Abstract
In the present study, experiments were performed to explore the action of quercetin, the most widely distributed flavonoids, and its major metabolite, quercetin-3'-sulfate, on lipopolysaccharide (LPS)- and interferon-gamma (IFN-gamma)-induced nitric oxide (NO) production in BV-2 microglia. Quercetin could suppress LPS- and IFN-gamma-induced NO production and inducible nitric oxide synthase (iNOS) gene transcription, while quercetin-3'-sulfate had no effect. LPS-induced IkappaB kinase (IKK), nuclear factor-kappaB (NF-kappaB) and activating protein-1 (AP-1) activation, and IFN-gamma-induced NF-kappaB, signal transducer and activator of transcription-1 (STAT1) and interferon regulatory factor-1 (IRF-1) activation were reduced by quercetin. Moreover quercetin was able to induce heme oxygenase-1 expression. To address the involvement of heme oxygenase-1 induction in iNOS inhibition, heme oxygenase-1 antisense oligodeoxynucleotide was used. Quercetin-mediated inhibition of NO production and iNOS protein expression were partially reversed by heme oxygenase-1 antisense oligodeoxynucleotide, but was mimicked by hemin, a heme oxygenase-1 inducer. The involvement of signal pathways in quercetin-induced heme oxygenase-1 gene expression was associated with tyrosine kinase and mitogen-activated protein kinases activation. All these results suggest quercetin should provide therapeutic benefits for suppression of inflammatory-related neuronal injury in neurodegenerative diseases.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Amides / pharmacology
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Animals
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Antioxidants / pharmacology
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Ascorbic Acid / pharmacology
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Butadienes / pharmacology
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Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
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Cell Line
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / pharmacology
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Flavonoids / pharmacology
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Gene Expression Regulation, Enzymologic / drug effects
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Heme Oxygenase-1 / genetics*
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Heme Oxygenase-1 / metabolism
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Hemin / pharmacology
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I-kappa B Kinase / antagonists & inhibitors*
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I-kappa B Kinase / metabolism
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Immunoblotting
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Interferon Regulatory Factor-1 / genetics
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Interferon Regulatory Factor-1 / metabolism
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Interferon-gamma / pharmacology
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Lipopolysaccharides / pharmacology
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Luciferases / genetics
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Luciferases / metabolism
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Mice
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Microglia / cytology
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Microglia / drug effects
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Microglia / metabolism
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NF-kappa B / metabolism*
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Nitric Oxide / metabolism
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Nitric Oxide Synthase Type II / antagonists & inhibitors
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Nitric Oxide Synthase Type II / genetics*
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Nitric Oxide Synthase Type II / metabolism
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Nitriles / pharmacology
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Phosphorylation / drug effects
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Pyridines / pharmacology
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Quercetin / pharmacology*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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STAT1 Transcription Factor / metabolism*
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Transcription Factor AP-1 / genetics
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Transcription Factor AP-1 / metabolism
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Transfection
Substances
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Amides
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Antioxidants
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Butadienes
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Enzyme Inhibitors
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Flavonoids
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Interferon Regulatory Factor-1
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Lipopolysaccharides
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NF-kappa B
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Nitriles
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Pyridines
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RNA, Messenger
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Recombinant Fusion Proteins
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STAT1 Transcription Factor
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Transcription Factor AP-1
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U 0126
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Y 27632
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Nitric Oxide
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Hemin
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Interferon-gamma
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Quercetin
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Luciferases
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Nitric Oxide Synthase Type II
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Heme Oxygenase-1
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I-kappa B Kinase
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Calcium-Calmodulin-Dependent Protein Kinases
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Ascorbic Acid
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one