroxisome proliferator-activated receptor gamma. Biochem Biophys Res Commun 337(3):824–831PubMedCrossRefGoogle Scholar
  37. O’Sullivan SE, Kendall DA, Randall MD (2006) Further characterization of the time-dependent vascular effects of delta9-tetrahydrocannabinol. J Pharmacol Exp Ther 317(1):428–438PubMedCrossRefGoogle Scholar
  38. Raikwar HP, Muthian G, Rajasingh J, Johnson C, Bright JJ (2005) PPARgamma antagonists exacerbate neural antigen-specific Th1 response and experimental allergic encephalomyelitis. J Neuroimmunol 167(1–2):99–107PubMedCrossRefGoogle Scholar
  39. Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK (1998) The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature 391(6662):79–82PubMedCrossRefGoogle Scholar
  40. Rockwell CE, Kaminski NE (2004) A cyclooxygenase metabolite of anandamide causes inhibition of interleukin-2 secretion in murine splenocytes. J Pharmacol Exp Ther 311(2):683–690PubMedCrossRefGoogle Scholar
  41. Rockwell CE, Snider NT, Thompson JT, Vanden Heuvel JP, Kaminski NE (2006) Interleukin-2 suppression by 2-arachidonyl glycerol is mediated through peroxisome proliferator-activated receptor gamma independently of cannabinoid receptors 1 and 2. Mol Pharmacol 70(1):101–111PubMedGoogle Scholar
  42. Sawano H, Haneda M, Sugimoto T, Inoki K, Koya D, Kikkawa R (2002) 15-Deoxy-Delta12,14-prostaglandin J2 inhibits IL-1beta-induced cyclooxygenase-2 expression in mesangial cells. Kidney Int 61(6):1957–1967PubMedCrossRefGoogle Scholar
  43. Sethi S, Ziouzenkova O, Ni H, Wagner DD, Plutzky J, Mayadas TN (2002) Oxidized omega-3 fatty acids in fish oil inhibit leukocyte-endothelial interactions through activation of PPAR alpha. Blood 100(4):1340–1346PubMedCrossRefGoogle Scholar
  44. Shearer BG, Billin AN (2007) The next generation of PPAR drugs: do we have the tools to find them? Biochim Biophys Acta 1771(8):1082–1093PubMedCrossRefGoogle Scholar
  45. Shie FS, Nivison M, Hsu PC, Montine TJ (2009) Modulation of microglial innate immunity in Alzheimer’s disease by activation of peroxisome proliferator-activated receptor gamma. Curr Med Chem 16(6):643–651PubMedCrossRefGoogle Scholar
  46. Shiojiri T, Wada K, Nakajima A, Katayama K, Shibuya A, Kudo C, Kadowaki T, Mayumi T, Yura Y, Kamisaki Y (2002) PPAR gamma ligands inhibit nitrotyrosine formation and inflammatory mediator expressions in adjuvant-induced rheumatoid arthritis mice. Eur J Pharmacol 448(2–3):231–238PubMedCrossRefGoogle Scholar
  47. Sun Y, Alexander SP, Kendall DA, Bennett AJ (2006) Cannabinoids and PPARalpha signalling. Biochem Soc Trans 34(Pt 6):1095–1097PubMedGoogle Scholar
  48. Sun Y, Alexander SP, Garle MJ, Gibson CL, Hewitt K, Murphy SP, Kendall DA, Bennett AJ (2007) Cannabinoid activation of PPAR alpha; a novel neuroprotective mechanism. Br J Pharmacol 152(5):734–743PubMedCrossRefGoogle Scholar
  49. Wellen KE, Hotamisligil GS (2005) Inflammation, stress, and diabetes. J Clin Invest 115(5): 1111–1119PubMedGoogle Scholar
  50. Woerly G, Honda K, Loyens M, Papin JP, Auwerx J, Staels B, Capron M, Dombrowicz D (2003) Peroxisome proliferator-activated receptors alpha and gamma down-regulate allergic inflammation and eosinophil activation. J Exp Med 198(3):411–421PubMedCrossRefGoogle Scholar
  51. Xu HE, Lambert MH, Montana VG, Parks DJ, Blanchard SG, Brown PJ, Sternbach DD, Lehmann JM, Wisely GB, Willson TM, Kliewer SA, Milburn MV (1999) Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol Cell 3(3):397–403PubMedCrossRefGoogle Scholar
  52. Xu J, Barger SW, Drew PD (2008) The PPAR-gamma agonist 15-deoxy-delta-prostaglandin J(2) attenuates microglial production of IL-12 family cytokines: potential relevance to Alzheimer’s disease. PPAR Res 2008:349185PubMedCrossRefGoogle Scholar
  53. Yang Y, Gocke AR, Lovett-Racke A, Drew PD, Racke MK (2008) PPAR alpha regulation of the immune response and autoimmune encephalomyelitis. PPAR Res 2008:546753PubMedGoogle Scholar
  54. Zandbergen F, Plutzky J (2007) PPARalpha in atherosclerosis and inflammation. Biochim Biophys Acta 1771(8):972–982PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Arthritis Research UK Pain Centre, School of Biomedical SciencesUniversity of Nottingham Medical School, Queen’s Medical CentreNottinghamUK
  2. 2.School of Biomedical SciencesUniversity of Nottingham Medical School, Queen’s Medical CentreNottinghamUK

Personalised recommendations