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The β-chemokine macrophage inflammatory protein-1α (MIP-1α) is chemotactic for many hemopoietic cell types and can inhibit hemopoietic stem cell (HSC) proliferation, effects mediated through G-protein coupled heptahelical receptors. We have isolated cDNAs for seven chemokine receptors, CCR-1 to -5, MIP-1αRL1, and a novel cDNA, D6. Chinese hamster ovary cells expressing CCR-1, -3, -5, and D6 bound 125I-murine MIP-1α: the order of affinity was D6 > CCR-5 > CCR-1 > CCR-3. Each bound a distinct subset of other β-chemokines: the order of competition for 125I-murine MIP-1α on D6 was murine MIP-1α > human and murine MIP-1β > human RANTES∼JE > human MCP-3 > human MCP-1. Human MIP-1α and the α-chemokines did not compete. Like other chemokine receptors, D6 induced transient increases in [Ca2+] in HEK 293 cells upon ligand binding. D6 mRNA was abundant in lung and detectable in many other tissues. Bone marrow cell fractionation demonstrated T-cell and macrophage/monocyte expression of D6, and CCR-1, -3, and -5. Moreover, we could detect expression of CCR-3, CCR-5, and to a greater extent D6 in a cell population enriched for HSCs. Thus, we have characterized four murine β chemokine receptors that are likely involved in mediating the pro-inflammatory functions of MIP-1α and other chemokines, and we present D6, CCR-3, and CCR-5 as candidate receptors in MIP-1α-induced HSC inhibition. |
