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Published online before print March 12, 2004
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* The Cardiovascular Institute, Department of Medicine, The Mount Sinai School of Medicine, New York, New York;
The Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts;
Departments of Pathology and Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, New York; and
Gladstone Institute of Cardiovascular Disease and the Cardiovascular Research Institute, Department of Medicine, University of California, San Francisco
1 Correspondence: Box 1030, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029. E-mail: alison.schecter{at}mssm.edu
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 G
i-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.
Key Words: chemokine • tissue factor • vascular smooth muscle • receptors • genetically altered mice • kinases
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