PPARγ antagonists reverse the inhibition of neural antigen-specific Th1 response and experimental allergic encephalomyelitis by Ciglitazone and 15-Deoxy-Δ12,14-Prostaglandin J2

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), reverse the inhibition of EAE by the PPARγ agonists, Ciglitazone and 15-Deoxy-Δ12,14-Prostaglandin J2, in C57BL/6 wild-type and PPARγ+/− mice. The reversal of EAE by BADGE and T0070907 was associated with restoration of neural antigen-induced T cell proliferation, IFNγ production and Th1 differentiation inhibited by Ciglitazone and 15d-PGJ2. These results suggest that Ciglitazone and 15d-PGJ2 ameliorate EAE through PPARγ-dependent mechanisms and further confirm a physiological role for PPARγ in the regulation of CNS inflammation and demyelination in EAE.