Inhibitory mechanism of chroman compound on LPS-induced nitric oxide production and nuclear factor-kappaB activation

Biochem Biophys Res Commun. 2004 Dec 3;325(1):223-8. doi: 10.1016/j.bbrc.2004.10.026.

Abstract

6-Hydroxy-7-methoxychroman-2-carboxylic acid phenylamide (KL-1156) is a novel chemically synthetic compound. In the present study, the chroman KL-1156 compound was found to inhibit lipopolysaccharide (LPS)-induced nitric oxide production in macrophages RAW 264.7. KL-1156 compound attenuated LPS-induced synthesis of both mRNA and protein of inducible nitric oxide synthase (iNOS), in parallel, and inhibited LPS-induced iNOS promoter activity, indicating that the chroman compound down-regulated iNOS expression at transcription level. As a mechanism of the anti-inflammatory action shown by KL-1156 compound, suppression of nuclear factor (NF)-kappaB has been documented. KL-1156 compound exhibited a dose-dependent inhibitory effect on LPS-induced NF-kappaB transcriptional activity in macrophages RAW 264.7. Furthermore, the compound inhibited LPS-induced nuclear translocation of NF-kappaB p65 and DNA binding activity of NF-kappaB complex, in parallel, but did not affect IkappaBalpha degradation. Taken together, this study demonstrated that chroman KL-1156 compound interfered with nuclear translocation step of NF-kappaB p65, which was attributable to its anti-inflammatory action.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / physiology
  • Animals
  • Cell Line
  • Chromans / chemistry
  • Chromans / pharmacology*
  • DNA / metabolism
  • Gene Expression Regulation, Enzymologic
  • I-kappa B Proteins / metabolism
  • Lipopolysaccharides / pharmacology*
  • Macrophages / cytology
  • Macrophages / drug effects*
  • Macrophages / immunology
  • Mice
  • Molecular Structure
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / immunology
  • NF-kappa B / metabolism*
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase / genetics
  • Nitric Oxide Synthase / metabolism
  • Nitric Oxide Synthase Type II
  • Promoter Regions, Genetic
  • Transcription Factor RelA
  • Transcription, Genetic

Substances

  • 6-hydroxy-7-methoxychroman-2-carboxylic acid phenylamide
  • Chromans
  • I-kappa B Proteins
  • Lipopolysaccharides
  • NF-kappa B
  • Nfkbia protein, mouse
  • Transcription Factor RelA
  • NF-KappaB Inhibitor alpha
  • Nitric Oxide
  • DNA
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse