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

Raikwar, Himanshu P.; Muthian, Gladson; Rajasingh, Johnson; Johnson, Caroline N.; Bright, John J.

doi:10.1016/j.jneuroim.2006.05.013

« Previous Next »Journal of Neuroimmunology
Volume 178, Issue 1 , Pages 76-86, September 2006

PPARγ antagonists reverse the inhibition of neural antigen-specific Th₁ response and experimental allergic encephalomyelitis by Ciglitazone and 15-Deoxy-Δ^12,14-Prostaglandin J₂

Himanshu P. Raikwar
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212, USA
Gladson Muthian
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212, USA
Johnson Rajasingh
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212, USA
Caroline N. Johnson
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212, USA
John J. Bright
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212, USA
- Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37212, USA
- Methodist Research Institute, Clarian Health Partners, Indianapolis, IN 46202, USA
- Corresponding author. Methodist Research Institute, Clarian Health Partners 1800 N Capital Ave, Noyes Bldg E-504C, Indianapolis, IN 46202, USA. Tel.: +1 317 962 8722; fax: +1 317 962 9369.

Received 5 October 2005; received in revised form 24 April 2006; accepted 16 May 2006. published online 18 July 2006.

Abstract

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-Δ^12,14-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.