Suppression by a sesquiterpene lactone from Carpesium divaricatum of inducible nitric oxide synthase by inhibiting nuclear factor-kappaB activation

Biochem Pharmacol. 2001 Apr 1;61(7):903-10. doi: 10.1016/s0006-2952(01)00538-x.

Abstract

Excessive nitric oxide (NO) produced by inducible NO synthase (iNOS) acts as a causative regulator in various inflammatory disease states. Carpesium divaricatum has been used in Korean traditional herbal medicine for its antipyretic, analgesic, vermifugic, and anti-inflammatory properties. We investigated the molecular mechanism for the suppression of lipopolysaccharide/interferon-gamma (LPS/IFN-gamma)-induced NO production in RAW 264.7 macrophages by the sesquiterpene lactone 2beta,5-epoxy-5,10-dihydroxy-6alpha-angeloyloxy-9beta-isobutyloxy-germacran-8alpha,12-olide (C-1), which has been identified recently as a new compound from C. divaricatum. C-1 decreased NO production in LPS/IFN-gamma-stimulated RAW 264.7 cells in a concentration-dependent manner, with an IC50 of approximately 2.16 microM; however, it had no direct effect on the iNOS activity of fully LPS/IFN-gamma-stimulated RAW 264.7 cells. Furthermore, treatment with C-1 led to a decrease in iNOS protein and mRNA. These effects appear to be due to inhibition of nuclear factor-kappaB (NF-kappaB) activation through a mechanism involving stabilization of the NF-kappaB/inhibitor of the kappaB (I-kappaB) complex, since inhibition of NF-kappaB DNA binding activity by C-1 was accompanied by a parallel reduction of nuclear translocation of subunit p65 of NF-kappaB and I-kappaBalpha degradation. Taken together, the results suggest that the ability of C-1 to inhibit iNOS gene expression may be responsible, in part, for its anti-inflammatory effects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Transport / drug effects
  • Catalysis
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cell Survival / drug effects
  • Cells, Cultured
  • DNA-Binding Proteins / metabolism
  • Enzyme Repression / drug effects
  • I-kappa B Proteins*
  • Interferon-gamma / pharmacology
  • Ligases / metabolism
  • Lipopolysaccharides / pharmacology
  • Mice
  • NF-KappaB Inhibitor alpha
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / metabolism
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase / biosynthesis*
  • Nitric Oxide Synthase / genetics
  • Nitric Oxide Synthase / metabolism
  • Nitric Oxide Synthase Type II
  • Nitrites / metabolism
  • Phytotherapy
  • Plants, Medicinal / chemistry*
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / drug effects
  • Sesquiterpenes / pharmacology*

Substances

  • DNA-Binding Proteins
  • I-kappa B Proteins
  • Lipopolysaccharides
  • NF-kappa B
  • Nfkbia protein, mouse
  • Nitrites
  • RNA, Messenger
  • Sesquiterpenes
  • NF-KappaB Inhibitor alpha
  • Nitric Oxide
  • Interferon-gamma
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Ligases
  • guanosine 3',5'-polyphosphate synthetases