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. PPAR gamma agonists have been used to treat obesity, diabetes, cancer and inflammation and recent studies have shown the protective effects of PPAR gamma agonists on experimental allergic encephalomyelitis (EAE), a Th-1 cell-mediated autoimmune disease model of multiple sclerosis (MS). Our studies have further demonstrated that the PPAR gamma agonists, 15d-PGJ(2) and Ciglitazone, inhibit EAE through blocking IL-12 signaling leading to Th-1 differentiation and the PPAR gamma deficient heterozygous mice (PPAR gamma(+/-)) or those treated with PPAR gamma antagonists develop an exacerbated EAE in association with an augmented Th-1 response. In this study, we show that the PPAR gamma antagonists, Bisphenol A diglycidyl ether (BADGE) and 2-chloro-5-nitro-N-(4-pyridyl)benzamide (T0070907), reverse the inhibition of EAE by the PPAR gamma agonists, Ciglitazonc and 15-Deoxy-Delta(12,14)-Prostaglandin J(2), in C57BL/6 wild-type and PPAR gamma(+/-) mice. The reversal of EAE by BADGE and T0070907 was associated with restoration of neural antigen-induced T cell proliferation, IFN gamma production and Th-1 differentiation inhibited by Ciglitazone and 15d-PGJ2. These results suggest that Ciglitazone and l5d-PGJ(2) ameliorate EAE through PPAR gamma-dependent mechanisms and further confirm a physiological role for PPAR-y in the regulation of CNS inflammation and demyelination in EAE. (c) 2006 Elsevier B.V. All rights reserved.