4-O-methylgallic Acid Down-Regulates Endothelial Adhesion Molecule Expression by Inhibiting NF-kappaB-DNA-binding Activity

Eur J Pharmacol. 2006 Dec 3;551(1-3):143-51. doi: 10.1016/j.ejphar.2006.08.061. Epub 2006 Sep 8.

Abstract

We here investigated the functional effect of 4-O-methylgallic acid (4-OMGA), a major metabolite of gallic acid abundant in red wine, on vascular inflammation and its action mechanism. 4-OMGA inhibited the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in human umbilical vein endothelial cells (HUVECs) stimulated with tumor necrosis factor-alpha (TNF-alpha), resulting in the suppression of leukocyte adhesion to HUVECs. In addition, 4-OMGA inhibited the promoter activities of ICAM-1 and VCAM-1 and the activity of nuclear factor-kappaB (NF-kappaB) without affecting cytosolic IkappaB kinase (IKK) activation, inhibitor of kappaB (IkappaB) phosphorylation and degradation, and nuclear translocation of NF-kappaB. This compound did not alter nitric oxide (NO) generation, but inhibited reactive oxygen species (ROS) production in TNF-alpha-stimulated HUVECs, suggesting that NO and ROS are not involved in 4-OMGA-mediated inhibition of NF-kappaB activity. Moreover, 4-OMGA directly blocked the binding activity of NF-kappaB to its consensus DNA oligonucleotide, when pre-incubated with the nuclear extract from TNF-alpha-stimulated HUVECs, but not with the oligonucleotide alone. This inhibition was completely abolished by the addition of dithiothreitol. 4-OMGA exhibits an anti-inflammatory property by interfering with the formation of the NF-kappaB-DNA complex in the nuclei through direct and redox-sensitive interactions and may play an important role in the prevention of inflammatory responses such as the atherosclerotic process.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Inflammatory Agents / pharmacology*
  • Anti-Inflammatory Agents / therapeutic use
  • Atherosclerosis / drug therapy
  • Cell Adhesion / drug effects
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism*
  • Cells, Cultured
  • DNA / metabolism*
  • Dose-Response Relationship, Drug
  • Down-Regulation / drug effects
  • Endothelial Cells / drug effects*
  • Endothelial Cells / metabolism
  • Gallic Acid / analogs & derivatives*
  • Gallic Acid / pharmacology
  • Gallic Acid / therapeutic use
  • Genes, Reporter
  • Humans
  • Intercellular Adhesion Molecule-1 / metabolism
  • Leukocytes / drug effects
  • Luciferases
  • NF-kappa B / antagonists & inhibitors*
  • NF-kappa B / metabolism
  • Nitric Oxide / metabolism
  • Promoter Regions, Genetic / drug effects
  • RNA, Messenger / metabolism
  • Reactive Oxygen Species / metabolism
  • Transcription, Genetic / drug effects
  • Transfection
  • Tumor Necrosis Factor-alpha / pharmacology
  • Vascular Cell Adhesion Molecule-1 / metabolism

Substances

  • Anti-Inflammatory Agents
  • Cell Adhesion Molecules
  • NF-kappa B
  • RNA, Messenger
  • Reactive Oxygen Species
  • Tumor Necrosis Factor-alpha
  • Vascular Cell Adhesion Molecule-1
  • 3,5-dihydroxy-4-methoxybenzoic acid
  • Intercellular Adhesion Molecule-1
  • Nitric Oxide
  • Gallic Acid
  • DNA
  • Luciferases