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(The FASEB Journal. 2008;22:lb461)
© 2008 FASEB
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lb461

Peroxisome proliferator-activated receptor-β/{delta} agonists regulate inflammation and demyelination in experimental allergic encephalomyelitis

John J Bright1,2, Wanida Chearwae1, Wade Iams1, Saravanan Kanakasabai1 and Suzanne M Adams1

1 Neuroscience Research Laboratory, Methodist Research Institute, Indianapolis, IN,
2 Department of Medicine, Indiana University School of Medicine, Indianapolis, IN

ABSTRACT

Peroxisome proliferator-activated receptors (PPAR) are nuclear hormone receptors that regulate cell growth, differentiation and homeostasis. PPAR agonists have been used to treat obesity, diabetes, cancer and inflammation. We and others have shown earlier that PPAR {alpha}, {delta} and {gamma} agonists ameliorate experimental allergic encephalomyelitis (EAE) model of multiple sclerosis (MS). In this study, we examined the effect of PPARβ/{delta} agonists on inflammation and demyelination in EAE. Four to six weeks old female C57BL/6 mice were induced to develop EAE by immunization with MOGp35–55 antigen on day 0 and 7 and treated (i.p.) with 25 or 100 µg PPAR{delta} agonists, GW501516 and L165041, on every other day from day 0 to 30. We found that in vivo treatment with PPAR{delta} agonists inhibits the clinical and pathological symptoms of EAE in a dose-dependent manner. To study the mechanism of action, brain and spleen tissues were isolated on day 14 following induction of EAE and the expression of inflammatory genes analyzed by quantitative real-time polymerase chain reaction, flow cytometry and ELISA. The CNS and lymphoid organs of mice with EAE showed an elevated expression of IL-17, IFN{gamma}, IL-12p40, IL-12p35 and IL-23p19 and that decreased significantly following treatment with PPAR{delta} agonists in vivo. The spleen cells from EAE mice treated with PPAR{delta} agonists showed a significant decrease in neural antigen-induced expression of IL-17 and IFN{gamma} ex vivo. However, PPAR{delta} agonists failed to inhibit neural antigen-induced or IL-12/IL-23-induced Th1/Th17 responses in vitro. These results highlight the fact that PPAR{delta} agonists ameliorate EAE by modulating neuroinflammatory response in vivo.





This Article
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