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-1α (MIP-1α)/regulated on activation, normal T expressed, and secreted protein (RANTES) receptor CC CKR1 (rank order for [Ca²⁺](i) changes = MIP-1α > MCP-3 > RANTES), which is expressed in monocytes > neutrophils > eosinophils. ¹²⁵I-MCP-3 bound directly to CC CKR1 and CC CKR2B (K(i) = 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.