Blockade of nuclear factor-kappaB signaling pathway and anti-inflammatory activity of cardamomin, a chalcone analog from Alpinia conchigera

J Pharmacol Exp Ther. 2006 Jan;316(1):271-8. doi: 10.1124/jpet.105.092486. Epub 2005 Sep 23.

Abstract

Nuclear factor-kappaB (NF-kappaB) and the signaling pathways that regulate its activity have become a focal point for intense drug discovery and development efforts. NF-kappaB regulates the transcription of a large number of genes, particularly those involved in immune, inflammatory, and antiapoptotic responses. In our search for NF-kappaB inhibitors from natural resources, we identified cardamomin, 2',4'-dihydroxy-6'-methoxychalcone, as an inhibitor of NF-kappaB activation from Alpinia conchigera Griff (Zingiberaceae). In present study, we demonstrated the effect of cardamomin on NF-kappaB activation in lipopolysaccharide (LPS)-stimulated RAW264.7 cells and LPS-induced mortality. This compound significantly inhibited the induced expression of NF-kappaB reporter gene by LPS or tumor necrosis factor (TNF)-alpha in a dose-dependent manner. LPS-induced production of TNF-alpha and NO as well as expression of inducible nitric-oxide synthase and cyclooxygenase-2 was significantly suppressed by the treatment of cardamomin in RAW264.7 cells. Also, cardamomin inhibited not only LPS-induced degradation and phosphorylation of inhibitor kappaBalpha (IkappaBalpha) but also activation of inhibitor kappaB (IkappaB) kinases and nuclear translocation of NF-kappaB. Further analyses revealed that cardamomin did not directly inhibit IkappaB kinases, but it significantly suppressed LPS-induced activation of Akt. Moreover, cardamomin suppressed transcriptional activity and phosphorylation of Ser536 of RelA/p65 subunit of NF-kappaB. However, this compound did not inhibit LPS-induced activation of extracellular signal-regulated kinase and stress-activated protein kinase/c-Jun NH(2)-terminal kinase, but significantly impaired activation of p38 mitogen-activated protein kinase. We also demonstrated that pretreatment of cardamomin rescued C57BL/6 mice from LPS-induced mortality in conjunction with decreased serum level of TNF-alpha. Together, cardamomin could be valuable candidate for the intervention of NF-kappaB-dependent pathological condition such as inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alpinia / chemistry*
  • Animals
  • Anti-Inflammatory Agents*
  • Blotting, Western
  • Cell Survival / drug effects
  • Chalcones / pharmacology*
  • Cyclooxygenase 2 Inhibitors / pharmacology
  • Electrophoretic Mobility Shift Assay
  • Enzyme Inhibitors / pharmacology
  • Humans
  • I-kappa B Proteins / drug effects
  • Lipopolysaccharides / pharmacology
  • Luciferases / genetics
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / antagonists & inhibitors*
  • Nitric Oxide Synthase Type II / antagonists & inhibitors
  • Oncogene Protein p65(gag-jun) / drug effects
  • Oncogene Protein p65(gag-jun) / metabolism
  • Phosphorylation
  • Plasmids / genetics
  • Signal Transduction / drug effects*
  • Transcriptional Activation / drug effects
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Anti-Inflammatory Agents
  • Chalcones
  • Cyclooxygenase 2 Inhibitors
  • Enzyme Inhibitors
  • I-kappa B Proteins
  • Lipopolysaccharides
  • NF-kappa B
  • Oncogene Protein p65(gag-jun)
  • Tumor Necrosis Factor-alpha
  • Luciferases
  • Nitric Oxide Synthase Type II
  • cardamonin