Transcriptional modulation of the immune response by peroxisome proliferator-activated receptor-α agonists in autoimmune disease

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

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

Peroxisome proliferator-activated receptor-α (PPARα) 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 PPARα 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 PPARα expression. Moreover, the protective effects of PPARα agonists in EAE were shown to be partially dependent on IL-4 and to occur in a receptor-dependent manner. PPARα 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 PPARα can directly transactivate the IL-4 gene. Finally, therapeutic administration of PPARα agonists ameliorated clinically established EAE, suggesting that PPARα agonists may provide a treatment option for immune-mediated inflammatory diseases.

Original languageEnglish (US)
Pages (from-to)4479-4487
Number of pages9
JournalJournal of Immunology
Volume182
Issue number7
DOIs
StatePublished - Apr 1 2009

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Gocke, A. R., Hussain, R. Z., Yang, Y., Peng, H., Weiner, J., Ben, L. H., Drew, P. D., Stuve, O., Lovett-Racke, A. E., & Racke, M. K. (2009). Transcriptional modulation of the immune response by peroxisome proliferator-activated receptor-α agonists in autoimmune disease. Journal of Immunology, 182(7), 4479-4487. https://doi.org/10.4049/jimmunol.0713927