Differential effects of leukotactin-1 and macrophage inflammatory protein-1 alpha on neutrophils mediated by CCR1

The human CC chemokine leukotactin-1 (Lkn-1) is both a strong chemoattracta nt for neutrophils, monocytes, and lymphocytes and a potent agonist for CCR 1 and CCR3. However, human neutrophils do not migrate when the cells are st imulated with other human CC chemokines, such as human macrophage inflammat ory protein-1 alpha (hMIP-1 alpha) and eotaxin, which also use the CCR1 and CCR3 as their receptors. In this report, we demonstrate that while hMIP-1 alpha induced a negligible level of calcium flux and chemotaxis, Lkn-1 prod uced a high level of calcium Bus and chemotaxis in human neutrophils. Lkn-1 cross-desensitized hMIP-1 alpha-induced calcium Bus, but hl hMIP-1 alpha h ad little effect on the Lkn-1-induced response in human neutrophils. The sa me pattern was observed in peritoneal neutrophils from wild-type mice, wher eas neutrophils from CCR1(-/-) mice failed to respond to either MIP-1 alpha or Lkn-1. Scatchard anal-sis revealed a single class of receptor for both hMIP-1 alpha: and Lkn-1 on human neutrophils with dissociation constants (K -d) of 3.2 nM and 1.1 nM, respectively. We conclude that CCR1 is a receptor mediating responses to both MIP-1 alpha and Lkn-1 on neutrophils and produ ces different biological responses depending on the ligand bound.