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Agonists for the peroxisome proliferator‐activated receptor‐α and the retinoid X receptor inhibit inflammatory responses of microglia
Author(s) -
Xu Jihong,
Storer Paul D.,
Chavis Janet A.,
Racke Michael K.,
Drew Paul D.
Publication year - 2005
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.20518
Subject(s) - microglia , retinoid x receptor , proinflammatory cytokine , fenofibrate , peroxisome proliferator activated receptor , agonist , gemfibrozil , experimental autoimmune encephalomyelitis , endocrinology , medicine , receptor , chemistry , pharmacology , cytokine , inflammation , biology , nuclear receptor , biochemistry , cholesterol , transcription factor , gene
The peroxisome proliferator‐activated receptor‐α (PPAR‐α) plays a key role in lipid metabolism and inflammation. Recently, we demonstrated that administration of the PPAR‐α agonists gemfibrozil and fenofibrate, inhibit the clinical signs of experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). In the present study we investigated the effects of PPAR‐α agonists on primary mouse microglia, a cell type implicated in the pathology of MS and EAE. Our studies demonstrated that the PPAR‐α agonists ciprofibrate, fenofibrate, gemfibrozil, and WY 14,643 each inhibited NO production by cytokine‐stimulated microglia in a dose‐dependent manner. However, fenofibrate and WY 14,643 were more potent inhibitors than gemfibrozil and ciprofibrate. In LPS‐stimulated microglia, only fenofibrate and WY 14,643 significantly suppressed NO production. Additionally, PPAR‐α agonists inhibited the secretion of the proinflammatory cytokines IL‐1β, TNF‐α, IL‐6, and IL‐12 p40 and the chemokine MCP‐1 by LPS‐stimulated microglia. Retinoid X receptors (RXRs) physically interact with PPAR‐α receptors, and the resulting heterodimers regulate the expression of PPAR‐responsive genes. Interestingly, the RXR agonist 9‐cis retinoic acid (9‐cis RA) inhibited NO production by LPS‐stimulated microglia. Furthermore, a combination of 9‐cis RA and the PPAR‐α agonist fenofibrate cooperatively inhibited NO production by these cells. A combination of these agonists also selectively inhibited the expression of proinflammatory cytokines including IL‐1β, TNF‐α, and IL‐6 by LPS‐stimulated microglia. Collectively, these results raise the possibility that PPAR‐α and RXR agonists might have benefit as a therapy in MS, where activated microglia are believed to contribute to disease pathology. © 2005 Wiley‐Liss, Inc.