COX-2 and CCR2 induced by CD40 ligand and MCP-1 are linked to VEGF production in endothelial cells

Prostaglandins Leukot Essent Fatty Acids. 2008 Feb;78(2):137-46. doi: 10.1016/j.plefa.2007.10.030. Epub 2008 Feb 21.


Recent studies have reported that expression of MCP-1 and its receptor, CCR2; and CD40-CD40 ligand (CD40L) interaction on mesenchymal cells play important roles in tumor development. Studies have also connected MCP-1, CCR2, and CD40L to COX-2 expression. The aim of this study was to examine the effect of MCP-1/CCR2 and CD40-CD40L interaction on COX-2 and VEGF expression in endothelial cells. We also investigated the localization of these proteins in gastric cancer tissue. COX-2 and CCR2 levels were evaluated in CD40L-stimulated HUVECs by Western blot and real-time PCR. VEGF secreted in the culture media was quantified by ELISA. Localizations of MCP-1, CD40L, CD34, CD40 and CCR2 in 34 gastric cancer tissue specimens were evaluated by immunohistochemistry. CD40-CD40L interaction-induced COX-2 production and subsequently, upregulated COX-2 production contributed to elevated VEGF and CCR2 levels in CD40L-stimulated HUVECs. CD40L-stimulated VEGF production was COX-2 but not COX-1 dependent. RS-102895, a CCR2-specific antagonist, significantly reduced VEGF production in CD40L- and MCP-1-stimulated HUVECs. MCP-1 had a synergistic effect on COX-2, CCR2 and VEGF levels in CD40L-stimulated HUVECs. In gastric cancer tissue, there was significant correlation between microvessel density and scores for CD40L, MCP-1 and CCR2 protein expression. Thus, MCP-1 had a synergistic effect on COX-2 and CCR2 protein expression in CD40L-stimulated HUVECs and thereby stimulated VEGF production in these cells.

MeSH terms

  • Benzoxazines / metabolism*
  • CD40 Antigens / metabolism
  • CD40 Ligand / metabolism*
  • Cell Line
  • Chemokine CCL2 / metabolism*
  • Culture Media, Conditioned
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism*
  • Endothelial Cells / cytology
  • Endothelial Cells / metabolism*
  • Gene Expression Regulation*
  • Humans
  • Microcirculation
  • Piperidines / metabolism*
  • Receptors, CCR2 / antagonists & inhibitors
  • Receptors, CCR2 / genetics
  • Receptors, CCR2 / metabolism*
  • Stomach Neoplasms / metabolism
  • Stomach Neoplasms / pathology
  • Vascular Endothelial Growth Factor A / metabolism*


  • Benzoxazines
  • CCL2 protein, human
  • CCR2 protein, human
  • CD40 Antigens
  • Chemokine CCL2
  • Culture Media, Conditioned
  • Piperidines
  • RS 102895
  • Receptors, CCR2
  • Vascular Endothelial Growth Factor A
  • CD40 Ligand
  • Cyclooxygenase 2
  • PTGS2 protein, human