Gemfibrozil, a lipid-lowering drug, inhibits the induction of nitric-oxide synthase in human astrocytes.
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-alpha (PPAR-alpha), we investigated the role of PPAR-alpha in gemfibrozil-mediated inhibition of iNOS. Gemfibrozil induced peroxisome proliferator-responsive element (PPRE)-dependent luciferase activity, which was inhibited by the expression of DeltahPPAR-alpha, the dominant-negative mutant of human PPAR-alpha. However, DeltahPPAR-alpha was unable to abrogate gemfibrozil-mediated inhibition of iNOS suggesting that gemfibrozil inhibits iNOS independent of PPAR-alpha. The human iNOS promoter contains consensus sequences for the binding of transcription factors, including interferon-gamma (IFN-gamma) regulatory factor-1 (IRF-1) binding to interferon-stimulated responsive element (ISRE), signal transducer and activator of transcription (STAT) binding to gamma-activation site (GAS), nuclear factor-kappaB (NF-kappaB), activator protein-1 (AP-1), and CCAAT/enhancer-binding protein beta (C/EBPbeta); therefore, we investigated the effect of gemfibrozil on the activation of these transcription factors. The combination of interleukin (IL)-1beta and IFN-gamma induced the activation of NF-kappaB, AP-1, C/EBPbeta, 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-kappaB, AP-1, and C/EBPbeta 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-kappaB, AP-1, and C/EBPbeta and that gemfibrozil, a prescribed drug for humans, may further find its therapeutic use in neuroinflammatory diseases.
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Gemfibrozil nitric-oxide gemfibrozil gemfibrozil gemfibrozil gemfibrozil gemfibrozil clofibrate fibrate gemfibrozil gemfibrozil gemfibrozil Gemfibrozil NO gemfibrozil gemfibrozil Gemfibrozil nitric-oxide iNOS inducible nitric-oxide synthase PPAR-alpha human iNOS promoter interferon-gamma (IFN-gamma) regulatory factor-1 IRF-1 interferon-stimulated responsive element ISRE signal transducer and activator of transcription STAT iNOS nuclear factor-kappaB NF-kappaB activator protein-1 AP-1 CCAAT/enhancer-binding protein beta C/EBPbeta interleukin (IL)-1beta IFN-gamma NF-kappaB AP-1 C/EBPbeta ISRE IRF-1 cytokine iNOS NF-kappaB AP-1 C/EBPbeta cytokine iNOS NF-kappaB AP-1 C/EBPbeta iNOS human iNOS promoter cytokine cytokine iNOS peroxisome proliferator-activated receptor-alpha PPAR-alpha PPAR-alpha iNOS peroxisome proliferator-responsive element PPRE DeltahPPAR-alpha human PPAR-alpha DeltahPPAR-alpha iNOS nitric-oxide synthase