MCP‐1‐dependent signaling in CCR2−/− aortic smooth muscle cells

Monocyte chemoattractant protein‐1 (MCP‐1, CCL2) is a mediator of inflammation that has been implicated in the pathogenesis of a wide variety of human diseases. CCR2, a heterotrimeric G‐coupled receptor, is the only known receptor that functions at physiologic concentrations of MCP‐1. Despite the importance of CCR2 in mediating MCP‐1 responses, several recent studies have suggested that there may be another functional MCP‐1 receptor. Using arterial smooth muscle cells (SMC) from CCR2−/− mice, we demonstrate that MCP‐1 induces tissue‐factor activity at physiologic concentrations. The induction of tissue factor by MCP‐1 is blocked by pertussis toxin and 1,2‐bis(O‐aminophenyl‐ethane‐ethan)‐N,N,N′,N′‐tetraacetic acid‐acetoxymethyl ester, suggesting that signal transduction through the alternative receptor is Gαi‐coupled and dependent on mobilization of intracellular Ca2+. MCP‐1 induces a time‐ and concentration‐dependent phosphorylation of the mitogen‐activated protein kinases p42/44. The induction of tissue factor activity by MCP‐1 is blocked by PD98059, an inhibitor of p42/44 activation, but not by SB203580, a selective p38 inhibitor. These data establish that SMC possess an alternative MCP‐1 receptor that signals at concentrations of MCP‐1 that are similar to those that activate CCR2. This alternative receptor may be important in mediating some of the effects of MCP‐1 in atherosclerotic arteries and in other inflammatory processes.

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