Inhibition of iNOS gene expression by quercetin is mediated by the inhibition of IkappaB kinase, nuclear factor-kappa B and STAT1, and depends on heme oxygenase-1 induction in mouse BV-2 microglia.
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.
Chen
Jui-Ching
JC
Department of Pharmacology, College of Medicine, National Taiwan University, No.1, Sec1, Jen Ai Rd., Taipei, Taiwan.
Ho
Feng-Ming
FM
Pei-Dawn Lee Chao
Chen
Chih-Ping
CP
Jeng
Kee-Ching G
KC
Hsu
Hsiu-Bao
HB
Lee
Sho-Tone
ST
Wen Tung Wu
Lin
Wan-Wan
WW
D000577:Amides / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000235:genetics* / Q000378:metabolism; D006427:Hemin / Q000494:pharmacology; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015151:Immunoblotting; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D011794:Quercetin / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D000577:Amides; D000975:Antioxidants; D002070:Butadienes; D004791:Enzyme Inhibitors; D005419:Flavonoids; D050856:Interferon Regulatory Factor-1; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009570:Nitriles; D011725:Pyridines; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D050794:STAT1 Transcription Factor; D018808:Transcription Factor AP-1; C113580:U 0126; C108830:Y 27632; D009569:Nitric Oxide; D006427:Hemin; D007371:Interferon-gamma; D011794:Quercetin; D008156:Luciferases; D052247:Nitric Oxide Synthase Type II; D051547:Heme Oxygenase-1; D051550:I-kappa B Kinase; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D001205:Ascorbic Acid; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one