4-Hydroxykobusin inhibits the induction of nitric oxide synthase by inhibiting NF-kappaB and AP-1 activation

Biol Pharm Bull. 2007 Jun;30(6):1097-101. doi: 10.1248/bpb.30.1097.

Abstract

We recently isolated a novel lignan, 4-hydroxykobusin from Geranium thunbergii (Liu et al., Arch. Pharm. Res., 29, 1109-1113, 2006). Here, we studied its effect on the expression of inducible nitric oxide synthase (iNOS) gene in RAW264.7 cells. 4-Hydroxykobusin inhibited nitric oxide (NO) production in a concentration-dependent manner and blocked the lipopolysaccharide (LPS)-induced expression of inducible nitric oxide synthase (iNOS). To identify the mechanistic basis for its inhibition of iNOS induction, we examined the effect of 4-hydroxykobusin on the transactivation of iNOS gene by luciferase reporter activity using -1.59 kb flanking region. The lignan suppressed the reporter gene activity and the LPS-induced reporter activations of nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) were also significantly blocked by 4-hydroxykobusin. These findings suggest that the inhibition of LPS-induced NO formation by 4-hydroxykobusin is due to its inhibition of NF-kappaB and AP-1 activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Line
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Enzyme Induction / drug effects
  • Formazans / metabolism
  • Furans / chemistry
  • Furans / pharmacology
  • Genes, Reporter
  • Geranium / chemistry
  • Lignans / chemistry
  • Lignans / pharmacology*
  • Lipopolysaccharides / toxicity
  • Luciferases / metabolism
  • Macrophages, Peritoneal / drug effects*
  • Mice
  • Molecular Structure
  • NF-kappa B / antagonists & inhibitors*
  • Nitric Oxide Synthase Type II / antagonists & inhibitors*
  • Nitric Oxide Synthase Type II / genetics
  • Plant Extracts / chemistry
  • Plant Extracts / pharmacology
  • Tetrazolium Salts / metabolism
  • Transcription Factor AP-1 / antagonists & inhibitors*
  • Transcriptional Activation

Substances

  • 4-hydroxykobusin
  • Formazans
  • Furans
  • Lignans
  • Lipopolysaccharides
  • NF-kappa B
  • Plant Extracts
  • Tetrazolium Salts
  • Transcription Factor AP-1
  • MTT formazan
  • Luciferases
  • Nitric Oxide Synthase Type II