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Involvement of Phosphatidylinositol 3-Kinase-Mediated Up-Regulation of IB in Anti-Inflammatory Effect of Gemfibrozil in Microglia¹

Malabendu Jana^*, Arundhati Jana^*, Xiaojuan Liu, Sankar Ghosh and Kalipada Pahan^2,*,

^* Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612; Section of Neuroscience, Department of Oral Biology, College of Dentistry, University of Nebraska Medical Center, Lincoln, NE 68583; and Section of Immunobiology and Department of Molecular Biophysics and Biochemistry, School of Medicine, Yale University, New Haven, CT 06536

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- (PPAR-) in microglial cells and isolating primary microglia from PPAR-^–/– mice, we have demonstrated that gemfibrozil inhibits the activation of microglia independent of PPAR-. Interestingly, gemfibrozil induced the activation of p85-associated PI3K (p110 but not p110) 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 (A)-, prion peptide (PrP)-, dsRNA (poly IC)-, HIV-1 Tat-, and 1-methyl-4-phenylpyridinium (MPP⁺)-, but not IFN--, induced microglial expression of iNOS. Inhibition of PI3K also abolished the inhibitory effect of gemfibrozil on A-, PrP-, poly IC-, Tat-, and MPP⁺-induced microglial expression of iNOS. Involvement of NF-B activation in LPS-, A-, PrP-, poly IC-, Tat-, and MPP⁺-, but not IFN--, induced microglial expression of iNOS and stimulation of IB expression and inhibition of NF-B activation by gemfibrozil via the PI3K pathway suggests that gemfibrozil inhibits the activation of NF-B and the expression of proinflammatory molecules in microglia via PI3K-mediated up-regulation of IB.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the National Multiple Sclerosis Society (RG3422A1/1) and the National Institutes of Health (NS39940 and NS48923).

² Address correspondence and reprint requests to Dr. Kalipada Pahan, Department of Neurological Sciences, Rush University Medical Center, 1735 West Harrison Street, Suite 320, Chicago, IL 60612. E-mail address: Kalipada_Pahan{at}rush.edu

³ Abbreviations used in this paper: AD, Alzheimer’s disease; HAD, HIV-associated dementia; MS, multiple sclerosis; PPAR, peroxisome proliferator-activated receptor; iNOS, inducible NO synthase; ChIP, chromatin immunoprecipitation; SH2, Src homology 2; A, amyloid ; PrP, prion peptide; MPP, 1-methyl-4-phenylpyridinium; SR, superrepressor.