Abstract
Members of the nuclear receptor superfamily function as transcription factors involved in innate and adaptive immunity as well as lipid metabolism. These highly conserved proteins participate in ligand-dependent or -independent regulatory mechanisms that affect gene expression. Peroxisome proliferator-activated receptors (PPARs), which include PPARα, PPARβ/δ, and PPARΓ, are a group of nuclear receptor proteins that play diverse roles in cellular differentiation, development, and metabolism. Each PPAR subfamily is activated by different endogenous and synthetic ligands. Recent studies using specific ligand treatments and cell type-specific PPAR knockout mice have revealed important roles for these proteins in T-cell-related autoimmune diseases. Moreover, PPARs have been shown to regulate T-cell survival, activation, and CD4+ T helper cell differentiation into the Th1, Th2, Th17, and Treg lineages. Here, we review the studies that provide insight into the important regulatory roles of PPARs in T-cell activation, survival, proliferation, differentiation, and autoimmune disease.
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Agostini, M., Schoenmakers, E., Mitchell, C., Szatmari, I., Savage, D., Smith, A., Rajanayagam, O., Semple, R., Luan, J., Bath, L., et al. (2006). Non-DNA binding, dominant-negative, human PPARgamma mutations cause lipodystrophic insulin resistance. Cell Metab. 4, 303–311.
Akiyama, T.E., Baumann, C.T., Sakai, S., Hager, G.L., and Gonzalez, F.J. (2002). Selective intranuclear redistribution of PPAR isoforms by RXR alpha. Mol. Endocrinol. 16, 707–721.
Azuma, Y.T., Nishiyama, K., Matsuo, Y., Kuwamura, M., Morioka, A., Nakajima, H., and Takeuchi, T. (2010). PPARalpha contributes to colonic protection in mice with DSS-induced colitis. Int. Immunopharmacol. 10, 1261–1267.
Baratelli, F., Lin, Y., Zhu, L., Yang, S.C., Heuze-Vourc’h, N., Zeng, G., Reckamp, K., Dohadwala, M., Sharma, S., and Dubinett, S.M. (2005). Prostaglandin E2 induces FOXP3 gene expression and T regulatory cell function in human CD4+ T cells. J. Immunol. 175, 1483–1490.
Barish, G.D., Atkins, A.R., Downes, M., Olson, P., Chong, L.W., Nelson, M., Zou, Y., Hwang, H., Kang, H., Curtiss, L., et al. (2008). PPARdelta regulates multiple proinflammatory pathways to suppress atherosclerosis. Proc. Natl. Acad. Sci. USA 105, 4271–4276.
Barroso, I., Gurnell, M., Crowley, V.E., Agostini, M., Schwabe, J.W., Soos, M.A., Maslen, G.L., Williams, T.D., Lewis, H., Schafer, A.J., et al. (1999). Dominant negative mutations in human PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension. Nature 402, 880–883.
Berger, J., Leibowitz, M.D., Doebber, T.W., Elbrecht, A., Zhang, B., Zhou, G., Biswas, C., Cullinan, C.A., Hayes, N.S., Li, Y., et al. (1999). Novel peroxisome proliferator-activated receptor (PPAR) gamma and PPARdelta ligands produce distinct biological effects. J. Biol. Chem. 274, 6718–6725.
Chan, M.M., Evans, K.W., Moore, A.R., and Fong, D. (2010). Peroxisome proliferator-activated receptor (PPAR): balance for survival in parasitic infections. J. Biomed. Biotechnol. 2010, 828951.
Chandra, V., Huang, P., Hamuro, Y., Raghuram, S., Wang, Y., Burris, T.P., and Rastinejad, F. (2008). Structure of the intact PPAR-gamma-RXR-nuclear receptor complex on DNA. Nature 456, 350–356.
Chawla, A., Repa, J.J., Evans, R.M., and Mangelsdorf, D.J. (2001) Nuclear receptors and lipid physiology: opening the X-files. Science 294, 1866–1870.
Choi, J.M., Ahn, M.H., Chae, W.J., Jung, Y.G., Park, J.C., Song, H.M., Kim, Y.E., Shin, J.A., Park, C.S., Park, J.W., et al. (2006). Intranasal delivery of the cytoplasmic domain of CTLA-4 using a novel protein transduction domain prevents allergic inflammation. Nat. Med. 12, 574–579.
Choi, J.M., Shin, J.H., Sohn, M.H., Harding, M.J., Park, J.H., Tobiasova, Z., Kim, D.Y., Maher, S.E., Chae, W.J., Park, S.H., et al. (2010). Cell-permeable Foxp3 protein alleviates autoimmune disease associated with inflammatory bowel disease and allergic airway inflammation. Proc. Natl. Acad. Sci. USA 107, 18575–18580.
Clark, R.B., Bishop-Bailey, D., Estrada-Hernandez, T., Hla, T., Puddington, L., and Padula, S.J. (2000). The nuclear receptor PPAR gamma and immunoregulation: PPAR gamma mediates inhibition of helper T cell responses. J. Immunol. 164, 1364–1371.
Daynes, R.A., and Jones, D.C. (2002). Emerging roles of PPARs in inflammation and immunity. Nat. Rev. Immunol. 2, 748–759.
Delerive, P., De Bosscher, K., Besnard, S., Vanden Berghe, W., Peters, J.M., Gonzalez, F.J., Fruchart, J.C., Tedgui, A., Haegeman, G., and Staels, B. (1999). Peroxisome proliferator-activated receptor alpha negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-kappaB and AP-1. J. Biol. Chem. 274, 32048–32054.
Desreumaux, P., Dubuquoy, L., Nutten, S., Peuchmaur, M., Englaro, W., Schoonjans, K., Derijard, B., Desvergne, B., Wahli, W., Chambon, P., et al. (2001). Attenuation of colon inflammation through activators of the retinoid X receptor (RXR)/peroxisome proliferator-activated receptor gamma (PPARgamma) heterodimer. A basis for new therapeutic strategies. J. Exp. Med. 193, 827–838.
Dunn, S.E., Ousman, S.S., Sobel, R.A., Zuniga, L., Baranzini, S.E., Youssef, S., Crowell, A., Loh, J., Oksenberg, J., and Steinman, L. (2007). Peroxisome proliferator-activated receptor (PPAR) alpha expression in T cells mediates gender differences in development of T cell-mediated autoimmunity. J. Exp. Med. 204, 321–330.
Dunn, S.E., Bhat, R., Straus, D.S., Sobel, R.A., Axtell, R., Johnson, A., Nguyen, K., Mukundan, L., Moshkova, M., Dugas, J.C., et al. (2010) Peroxisome proliferator-activated receptor delta limits the expansion of pathogenic Th cells during central nervous system autoimmunity. J. Exp. Med. 207, 1599–1608.
Fajas, L., Auboeuf, D., Raspe, E., Schoonjans, K., Lefebvre, A.M., Saladin, R., Najib, J., Laville, M., Fruchart, J.C., Deeb, S., et al. (1997). The organization, promoter analysis, and expression of the human PPARgamma gene. J. Biol. Chem. 272, 18779–18789.
Forman, B.M., Tontonoz, P., Chen, J., Brun, R.P., Spiegelman, B. M., and Evans, R.M. (1995). 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell 83, 803–812.
Forman, B.M., Chen, J., and Evans, R.M. (1997). Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta. Proc. Natl. Acad. Sci. USA 94, 4312–4317.
Gervois, P., Fruchart, J.C., and Staels, B. (2007). Drug Insight:mechanisms of action and therapeutic applications for agonists of peroxisome proliferator-activated receptors. Nat. Clin. Pract. Endocrinol. Metab. 3, 145–156.
Glass, C.K., and Ogawa, S. (2006). Combinatorial roles of nuclear receptors in inflammation and immunity. Nat. Rev. Immunol. 6, 44–55.
Glass, C.K., and Saijo, K. (2010). Nuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells. Nat. Rev. Immunol. 10, 365–376.
Gocke, A.R., Hussain, R.Z., Yang, Y., Peng, H., Weiner, J., Ben, L.H., Drew, P.D., Stuve, O., Lovett-Racke, A.E., and Racke, M.K. (2009). Transcriptional modulation of the immune response by peroxisome proliferator-activated receptor-{alpha} agonists in autoimmune disease. J. Immunol. 182, 4479–4487.
Gosset, P., Charbonnier, A.S., Delerive, P., Fontaine, J., Staels, B., Pestel, J., Tonnel, A.B., and Trottein, F. (2001). Peroxisome proliferator-activated receptor gamma activators affect the maturation of human monocyte-derived dendritic cells. Eur. J. Immunol. 31, 2857–2865.
Guan, H.P., Ishizuka, T., Chui, P.C., Lehrke, M., and Lazar, M.A. (2005). Corepressors selectively control the transcriptional activity of PPARgamma in adipocytes. Genes Dev. 19, 453–461.
Guri, A.J., Mohapatra, S.K., Horne, W.T., 2nd, Hontecillas, R., and Bassaganya-Riera, J. (2010). The role of T cell PPAR gamma in mice with experimental inflammatory bowel disease. BMC Gastroenterol. 10, 60.
Harris, S.G., and Phipps, R.P. (2001). The nuclear receptor PPAR gamma is expressed by mouse T lymphocytes and PPAR gamma agonists induce apoptosis. Eur. J. Immunol. 31, 1098–1105.
Hegele, R.A., Cao, H., Frankowski, C., Mathews, S.T., and Leff, T. (2002). PPARG F388L, a transactivation-deficient mutant, in familial partial lipodystrophy. Diabetes 51, 3586–3590.
Hontecillas, R., and Bassaganya-Riera, J. (2007). Peroxisome proliferator-activated receptor gamma is required for regulatory CD4+ T cell-mediated protection against colitis. J. Immunol. 178, 2940–2949.
Housley, W.J., Adams, C.O., Vang, A.G., Brocke, S., Nichols, F.C., LaCombe, M., Rajan, T.V., and Clark, R.B. (2011). Peroxisome proliferator-activated receptor gamma is required for CD4+ T cell-mediated lymphopenia-associated autoimmunity. J. Immunol. 187, 4161–4169.
Itoh, T., Fairall, L., Amin, K., Inaba, Y., Szanto, A., Balint, B.L., Nagy, L., Yamamoto, K., and Schwabe, J.W. (2008). Structural basis for the activation of PPARgamma by oxidized fatty acids. Nat. Struct. Mol. Biol. 15, 924–931.
Jiang, C., Ting, A.T., and Seed, B. (1998). PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature 391, 82–86.
Jo, S.H., Yang, C., Miao, Q., Marzec, M., Wasik, M.A., Lu, P., and Wang, Y.L. (2006). Peroxisome proliferator-activated receptor gamma promotes lymphocyte survival through its actions on cellular metabolic activities. J. Immunol. 177, 3737–3745.
Jones, D.C., Ding, X., and Daynes, R.A. (2002). Nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha) is expressed in resting murine lymphocytes. The PPARalpha in T and B lymphocytes is both transactivation and transrepression competent. J. Biol. Chem. 277, 6838–6845.
Kanakasabai, S., Chearwae, W., Walline, C.C., Iams, W., Adams, S.M., and Bright, J.J. (2010). Peroxisome proliferator-activated receptor delta agonists inhibit T helper type 1 (Th1) and Th17 responses in experimental allergic encephalomyelitis. Immunology 130, 572–588.
Kliewer, S.A., Forman, B.M., Blumberg, B., Ong, E.S., Borgmeyer, U., Mangelsdorf, D.J., Umesono, K., and Evans, R.M. (1994). Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc. Natl. Acad. Sci. USA 91, 7355–7359.
Kliewer, S.A., Sundseth, S.S., Jones, S.A., Brown, P.J., Wisely, G.B., Koble, C.S., Devchand, P., Wahli, W., Willson, T.M., Lenhard, J.M., et al. (1997). Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc. Natl. Acad. Sci. USA 94, 4318–4323.
Klotz, L., Dani, I., Edenhofer, F., Nolden, L., Evert, B., Paul, B., Kolanus, W., Klockgether, T., Knolle, P., and Diehl, L. (2007). Peroxisome proliferator-activated receptor gamma control of dendritic cell function contributes to development of CD4+ T cell anergy. J. Immunol. 178, 2122–2131.
Klotz, L., Burgdorf, S., Dani, I., Saijo, K., Flossdorf, J., Hucke, S., Alferink, J., Nowak, N., Beyer, M., Mayer, G., et al. (2009). The nuclear receptor PPAR gamma selectively inhibits Th17 differentiation in a T cell-intrinsic fashion and suppresses CNS autoimmunity. J. Exp. Med. 206, 2079–2089.
Lee, J.W., Bajwa, P.J., Carson, M.J., Jeske, D.R., Cong, Y., Elson, C.O., Lytle, C., and Straus, D.S. (2007). Fenofibrate represses interleukin-17 and interferon-gamma expression and improves colitis in interleukin-10-deficient mice. Gastroenterology 133, 108–123.
Lehmann, J.M., Moore, L.B., Smith-Oliver, T.A., Wilkison, W.O., Willson, T.M., and Kliewer, S.A. (1995). An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferatoractivated receptor gamma (PPAR gamma). J. Biol. Chem. 270, 12953–12956.
Mangelsdorf, D.J., Thummel, C., Beato, M., Herrlich, P., Schutz, G., Umesono, K., Blumberg, B., Kastner, P., Mark, M., Chambon, P., et al. (1995). The nuclear receptor superfamily: the second decade. Cell 83, 835–839.
McKenna, N.J., and O’Malley, B.W. (2002). Combinatorial control of gene expression by nuclear receptors and coregulators. Cell 108, 465–474.
Moras, D., and Gronemeyer, H. (1998). The nuclear receptor ligand-binding domain: structure and function. Curr. Opin. Cell Biol. 10, 384–391.
Ogawa, S., Lozach, J., Benner, C., Pascual, G., Tangirala, R.K., Westin, S., Hoffmann, A., Subramaniam, S., David, M., Rosenfeld, M.G., et al. (2005). Molecular determinants of crosstalk between nuclear receptors and toll-like receptors. Cell 122, 707–721.
Oliver, W.R., Jr., Shenk, J.L., Snaith, M.R., Russell, C.S., Plunket, K.D., Bodkin, N.L., Lewis, M.C., Winegar, D.A., Sznaidman, M. L., Lambert, M.H., et al. (2001). A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport. Proc. Natl. Acad. Sci. USA 98, 5306–5311.
Pascual, G., Fong, A.L., Ogawa, S., Gamliel, A., Li, A.C., Perissi, V., Rose, D.W., Willson, T.M., Rosenfeld, M.G., and Glass, C.K. (2005). A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. Nature 437, 759–763.
Peraza, M.A., Burdick, A.D., Marin, H.E., Gonzalez, F.J., and Peters, J.M. (2006). The toxicology of ligands for peroxisome pro-liferator-activated receptors (PPAR). Toxicol. Sci. 90, 269–295.
Polak, P.E., Kalinin, S., Dello Russo, C., Gavrilyuk, V., Sharp, A., Peters, J.M., Richardson, J., Willson, T.M., Weinberg, G., and Feinstein, D.L. (2005). Protective effects of a peroxisome proliferator-activated receptor-beta/delta agonist in experimental autoimmune encephalomyelitis. J. Neuroimmunol. 168, 65–75.
Renaud, J.P., Rochel, N., Ruff, M., Vivat, V., Chambon, P., Gronemeyer, H., and Moras, D. (1995). Crystal structure of the RARgamma ligand-binding domain bound to all-trans retinoic acid. Nature 378, 681–689.
Ricote, M., Li, A.C., Willson, T.M., Kelly, C.J., and Glass, C.K. (1998). The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature 391, 79–82.
Ristow, M., Muller-Wieland, D., Pfeiffer, A., Krone, W., and Kahn, C.R. (1998). Obesity associated with a mutation in a genetic regulator of adipocyte differentiation. N. Engl. J. Med. 339, 953–959.
Sanderson, L.M., Degenhardt, T., Koppen, A., Kalkhoven, E., Desvergne, B., Muller, M., and Kersten, S. (2009). Peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) but not PPARalpha serves as a plasma free fatty acid sensor in liver. Mol. Cell. Biol. 29, 6257–6267.
Setoguchi, K., Misaki, Y., Terauchi, Y., Yamauchi, T., Kawahata, K., Kadowaki, T., and Yamamoto, K. (2001). Peroxisome proliferator-activated receptor-gamma haploinsufficiency enhances B cell proliferative responses and exacerbates experimentally induced arthritis. J. Clin. Invest. 108, 1667–1675.
Su, C.G., Wen, X., Bailey, S.T., Jiang, W., Rangwala, S.M., Keilbaugh, S.A., Flanigan, A., Murthy, S., Lazar, M.A., and Wu, G.D. (1999a). A novel therapy for colitis utilizing PPAR-gamma ligands to inhibit the epithelial inflammatory response. J. Clin. Invest. 104, 383–389.
Su, J.L., Winegar, D.A., Wisely, G.B., Sigel, C.S., and Hull-Ryde, E.A. (1999b). Use of a PPAR gamma-specific monoclonal antibody to demonstrate thiazolidinediones induce PPAR gamma receptor expression in vitro. Hybridoma 18, 273–280.
Szanto, A., Balint, B.L., Nagy, Z.S., Barta, E., Dezso, B., Pap, A., Szeles, L., Poliska, S., Oros, M., Evans, R.M., et al. (2010). STAT6 transcription factor is a facilitator of the nuclear receptor PPARgamma-regulated gene expression in macrophages and dendritic cells. Immunity 33, 699–712.
Szatmari, I., Pap, A., Ruhl, R., Ma, J.X., Illarionov, P.A., Besra, G.S., Rajnavolgyi, E., Dezso, B., and Nagy, L. (2006). PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. J. Exp. Med. 203, 2351–2362.
Szatmari, I., Torocsik, D., Agostini, M., Nagy, T., Gurnell, M., Barta, E., Chatterjee, K., and Nagy, L. (2007). PPARgamma regulates the function of human dendritic cells primarily by altering lipid metabolism. Blood 110, 3271–3280.
Takata, Y., Liu, J., Yin, F., Collins, A.R., Lyon, C.J., Lee, C.H., Atkins, A.R., Downes, M., Barish, G.D., Evans, R.M., et al. (2008). PPARdelta-mediated antiinflammatory mechanisms inhibit angiotensin II-accelerated atherosclerosis. Proc. Natl. Acad. Sci. USA 105, 4277–4282.
Tobiasova, Z., Zhang, L., Yi, T., Qin, L., Manes, T.D., Kulkarni, S., Lorber, M.I., Rodriguez, F.C., Choi, J.M., Tellides, G., et al. (2011). Peroxisome proliferator-activated receptor-gamma agonists prevent in vivo remodeling of human artery induced by alloreactive T cells. Circulation 124, 196–205.
Varga, T., Czimmerer, Z., and Nagy, L. (2011). PPARs are a unique set of fatty acid regulated transcription factors controlling both lipid metabolism and inflammation. Biochim. Biophys. Acta 1812, 1007–1022.
Wang, Y.L., Frauwirth, K.A., Rangwala, S.M., Lazar, M.A., and Thompson, C.B. (2002). Thiazolidinedione activation of peroxisome proliferator-activated receptor gamma can enhance mitochondrial potential and promote cell survival. J. Biol. Chem. 277, 31781–31788.
Wohlfert, E.A., Nichols, F.C., Nevius, E., and Clark, R.B. (2007). Peroxisome proliferator-activated receptor gamma (PPAR gamma) and immunoregulation: enhancement of regulatory T cells through PPARgamma-dependent and -independent mechanisms. J. Immunol. 178, 4129–4135.
Yang, X.Y., Wang, L.H., Chen, T., Hodge, D.R., Resau, J.H., Da Silva, L., and Farrar, W.L. (2000). Activation of human T lymphocytes is inhibited by peroxisome proliferator-activated receptor gamma (PPARgamma) agonists. PPARgamma co-association with transcription factor NFAT. J. Biol. Chem. 275, 4541–4544.
Yang, Y., Lovett-Racke, A.E., and Racke, M.K. (2010). Regulation of immune responses and autoimmune encephalomyelitis by PPARs. PPAR Res. 2010, 104705.
Zieleniak, A., Wojcik, M., and Wozniak, L.A. (2008). Structure and physiological functions of the human peroxisome proliferatoractivated receptor gamma. Arch. Immunol. Ther. Exp. (Warsz) 56, 331–345.
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Choi, JM., Bothwell, A.L.M. The nuclear receptor PPARs as important regulators of T-cell functions and autoimmune diseases. Mol Cells 33, 217–222 (2012). https://doi.org/10.1007/s10059-012-2297-y
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DOI: https://doi.org/10.1007/s10059-012-2297-y