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

Peroxisome proliferator-activated receptor-alpha (PPAR alpha) 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 alpha 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 alpha expression. Moreover, the protective effects of PPAR alpha agonists in EAE were shown to be partially dependent on IL-4 and to occur in a receptor-dependent manner. PPAR alpha 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 alpha can directly transactivate the IL-4 gene. Finally, therapeutic administration of PPAR alpha agonists ameliorated clinically established EAE, suggesting that PPAR alpha agonists may provide a treatment option for immune-mediated inflammatory diseases. The Journal of Immunology, 2009, 182: 4479-4487.