NR AYHB
AU Jana,M.; Jana,A.; Liu,X.; Ghosh,S.; Pahan,K.
TI Involvement of phosphatidylinositol 3-kinase-mediated up-regulation of I kappa B alpha in anti-inflammatory effect of gemfibrozil in microglia
QU Journal of Immunology 2007 Sep 15; 179(6): 4142-52
PT journal article; research support, n.i.h., extramural; research support, non-u.s. gov't
AB 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 (p110ß 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 ß (Aß)-, 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 Aß-, PrP-, poly IC-, Tat-, and MPP+-induced microglial expression of iNOS. Involvement of NF-kappaB activation in LPS-, Aß-, 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.
MH 1-Phosphatidylinositol 3-Kinase/metabolism/*physiology; Amyloid ß-Protein/antagonists & inhibitors/physiology; Androstadienes/pharmacology; Animals; Anti-Inflammatory Agents, Non-Steroidal/*pharmacology; Cell Line; Cells, Cultured; Cytokines/antagonists & inhibitors/biosynthesis; Enzyme Activation/drug effects; Gemfibrozil/antagonists & inhibitors/*pharmacology; I-kappa B Proteins/*biosynthesis; Inflammation Mediators/antagonists & inhibitors/metabolism; Lipopolysaccharides/pharmacology; Mice; Mice, Knockout; Microglia/*drug effects/*enzymology/metabolism; Nitric Oxide Synthase Type II/antagonists & inhibitors/biosynthesis; PPAR alpha/physiology; Poly I-C/antagonists & inhibitors/pharmacology; Prions/antagonists & inhibitors/physiology; RNA, Double-Stranded/antagonists & inhibitors/physiology; Signal Transduction/drug effects/physiology; Up-Regulation/*drug effects/immunology
AD Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA.
SP englisch
PO USA