COX-2 and CCR2 induced by CD40 ligand and MCP-1 are linked to VEGF production in endothelial cells |
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Authors: | Futagami Seiji Hiratsuka Tetsuro Shindo Tomotaka Hamamoto Tatsuhiko Tatsuguchi Atsushi Nobue Ueki Shinji Yoko Suzuki Kenji Kusunoki Masanori Tanaka Shu Wada Ken Miyake Kazumasa Gudis Katya Tsukui Taku Sakamoto Choitsu |
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Institution: | Division of Gastroenterology, Department of Internal Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 1138603, Japan. seiji-f@nms.ac.jp |
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Abstract: | 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. |
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