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A role for the peroxisome proliferator-activated receptor α in T-cell physiology and ageing immunobiology

Published online by Cambridge University Press:  05 March 2007

Dallas C. Jones ,
Bernadette M. Manning  and
Raymond A. Daynes
Dallas C. Jones
Affiliation:
Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA
Bernadette M. Manning
Affiliation:
Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA
Raymond A. Daynes*
Affiliation:
Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA Geriatric Research, Education and Clinical Center, Veterans Affairs Medical Center, Salt Lake City, Utah 84112, USA
*
*Corresponding author: Dr Raymond A. Daynes, fax + 1 801 581 8946, email daynes.office@path.utah.edu
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Abstract

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Peroxisome proliferator-activated receptor (PPAR) α represents an important member of the nuclear hormone receptor superfamily that can be activated by a variety of natural fatty acids, some of their metabolites and by commonly-used anti-lipidaemic drugs. We recently demonstrated PPARα expression in T lymphocytes, where it controls the initiation of transcription of T-box expressed in T-cells (T-bet) independent of added agonist. T-bet is an activation-inducible transcription factor regulator of interleukin 2 (suppression) and interferon γ (stimulation) synthesis. A suppressed ability to produce interleukin 2 and an enhanced production of interferon γ occurs in activated T-cells from PPARα-/- mice, as well as in T-cells from wild-type aged animals whose lymphocytes express lowered basal levels of PPARα. The dysregulated expression and/or function of cytokines, glucocorticoids or leptin that occurs with advanced age could all be responsible for the reduced expression of PPARα. Dietary supplementation of aged mice with vitamin E, or supplementation with known agonists of PPARα, was associated with elevation of lymphocyte expression of this nuclear hormone receptor, restoration of control over T-bet expression and elimination of the dysregulated production of interleukin 2 and interferon γ following lymphocyte activation. Interleukin 2 and interferon γ play very important roles in the initiation and/or regulation of immune, inflammatory and autoimmune disease states. Thus, the mechanisms that control the timing, magnitude and duration of specific cytokine production by activated T lymphocytes need clarification before appropriate nutritional or therapeutic strategies can be devised to treat disease conditions where cytokine expression and/or activities are deemed to be dysregulated and responsible.

Keywords

AgeingPPARαImmunobiology
Type
Mechanisms in nutrient regulation of inflammation
Information
Proceedings of the Nutrition Society , Volume 61 , Issue 3 , August 2002 , pp. 363 - 369
Copyright
Copyright © The Nutrition Society 2002

References

Ahima, RS & Flier, JS (2000) Leptin. Annual Review of Physiology 62, 413–437.CrossRefGoogle ScholarPubMed
Bannister, AJ & Kouzarides, T (1996) The CBP co-activator is a histone acetyltransferase. Nature 384, 641–643.CrossRefGoogle ScholarPubMed
Berger, J & Moller, DE (2002) The mechanisms of action of ppars. Annual Review of Medicine 53, 409–435.CrossRefGoogle ScholarPubMed
Bordji, K, Grillasca, JP, Gouze, JN, Magdalou, J, Schohn, H, Keller, JM, Bianchi, A, Dauca, M, Netter, P & Terlain, B (2000) Evidence for the presence of peroxisome proliferator-activated receptor (PPAR) alpha and gamma and retinoid Z receptor in cartilage. PPARgamma activation modulates the effects of interleukin-1beta on rat chondrocytes. Journal of Biological Chemistry 275, 12243–12250.CrossRefGoogle ScholarPubMed
Braissant, O, Foufelle, F, Scotto, C, Dauca, M & Wahli, W (1996) Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha,-beta, and -gamma in the adult rat. Endocrinology 137, 354–366.CrossRefGoogle Scholar
Chen, F, Law, SW & O'Malley, BW (1993) Identification of two mPPAR related receptors and evidence for the existence of five subfamily members. Biochemical and Biophysical Research Communications 196, 671–677.CrossRefGoogle ScholarPubMed
Chinetti, G, Fruchart, JC & Staels, B (2000) Peroxisome proliferator-activated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism and inflammation. Inflammation Research 49, 497–505.CrossRefGoogle ScholarPubMed
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. Journal of Biological Chemistry 273, 25573–25580.CrossRefGoogle ScholarPubMed
Desreumaux, P, Dubuquoy, L, Nutten, S, Peuchmaur, M, Englaro, W, Schoonjans, K, Derijard, B, Desvergne, B, Wahli, W, Chambon, P, Leibowitz, MD, Colombel, JF & Auwerx, J (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. Journal of Experimental Medicine 193, 827–838.CrossRefGoogle ScholarPubMed
Devchand, PR, Keller, H, Peters, JM, Vazquez, M, Gonzalez, FJ & Wahli, W (1996) The PPARalpha-leukotriene B4 pathway to inflammation control. Nature 384, 39–43.CrossRefGoogle ScholarPubMed
Direnzo, J, Soderstrom, M, Kurokawa, R, Ogliastro, MH, Ricote, M, Ingrey, S, Horlein, A, Rosenfeld, MG & Glass, CK (1997) Peroxisome proliferator-activated receptors and retinoic acid receptors differentially control the interactions of retinoid X receptor heterodimers with ligands, coactivators, and corepressors. Molecular and Cellular Biology 17, 2166–2176.CrossRefGoogle ScholarPubMed
Djouadi, F, Weinheimer, CJ & Kelly, DP (1999) The role of PPARalpha as a ‘lipostat’ transcription factor. Advances in Experimental Medicine and Biology 466, 211–220.CrossRefGoogle ScholarPubMed
Dreyer, C, Krey, G, Keller, H, Givel, F, Helftenbein, G & Wahli, W (1992) Control of the peroxisomal beta-oxidation pathway by a novel family of nuclear hormone receptors. Cell 68, 879–887.CrossRefGoogle ScholarPubMed
Engwerda, CR, Fox, BS & Handwerger, BS (1996) Cytokine production by T lymphocytes from young and aged mice. Journal of Immunology 156, 3621–3630.CrossRefGoogle Scholar
Forman, BM, Chen, J & Evans, RM (1997) Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta. Proceedings of the National Academy of Sciences USA 94, 4312–4317.CrossRefGoogle ScholarPubMed
Gottlicher, M, Widmark, E, Li, Q & Gustafsson, JA (1992) Fatty acids activate a chimera of the clofibric acid-activated receptor and the glucocorticoid receptor. Proceedings of the National Academy of Sciences USA 89, 4653–4657.CrossRefGoogle ScholarPubMed
Hanley, K, Komuves, LG, Ng, DC, Schoonjans, K, He, SS, Lau, P, Bikle, DD, Williams, ML, Elias, PM, Auwerx, J & Feingold, KR (2000) Farnesol stimulates differentiation in epidermal keratinocytes via PPARalpha. Journal of Biological Chemistry 275, 11484–11491.CrossRefGoogle ScholarPubMed
Harris, SG & Phipps, RP (2001) The nuclear receptor PPAR gamma is expressed by mouse T lymphocytes and PPAR gamma agonists induce apoptosis. European Journal of Immunology 31, 1098–1105.3.0.CO;2-I>CrossRefGoogle Scholar
Issemann, I & Green, S (1990) Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 347, 645–650.CrossRefGoogle ScholarPubMed
Jiang, C, Ting, AT & Seed, B (1998) PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature 391, 82–86.CrossRefGoogle ScholarPubMed
Jones, DC, Ding, X & Daynes, RA (2002) Nuclear receptor PPARa is expressed in resting murine lymphocytes: The PPARa in T and B lymphocytes is both transactivation and transrepression competent. Journal of Biological Chemistry 277, 6838–6845.CrossRefGoogle Scholar
Kamei, Y, Xu, L, Heinzel, T, Torchia, J, Kurokawa, R, Gloss, B, Lin, SC, Heyman, RA, Rose, DW, Glass, CK & Rosenfeld, MG (1996) A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors. Cell 85, 403–414.CrossRefGoogle ScholarPubMed
Kliewer, SA, Forman, BM, Blumberg, B, Ong, ES, Borgmeyer, U, Mangelsdorf, DJ, Umesono, K & Evans, RM (1994) Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proceedings of the National Academy of Sciences USA 91, 7355–7359.CrossRefGoogle ScholarPubMed
Kliewer, SA, Sundseth, SS, Jones, SA, Brown, PJ, Wisely, GB, Koble, CS, Devchand, P, Wahli, W, Willson, TM, Lenhard, JM & Lehmann, JM (1997) Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proceedings of the National Academy of Sciences USA 94, 4318–4323.CrossRefGoogle ScholarPubMed
Lemberger, T, Desvergne, B & Wahli, W (1996) Peroxisome proliferator-activated receptors: a nuclear receptor signaling pathway in lipid physiology. Annual Review of Cell and Developmental Biology 12, 335–363.CrossRefGoogle ScholarPubMed
Li, M, Pascual, G & Glass, CK (2000) Peroxisome proliferator-activated receptor gamma-dependent repression of the inducible nitric oxide synthase gene. Molecular and Cellular Biology 20, 4699–4707.CrossRefGoogle ScholarPubMed
Lu, B, Yu, H, Chow, C, Li, B, Zheng, W, Davis, RJ & Flavell, RA (2001) GADD45gamma mediates the activation of the p38 and JNK MAP kinase pathways and cytokine production in effector TH1 cells. Immunity 14, 583–590.CrossRefGoogle ScholarPubMed
Miyata, KS, Mccaw, SE, Patel, HV, Rachubinski, RA & Capone, JP (1996) The orphan nuclear hormone receptor LXR alpha interacts with the peroxisome proliferator-activated receptor and inhibits peroxisome proliferator signaling. Journal of Biological Chemistry 271, 9189–9192.CrossRefGoogle ScholarPubMed
Mueller, E, Smith, M, Sarraf, P, Kroll, T, Aiyer, A, Kaufman, DS, Oh, W, Demetri, G, Figg, WD, Zhou, XP, Eng, C, Spiegelman, BM & Kantoff, PW (2000) Effects of ligand activation of peroxisome proliferator-activated receptor gamma in human prostate cancer. Proceedings of the National Academy of Sciences USA 97, 10990–10995.CrossRefGoogle ScholarPubMed
Onate, SA, Tsai, SY, Tsai, MJ & O'Malley, BW (1995) Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science 270, 1354–1357.CrossRefGoogle ScholarPubMed
Padilla, J, Kaur, K, Cao, HJ, Smith, TJ & Phipps, RP (2000) Peroxisome proliferator activator receptor-gamma agonists and 15-deoxy-delta(12,14)(12,14)-PGJ(2) induce apoptosis in normal and malignant B-lineage cells. Journal of Immunology 165, 6941–6948.CrossRefGoogle Scholar
Poynter, ME & Daynes, RA (1998) Peroxisome proliferator-activated receptor alpha activation modulates cellular redox status, represses nuclear factor-kappa B signaling, and reduces inflammatory cytokine production in aging. Journal of Biological Chemistry 273, 32833–32841.CrossRefGoogle ScholarPubMed
Ren, B, Thelen, A & Jump, DB (1996) Peroxisome proliferator-activated receptor alpha inhibits hepatic S14 gene transcription. Evidence against the peroxisome proliferator-activated receptor alpha as the mediator of polyunsaturated fatty acid regulation of s14 gene transcription. Journal of Biological Chemistry 271, 17167–17173.CrossRefGoogle ScholarPubMed
Ricote, M, Li, AC, Wilson, TM, Kelly, CJ & Glass, CK (1998) The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature 391, 79–82.CrossRefGoogle ScholarPubMed
Rincon, M, Enslen, H, Raingeaud, J, Recht, M, Zapton, T, Su, MS, Penix, LA, Davis, RJ & Flavell, RA (1998) Interferon-gamma expression by Th1 effector T cells mediated by the p38 MAP kinase signaling pathway. EMBO Journal 17, 2817–2829.CrossRefGoogle ScholarPubMed
Spencer, NFL, Poynter, ME, Im, S-Y & Daynes, RA (1997) Constitutive activation of NF-kB in an animal model of aging. International Immunology 9, 1581–1588.CrossRefGoogle Scholar
Staels, B, Koenig, W, Habib, A, Merval, R, Lebret, M, Torra, IP, Delerive, P, Fadel, A, Chinetti, G, Fruchart, JC, Najib, J, Maclouf, J & Tedgui, A (1998) Activation of human aortic smooth-muscle cells is inhibited by PPARalpha but not by PPARgamma activators. Nature 393, 790–793.CrossRefGoogle Scholar
Szabo, SJ, Kim, ST, Costa, GL, Zhang, X, Fathman, CG & Glimcher, LH (2000) A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100, 655–669.CrossRefGoogle ScholarPubMed
Szabo, SJ, Sullivan, BM, Stemmann, C, Satoskar, AR, Sleckman, BP & Glimcher, LH (2002) Distinct effects of T-bet in TH1 lineage commitment and IFN-gamma production in CD4 and CD8 T cells. Science 295, 338–342.CrossRefGoogle ScholarPubMed
Takano, H & Komuro, I (2002) Roles of peroxisome proliferator-activated receptor gamma in cardiovascular disease. Journal of Diabetes and Its Complications 16, 108–114.CrossRefGoogle ScholarPubMed
Torchia, J, Rose, DW, Inostroza, J, Kamei, Y, Westin, S, Glass, CK & Rosenfeld, MG (1997) The transcriptional co-activator p/CIP binds CBP and mediates nuclear-receptor function. Nature 387, 677–684.CrossRefGoogle ScholarPubMed
Unger, RH & Zhou, YT (2001) Lipotoxicity of beta-cells in obesity and in other causes of fatty acid spillover. Diabetes 50Suppl. 1, S118–S121.Google Scholar
Wang, ZW, Pan, WT, Lee, Y, Kakuma, T, Zhou, YT & Unger, RH (2001) The role of leptin resistance in the lipid abnormalities of aging. FASEB Journal 15, 108–114.CrossRefGoogle ScholarPubMed
Watanabe, K, Fujii, H, Takahashi, T, Kodama, M, Aizawa, Y, Ohta, Y, Ono, T, Hasegawa, G, Naito, M, Nakajima, T, Kamijo, Y, Gonzalez, FJ & Aoyama, T (2000) Constitutive regulation of cardiac fatty acid metabolism through peroxisome proliferator-activated receptor alpha assocaited with age-dependent cardiac toxicity. Journal of Biological Chemistry 275, 22293–22299.CrossRefGoogle Scholar
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. Molecular Cell 3, 397–403.CrossRefGoogle ScholarPubMed