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

Eur J Pharmacol. 2005 Oct 3;521(1-3):9-20. doi: 10.1016/j.ejphar.2005.08.005. Epub 2005 Sep 19.

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

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / pharmacology
  • Animals
  • Antioxidants / pharmacology
  • Ascorbic Acid / pharmacology
  • Butadienes / pharmacology
  • Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
  • Cell Line
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Flavonoids / pharmacology
  • Gene Expression Regulation, Enzymologic / drug effects
  • Heme Oxygenase-1 / genetics*
  • Heme Oxygenase-1 / metabolism
  • Hemin / pharmacology
  • I-kappa B Kinase / antagonists & inhibitors*
  • I-kappa B Kinase / metabolism
  • Immunoblotting
  • Interferon Regulatory Factor-1 / genetics
  • Interferon Regulatory Factor-1 / metabolism
  • Interferon-gamma / pharmacology
  • Lipopolysaccharides / pharmacology
  • Luciferases / genetics
  • Luciferases / metabolism
  • Mice
  • Microglia / cytology
  • Microglia / drug effects
  • Microglia / metabolism
  • NF-kappa B / metabolism*
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase Type II / antagonists & inhibitors
  • Nitric Oxide Synthase Type II / genetics*
  • Nitric Oxide Synthase Type II / metabolism
  • Nitriles / pharmacology
  • Phosphorylation / drug effects
  • Pyridines / pharmacology
  • Quercetin / pharmacology*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • STAT1 Transcription Factor / metabolism*
  • Transcription Factor AP-1 / genetics
  • Transcription Factor AP-1 / metabolism
  • Transfection

Substances

  • Amides
  • Antioxidants
  • Butadienes
  • Enzyme Inhibitors
  • Flavonoids
  • Interferon Regulatory Factor-1
  • Lipopolysaccharides
  • NF-kappa B
  • Nitriles
  • Pyridines
  • RNA, Messenger
  • Recombinant Fusion Proteins
  • STAT1 Transcription Factor
  • Transcription Factor AP-1
  • U 0126
  • Y 27632
  • Nitric Oxide
  • Hemin
  • Interferon-gamma
  • Quercetin
  • Luciferases
  • Nitric Oxide Synthase Type II
  • Heme Oxygenase-1
  • I-kappa B Kinase
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Ascorbic Acid
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one