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Peroxisome proliferator‐activated receptor‐β/δ agonists regulate inflammation and demyelination in experimental allergic encephalomyelitis
Author(s) -
Bright John J,
Chearwae Wanida,
Iams Wade,
Kanakasabai Saravanan,
Adams Suzanne M
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.2_supplement.461
Subject(s) - experimental autoimmune encephalomyelitis , inflammation , encephalomyelitis , peroxisome proliferator activated receptor , receptor , spleen , multiple sclerosis , myelin oligodendrocyte glycoprotein , in vivo , immunology , endocrinology , medicine , pharmacology , biology , microbiology and biotechnology
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 α, δ and γ agonists ameliorate experimental allergic encephalomyelitis (EAE) model of multiple sclerosis (MS). In this study, we examined the effect of PPARβ/δ agonists on inflammation and demyelination in EAE. Four to six weeks old female C57BL/6 mice were induced to develop EAE by immunization with MOGp 35–55 antigen on day 0 and 7 and treated (i.p.) with 25 or 100 μg PPARδ agonists, GW501516 and L165041, on every other day from day 0 to 30. We found that in vivo treatment with PPARδ 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, IFNγ, IL‐12p40, IL‐12p35 and IL‐23p19 and that decreased significantly following treatment with PPARδ agonists in vivo. The spleen cells from EAE mice treated with PPARδ agonists showed a significant decrease in neural antigen‐induced expression of IL‐17 and IFNγ ex vivo. However, PPARδ agonists failed to inhibit neural antigen‐induced or IL‐12/IL‐23‐induced Th1/Th17 responses in vitro. These results highlight the fact that PPARδ agonists ameliorate EAE by modulating neuroinflammatory response in vivo.