A novel cell adhesion inhibitor, K-7174, reduces the endothelial VCAM-1 induction by inflammatory cytokines, acting through the regulation of GATA

Biochem Biophys Res Commun. 2000 Jun 7;272(2):370-4. doi: 10.1006/bbrc.2000.2784.

Abstract

A novel inhibitor for the adhesion of monocytes to cytokine-stimulated endothelial cells, K-7174, was selected by an assay system using the cultured human monocytic cells and human endothelial cells. K-7174 inhibited the expression of vascular cell adhesion molecule-1 (VCAM-1) induced by either tumor necrosis factor alpha or interleukin-1beta, without affecting the induction of intercellular adhesion molecule-1 or E-selectin. K-7174 had no effect on the stability of VCAM-1 mRNA. Electrophoretic mobility shift assay revealed that its inhibitory effect on VCAM-1 induction was mediated by an effect on the binding to the GATA motifs in the VCAM-1 gene promoter region. K-7174 did not influence the binding to any of the following binding motifs: octamer binding protein, AP-1, SP-1, ets, NFkappaB, or interferon regulatory factor. These results suggest that the regulation of GATA binding may become a new target for anti-inflammatory drug development, acting through a mechanism independent from NFkappaB activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anisoles / chemistry
  • Anisoles / pharmacology*
  • Azepines / chemistry
  • Azepines / pharmacology*
  • Cell Adhesion / drug effects
  • DNA / genetics
  • DNA / metabolism
  • DNA-Binding Proteins / metabolism*
  • E-Selectin / metabolism
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / metabolism
  • Erythroid-Specific DNA-Binding Factors
  • Humans
  • Intercellular Adhesion Molecule-1 / metabolism
  • Interleukin-1 / antagonists & inhibitors*
  • Interleukin-1 / pharmacology
  • Molecular Weight
  • Monocytes / cytology
  • Monocytes / drug effects
  • Nuclear Proteins / metabolism
  • Promoter Regions, Genetic / genetics
  • RNA Stability / drug effects
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Response Elements / genetics
  • Transcription Factors / metabolism*
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Tumor Necrosis Factor-alpha / pharmacology
  • U937 Cells
  • Umbilical Veins
  • Up-Regulation / drug effects
  • Vascular Cell Adhesion Molecule-1 / genetics*
  • Vascular Cell Adhesion Molecule-1 / metabolism

Substances

  • Anisoles
  • Azepines
  • DNA-Binding Proteins
  • E-Selectin
  • Erythroid-Specific DNA-Binding Factors
  • Interleukin-1
  • Nuclear Proteins
  • RNA, Messenger
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • Vascular Cell Adhesion Molecule-1
  • Intercellular Adhesion Molecule-1
  • K 7174
  • DNA