Involvement of phosphatidylinositol 3-kinase-mediated up-regulation of IκBα in anti-inflammatory effect of gemfibrozil in microglia

The present study underlines the importance of PI3K in mediating the anti-inflammatory effect of gemfibrozil, a prescribed lipid-lowering drug for humans, in mouse microglia. Gemfibrozil inhibited LPS-induced expression of inducible NO synthase (iNOS) and proinflammatory cytokines in mouse BV-2 microglial cells and primary microglia. By overexpressing wild-type and dominant-negative constructs of peroxisome proliferator-activated receptor-a (PPAR-a) in microglial cells and isolating primary microglia from PPAR-alpha(-/-) mice, we have demonstrated that gemfibrozil inhibits the activation of microglia independent of PPAR-a. Interestingly, gemfibrozil induced the activation of p85 alpha-associated PI3K (p110 beta but not p110 alpha) and inhibition of that PI3K by either chemical inhibitors or dominant-negative mutants abrogated the inhibitory effect of gemfibrozil. Conversely, overexpression of the constitutively active mutant of p110 enhanced the inhibitory effect of gemfibrozil on LPS-induced expression of proinflammatory molecules. Similarly, gemfibrozil also inhibited fibrillar amyloid beta (A beta)-, prion peptide (PrP)-, dsRNA (poly IC)-, HIV-1 Tat-, and 1-methyl-4-phenylpyridinium (MPP+)-, but not IFN-gamma-, induced microglial expression of iNOS. Inhibition of PI3K also abolished the inhibitory effect of gemfibrozil on A beta-, PrP-, poly IC-, Tat-, and MPP+ -induced microglial expression of iNOS. Involvement of NF-kappa B activation in LPS-, A beta-, PrP-, poly IC-, Tat-, and MPP+-, but not IFN-gamma-, induced microglial expression of iNOS and stimulation of I kappa B alpha expression and inhibition of NF-kappa B activation by gemfibrozil via the PI3K pathway suggests that gemfibrozil inhibits the activation of NF-kappa B and the expression of proinflammatory molecules in microglia via PI3K-mediated up-regulation of I kappa B alpha.