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Transcriptional Modulation of the Immune Response by Peroxisome Proliferator-Activated Receptor- Agonists in Autoimmune Disease¹

Anne R. Gocke^*, Rehana Z. Hussain^*, Yuhong Yang^¶, Haiyan Peng^¶, Jeffrey Weiner^¶, Li-Hong Ben^*, Paul D. Drew, Olaf Stuve^*, Amy E. Lovett-Racke^*, and Michael K. Racke^2,*,,¶

^* Department of Neurology and Center for Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Neurobiology and Developmental Sciences, University of Arkansas for Health Sciences, Little Rock, AR 72205; and Department of Molecular Virology, Immunology, and Medical Genetics and ^¶ Department of Neurology, Ohio State University Medical Center, Columbus, OH 43210

Peroxisome proliferator-activated receptor- (PPAR) agonists have been shown to have a therapeutic benefit in experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). In this study, we investigated the mechanism by which the PPAR agonist gemfibrozil induces immune deviation and protects mice from EAE. We demonstrated that treatment with gemfibrozil increases expression of the Th2 transcription factor GATA-3 and decreases expression of the Th1 transcription factor T-bet in vitro and directly ex vivo. These changes correlated with an increase in nuclear PPAR expression. Moreover, the protective effects of PPAR agonists in EAE were shown to be partially dependent on IL-4 and to occur in a receptor-dependent manner. PPAR was demonstrated, for the first time, to regulate the IL-4 and IL-5 genes and to bind the IL-4 promoter in the presence of steroid receptor coactivator-1, indicating that PPAR can directly transactivate the IL-4 gene. Finally, therapeutic administration of PPAR agonists ameliorated clinically established EAE, suggesting that PPAR agonists may provide a treatment option for immune-mediated inflammatory diseases.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported National Multiple Sclerosis Society Grants RG3427-A-8 and RG3812-A-3 and the National Institutes of Health Grants NS44250 and NS37513. A.E.L.-R. is a National Multiple Sclerosis Society Harry Weaver Neuroscience Scholar.

² Address correspondence and reprint requests to Dr. Michael K. Racke, Department of Neurology, Ohio State University Medical Center, 1654 Upham Drive, 445 Means Hall, Columbus, OH 43210-1228. E-mail address: Michael.Racke{at}osumc.edu

³ Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; Ac, N-terminally acetylated peptide; ChIP, chromatin immunoprecipitation; EtOH, ethanol; MBP, myelin basic protein; MS, multiple sclerosis; NS, nonsense; PPAR, peroxisome proliferator-activated receptor; PPRE, PPAR response element; RNAi, RNA interference; RXR, retinoid X receptor; siRNA, small interfering RNA; SRC, steroid receptor coactivator; WT, wild type.

⁴ The online version of this article contains supplemental material.