Identification of C-C chemokine receptor 1 (CCR1) as the monocyte hemofiltrate C-C chemokine (HCC)-1 receptor.
Hemofiltrate C-C chemokine (HCC)-1 is a recently cloned C-C chemokine that is structurally similar to macrophage inflammatory protein (MIP)-1alpha. 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-1alpha 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-1alpha for binding to CCR1-transfected cells, but with a markedly reduced affinity (IC50 = 93 nM versus 1.3 nM for MIP-1alpha). Similarly, HCC-1 was less potent than MIP-1alpha 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 approximately 100-fold lower than that of MIP-1alpha (1 nM). These data demonstrate that HCC-1 is a chemoattractant and identify CCR1 as a functional HCC-1 receptor on human monocytes.
Gladstone Institute of Cardiovascular Disease, the Cardiovascular Research Institute, and the Department of Medicine, University of California, San Francisco, California 94141, USA.
C L
CL
Tsou
R P
RP
Gladue
L A
LA
Carroll
T
T
Paradis
J G
JG
Boyd
R T
RT
Nelson
K
K
Neote
I F
IF
Charo
D002460:Cell Line; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019742:Chemokines, CC / Q000138:chemical synthesis / Q000378:metabolism*; D002633:Chemotaxis; D006801:Humans; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism* / Q000502:physiology; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D015290:Second Messenger Systems
C097720:CCL14 protein, human; C515300:CCR1 protein, human; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019742:Chemokines, CC; D019402:Macrophage Inflammatory Proteins; D054389:Receptors, CCR1; D019707:Receptors, Chemokine