PPARγ antagonists exacerbate neural antigen-specific Th1 response and experimental allergic encephalomyelitis

Peroxisome proliferator-activated receptor-gamma is a nuclear receptor transcription factor that regulates cell growth, differentiation and homeostasis. PPARγ agonists have been used in the treatment of obesity, diabetes, cancer and inflammation. We and others have shown recently that PPARγ agonists ameliorate experimental allergic encephalomyelitis (EAE), a Th1 cell-mediated autoimmune disease model of multiple sclerosis (MS). We have further shown that PPARγ agonists inhibit EAE through blocking IL-12 signaling leading to Th1 differentiation and the PPARγ-deficient heterozygous mice (PPARγ+/−) develop an exacerbated EAE. In this study, we show that in vivo treatment (i.p.) with 100 μg PPARγ antagonists, Bisphenol A diglycidyl ether (BADGE) or 2-Chloro-5-nitro-N-(4-pyridyl)benzamide (T0070907), on every other day from day 0 to 30, increased the severity and duration of EAE in C57BL/6 wild-type and PPARγ+/− mice. The exacerbation of EAE by PPARγ antagonists associates with an augmented neural antigen-induced T cell proliferation, IFNγ production or Th1 differentiation. These results further suggest that PPARγ is a critical physiological regulator of CNS inflammation and demyelination in EAE.