Monocyte chemoattractant protein-3 is a functional ligand for CC chemokine receptors 1 and 2B.
The CC chemokine monocyte chemoattractant protein-3 (MCP-3) activates human monocytes, lymphocytes, basophils, and eosinophils. MCP-3 has been reported to induce [Ca2+]i changes in cells transfected with the monocyte-selective MCP-1 receptor 2B (CC CKR2B) and competes for 125I-MCP-1 binding on CC CKR2B, suggesting that it may mediate monocyte responses to MCP-3. However, we now show that MCP-3 is a ligand and potent agonist for the macrophage inflammatory protein-1 alpha (MIP-1 alpha)/regulated on activation, normal T expressed, and secreted protein (RANTES) receptor CC CKR1 (rank order for [Ca2+]i changes = MIP-1 alpha > MCP-3 > RANTES), which is expressed in monocytes > neutrophils > eosinophils. 125I-MCP-3 bound directly to CC CKR1 and CC CKR2B (Ki = 8 and 7 nM, respectively). Binding to CC CKR1 was competed by all CC chemokines tested except MCP-1. In contrast, binding to CC CKR2B was competed only by MCP-3 and MCP-1. Both MCP-1 and MCP-3 were equipotent agonists (EC50 = 10 nM for [Ca2+]i changes). Thus, MCP-3 is a functional ligand for both CC CKR1 and CC CKR2B, which otherwise have distinct selectivities for CC chemokines. These data suggest that monocyte responses to MCP-3 could be mediated by both CC CKR2B and CC CKR1, whereas eosinophil responses to MCP-3 could be mediated by CC CKR1.
Laboratory of Host Defenses, NIAID, National Institutes of Health, Bethesda, Maryland 20892, USA.
C
C
Combadiere
S K
SK
Ahuja
J
J
Van Damme
H L
HL
Tiffany
J L
JL
Gao
P M
PM
Murphy
D000595:Amino Acid Sequence; D001491:Basophils / Q000502:physiology; D001667:Binding, Competitive; D054410:Chemokine CCL7; D018925:Chemokines / Q000494:pharmacology; D016207:Cytokines; D004804:Eosinophils / Q000502:physiology; D006801:Humans; D007457:Iodine Radioisotopes; D007700:Kinetics; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology*; D008024:Ligands; D008214:Lymphocytes / Q000502:physiology; D008969:Molecular Sequence Data; D018945:Monocyte Chemoattractant Proteins / Q000378:metabolism* / Q000494:pharmacology; D009000:Monocytes / Q000502:physiology; D011869:Radioligand Assay; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013997:Time Factors
C515450:CCL7 protein, human; C515334:CCR2 protein, human; D054410:Chemokine CCL7; D018925:Chemokines; D016207:Cytokines; D007457:Iodine Radioisotopes; D008024:Ligands; D018945:Monocyte Chemoattractant Proteins; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine; D011994:Recombinant Proteins; C080633:macrophage inflammatory protein 1alpha receptor