The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/8/603/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 3, August 3, 1998 603-608

Brief Definitive Reports

Identification of C-C Chemokine Receptor 1 (CCR1) as the Monocyte Hemofiltrate C-C Chemokine (HCC)-1 Receptor

Chia-Lin Tsou*, Ron P. Gladue§, Laurie A. Carroll§, Tim Paradis§, James G. Boyd§, Robin T. Nelson§, Kuldeep Neote§, and Israel F. Charo*,{ddagger}

From the * Gladstone Institute of Cardiovascular Disease, the Cardiovascular Research Institute, the {ddagger} Daiichi Research Center, and the Department of Medicine, University of California, San Francisco, California 94141; and § Pfizer Inc., Groton, Connecticut 06340

Hemofiltrate C-C chemokine (HCC)-1 is a recently cloned C-C chemokine that is structurally similar to macrophage inflammatory protein (MIP)-1{alpha}. Unlike most chemokines, it is constitutively secreted by tissues and is present at high concentrations in normal human plasma. Also atypical for chemokines, HCC-1 is reported not to be chemotactic for leukocytes. In this paper, we have investigated the chemokine receptor usage and downstream signaling pathways of HCC-1. Cross-desensitization experiments using THP-1 cells suggested that HCC-1 and MIP-1{alpha} activated the same receptor. Experiments using a panel of cloned chemokine receptors revealed that HCC-1 specifically activated C-C chemokine receptor (CCR)1, but not closely related receptors, including CCR5. HCC-1 competed with MIP-1{alpha} for binding to CCR1-transfected cells, but with a markedly reduced affinity (IC50 = 93 nM versus 1.3 nM for MIP-1{alpha}). Similarly, HCC-1 was less potent than MIP-1{alpha} in inducing inhibition of adenylyl cyclase in CCR1-transfected cells. HCC-1 induced chemotaxis of freshly isolated human monocytes, THP-1 cells, and CCR1-transfected cells, and the optimal concentration for cell migration (100 nM) was ~100-fold lower than that of MIP-1{alpha} (1 nM). These data demonstrate that HCC-1 is a chemoattractant and identify CCR1 as a functional HCC-1 receptor on human monocytes.

Key Words: hemofiltrate C-C chemokine • C-C chemokine receptor 1 • chemokine • chemotaxis • macrophage inflammatory protein 1{alpha}

Address correspondence to Israel F. Charo, Gladstone Institute of Cardiovascular Disease, PO Box 419100, San Francisco, CA 94141-9100. Phone: 415-826-7500; Fax: 415-285-5632; E-mail: izzy_charo{at}quickmail.ucsf.edu


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