PPAR-alpha activators suppress STAT1 inflammatory signaling in lipopolysaccharide-activated rat glia.
Signal transducers and activators of transcription (STATs) have recently been reported to mediate glial activation, and thus potentially play important roles in many neuroinflammatory diseases. We examined the effect of peroxisome proliferator-activated receptor (PPAR) activators on inflammatory responses in cultured rat brain glial cells. Four PPAR-alpha activators were tested, three fibrates (WY14643, clofibrate and fenofibrate) and an arachidonic acid derivative (5,8,11,14-eicosatetraynoic acid). We found that all four PPAR-alpha activators suppressed lipopolysaccharide-stimulated STAT1 phosphorylation and nuclear factor binding to gamma-interferon-activated sequence/interferon-alpha-stimulated response element sites known to contain STAT binding sites. PPAR-alpha activators also suppressed lipopolysaccharide-stimulated tumor necrosis factor-alpha and monocyte chemoattractant protein-1 transcription and release. These results suggest that PPAR-alpha activators may be useful in the treatment of inflammatory brain diseases.
Lee
Jee Hoon
JH
Department of Pharmacology, Ajou University School of Medicine, Suwon, 442-721 Korea.
Joe
Eun-hye
EH
Jou
Ilo
I
D000818:Animals; D000831:Animals, Newborn; D001095:Arachidonic Acids / Q000494:pharmacology; D015153:Blotting, Western / Q000379:methods; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D002995:Clofibric Acid / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D004789:Enzyme Activation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D007249:Inflammation / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008954:Models, Biological; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D001095:Arachidonic Acids; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D004268:DNA-Binding Proteins; D008070:Lipopolysaccharides; D047493:PPAR alpha; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494081:Stat1 protein, rat; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D002995:Clofibric Acid