Virology, Nebraska Center for
Date of this Version
2002
Abstract
Gemfibrozil, a lipid-lowering drug, inhibited cytokine- induced production of NO and the expression of inducible nitric-oxide synthase (iNOS) in human U373MG astroglial cells and primary astrocytes. Similar to gemfibrozil, clofibrate, another fibrate drug, also inhibited the expression of iNOS. Inhibition of human iNOS promoter-driven luciferase activity by gemfibrozil in cytokine-stimulated U373MG astroglial cells suggests that this compound inhibits the transcription of iNOS. Since gemfibrozil is known to activate peroxisome proliferator- activated receptor-α (PPAR-α), we investigated the role of PPAR- α in gemfibrozil-mediated inhibition of iNOS. Gemfibrozil induced peroxisome proliferator-responsive element (PPRE)-dependent luciferase activity, which was inhibited by the expression of ΔhPPAR- α, the dominant-negative mutant of human PPAR- α. However, ΔhPPAR- α was unable to abrogate gemfibrozil-mediated inhibition of iNOS suggesting that gemfibrozil inhibits iNOS independent of PPAR- α. The human iNOS promoter contains consensus sequences for the binding of transcription factors, including interferon-γ (IFN-γ) regulatory factor-1 (IRF-1) binding to interferon-stimulated responsive element (ISRE), signal transducer and activator of transcription (STAT) binding to γ -activation site (GAS), nuclear factor-κB (NF-κB), activator protein- 1 (AP-1), and CCAAT/enhancer-binding protein β (C/EBP β); therefore, we investigated the effect of gemfibrozil on the activation of these transcription factors. The combination of interleukin (IL)-1β and IFN-γ induced the activation of NF-κB, AP-1, C/EBP β, and GAS but not that of ISRE, suggesting that IRF-1 may not be involved in cytokine-induced expression of iNOS in human astrocytes. Interestingly, gemfibrozil strongly inhibited the activation of NF-κB, AP-1, and C/EBPβ but not that of GAS in cytokine-stimulated astroglial cells. These results suggest that gemfibrozil inhibits the induction of iNOS probably by inhibiting the activation of NF-κB, AP-1, and C/EBP β and that gemfibrozil, a prescribed drug for humans, may further find its therapeutic use in neuroinflammatory diseases.
Comments
Published in THE JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 277, No. 48, Issue of November 29, pp. 45984–45991, 2002. Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc. Used by permission.