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 chemoattractant for neutrophils, monocytes, and lymphocytes and a potent agonist for CCR1 and CCR3. However, human neutrophils do not migrate when the cells are stimulated with other human CC chemokines, such as human macrophage inflammatory 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 produced a high level of calcium flux and chemotaxis in human neutrophils. Lkn-1 cross-desensitized hMIP-1 alpha-induced calcium flux, but hMIP-1 alpha had little effect on the Lkn-1-induced response in human neutrophils. The same pattern was observed in peritoneal neutrophils from wild-type mice, whereas neutrophils from CCR1-/- mice failed to respond to either MIP-1 alpha or Lkn-1. Scatchard analysis revealed a single class of receptor for both hMIP-1 alpha and Lkn-1 on human neutrophils with dissociation constants (Kd) 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 produces different biological responses depending on the ligand bound.
Zhang
S
S
Department of Microbiology and Immunology, Walther Oncology Center, Indiana University School of Medicine, Indianapolis 46202, USA.
Youn
B S
BS
Gao
J L
JL
Murphy
P M
PM
Kwon
B S
BS
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D001665:Binding Sites / Q000276:immunology; D020013:Calcium Signaling / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D054413:Chemokine CCL11; D054407:Chemokine CCL4; D019742:Chemokines, CC / Q000494:pharmacology*; D016207:Cytokines / Q000494:pharmacology; D004306:Dose-Response Relationship, Immunologic; D006801:Humans; D019402:Macrophage Inflammatory Proteins / Q000494:pharmacology*; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D010537:Peritoneum / Q000166:cytology / Q000276:immunology; D011869:Radioligand Assay; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000378:metabolism / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology
D000276:Adjuvants, Immunologic; C515456:CCL11 protein, human; C515300:CCR1 protein, human; D054413:Chemokine CCL11; D054407:Chemokine CCL4; D019742:Chemokines, CC; D016207:Cytokines; D019402:Macrophage Inflammatory Proteins; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; D011994:Recombinant Proteins