Division of Neuroimmunology, Department of Neurology, Vanderbilt University School of Medicine, Nashville, TN 37212, USA

Correspondence to: J J Bright, PhD, Department of Neurology, Vanderbilt University Medical Center, 1222F VSRH, 2201 Capers Avenue, Nashville, TN37212, USA. E-mail: john.brightj@mcmail.vanderbilt.edu

^aThis work was supported in part by National Multiple Sclerosis Society Grant RG 3069A2/1 and national Institutes of Health Grant R01 NS42257-01A1 (to J J B).

Peroxisome proliferator-activated receptor-gamma (PPAR) is a nuclear receptor transcription factor that regulates adipocyte differentiation and glucose homeostasis. PPAR agonists are potent therapeutic agents for the treatment of type 2 diabetes and obesity. PPAR agonists also prevent inflammation in animal models, suggesting their use for the treatment of human inflammatory diseases. Experimental allergic encephalomyelitis (EAE) is a Th1 cell-mediated inflammatory demyelinating disease model of multiple sclerosis (MS) and IL-12 plays a crucial role in the pathogenesis of EAE and MS. In this study we have examined the effect of PPAR agonists on the pathogenesis of EAE. In vivo treatment of SJL/J mice with PPAR agonists, 15-deoxy^12,14 prostaglandin J₂ or Ciglitazone, decreased the duration and clinical severity of active immunization and adoptive transfer models of EAE. PPAR agonists inhibited EAE in association with a decrease in IL-12 production and differentiation of neural antigen-specific Th1 cells. In vitro treatment of activated T cells with PPAR agonists inhibited IL-12-induced activation of JAK-STAT signaling pathway and Th1 differentiation. These findings highlight the fact that PPAR agonists regulate central nervous system inflammation and demyelination by inhibiting IL-12 production, IL-12 signaling and Th1 differentiation in EAE.

Genes and Immunity (2002) 3, 59-70. DOI: 10.1038/sj/gene/6363832

cytokine; signal transduction; Th1 cells; inflammation; immunomodulation