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-α 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-α activators suppressed lipopolysaccharide-stimulated STAT1 phosphorylation and nuclear factor binding to γ-interferon-activated sequence/interferon-α-stimulated response element sites known to contain STAT binding sites. PPAR-α activators also suppressed lipopolysaccharide-stimulated tumor necrosis factor-α and monocyte chemoattractant protein-1 transcription and release. These results suggest that PPAR-α activators may be useful in the treatment of inflammatory brain diseases.