Involvement of phosphatidylinositol 3-kinase-mediated up-regulation of I kappa B alpha in anti-inflammatory effect of gemfibrozil in microglia

J Immunol. 2007 Sep 15;179(6):4142-52. doi: 10.4049/jimmunol.179.6.4142.


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-alpha (PPAR-alpha) in microglial cells and isolating primary microglia from PPAR-alpha-/- mice, we have demonstrated that gemfibrozil inhibits the activation of microglia independent of PPAR-alpha. Interestingly, gemfibrozil induced the activation of p85alpha-associated PI3K (p110beta but not p110alpha) 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 (Abeta)-, 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 Abeta-, PrP-, poly IC-, Tat-, and MPP+-induced microglial expression of iNOS. Involvement of NF-kappaB activation in LPS-, Abeta-, PrP-, poly IC-, Tat-, and MPP+-, but not IFN-gamma-, induced microglial expression of iNOS and stimulation of IkappaBalpha expression and inhibition of NF-kappaB activation by gemfibrozil via the PI3K pathway suggests that gemfibrozil inhibits the activation of NF-kappaB and the expression of proinflammatory molecules in microglia via PI3K-mediated up-regulation of IkappaBalpha.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / physiology
  • Androstadienes / pharmacology
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Cell Line
  • Cells, Cultured
  • Cytokines / antagonists & inhibitors
  • Cytokines / biosynthesis
  • Enzyme Activation / drug effects
  • Gemfibrozil / antagonists & inhibitors
  • Gemfibrozil / pharmacology*
  • I-kappa B Proteins / biosynthesis*
  • Inflammation Mediators / antagonists & inhibitors
  • Inflammation Mediators / metabolism
  • Lipopolysaccharides / pharmacology
  • Mice
  • Mice, Knockout
  • Microglia / drug effects*
  • Microglia / enzymology*
  • Microglia / metabolism
  • NF-KappaB Inhibitor alpha
  • Nitric Oxide Synthase Type II / antagonists & inhibitors
  • Nitric Oxide Synthase Type II / biosynthesis
  • PPAR alpha / physiology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphatidylinositol 3-Kinases / physiology*
  • Poly I-C / antagonists & inhibitors
  • Poly I-C / pharmacology
  • Prions / antagonists & inhibitors
  • Prions / physiology
  • RNA, Double-Stranded / antagonists & inhibitors
  • RNA, Double-Stranded / physiology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Up-Regulation / drug effects*
  • Up-Regulation / immunology
  • Wortmannin


  • Amyloid beta-Peptides
  • Androstadienes
  • Anti-Inflammatory Agents, Non-Steroidal
  • Cytokines
  • I-kappa B Proteins
  • Inflammation Mediators
  • Lipopolysaccharides
  • NFKBIA protein, human
  • Nfkbia protein, mouse
  • PPAR alpha
  • Prions
  • RNA, Double-Stranded
  • NF-KappaB Inhibitor alpha
  • Nitric Oxide Synthase Type II
  • Phosphatidylinositol 3-Kinases
  • Poly I-C
  • Gemfibrozil
  • Wortmannin