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Peroxisome proliferator-activated receptor-gamma is a nuclear receptor transcription factor that regulates cell growth, differentiation and homeostasis. PPARγ agonists have been used to treat obesity, diabetes, cancer and inflammation and recent studies have shown the protective effects of PPARγ agonists on experimental allergic encephalomyelitis (EAE), a Th₁ cell-mediated autoimmune disease model of multiple sclerosis (MS). Our studies have further demonstrated that the PPARγ agonists, 15d-PGJ₂ and Ciglitazone, inhibit EAE through blocking IL-12 signaling leading to Th₁ differentiation and the PPARγ deficient heterozygous mice (PPARγ^+/−) or those treated with PPARγ antagonists develop an exacerbated EAE in association with an augmented Th₁ response. In this study, we show that the PPARγ antagonists, Bisphenol A diglycidyl ether (BADGE) and 2-chloro-5-nitro-N-(4-pyridyl)benzamide (T0070907 …