title: Uncoupling of early signal transduction events from effector function in human peripheral blood neutrophils in response to recombinant macrophage inflammatory proteins-1 alpha and -1 beta.
abstract: Macrophage inflammatory proteins-1 (MIP-1) alpha and beta are members of the C-C branch of the platelet factor 4 superfamily of cytokines, recently designated the "chemokine" superfamily. It has been suggested that the major cellular targets for the biologic activities of the C-C chemokines are the mononuclear leukocytes. However, the original designation of murine MIP-1 proteins as inflammatory mediators was based on suggestions that they activated neutrophil functions such as chemotaxis, the respiratory burst, and degranulation. In this study, we have evaluated the ability of human (Hu) MIP-1 alpha and beta to affect purified human neutrophil function. Although both rHuMIP-1 alpha and -1 beta stimulated significant calcium mobilization in human monocytes, only HuMIP-1 alpha exerted a detectable effect on neutrophils. HuMIP-1 alpha stimulated a small, dose-dependent increase in intracellular calcium, which was accompanied by a simultaneous change in right-angle light scatter, the latter indicating induction of shape change. While the effect of HuMIP-1 alpha on calcium mobilization in neutrophils was small when compared with that elicited by IL-8 or Gro alpha, it had similar characteristics to that by other receptor-dependent neutrophil agonists in that it was dependent on pertussis toxin-sensitive G proteins and on both mobilization of calcium from intracellular sources as well as influx from the extracellular environment. In addition, stimulation of neutrophils with HuMIP-1 alpha led to desensitization to subsequent additions of HuMIP-1 alpha. The stimulatory effect of HuMIP-1 alpha on neutrophil calcium mobilization and shape change was not coupled to other standard measures of neutrophil effector function. For instance, neither HuMIP-1 alpha nor -1 beta had any detectable stimulatory effect on the Na+/H+ antiport, degranulation, actin polymerization, or chemotaxis. Moreover, although HuMIP-1 alpha binding could easily be measured on monocytes or monocytic cell lines, the number of sites were too few to characterize on neutrophils by the same technique. Taken together, these results show that neither HuMIP-1 alpha nor -1 beta stimulate significant neutrophil activation and support the concept that the biologic effects of members of the C-C branch of the platelet factor 4 superfamily are not primarily directed toward neutrophils.
authors: Centre de Recherche en Inflammation, Immunologie et Rhumatologie, Université Laval, Sainte-Foy, Québec, Canada.
authors: S R
authors: SR
authors: McColl
authors: M
authors: M
authors: Hachicha
authors: S
authors: S
authors: Levasseur
authors: K
authors: K
authors: Neote
authors: T J
authors: TJ
authors: Schall
mesh_terms: D008841:Actin Cytoskeleton / Q000648:ultrastructure; D000199:Actins / Q000378:metabolism; D002118:Calcium / Q000502:physiology; D015550:Cell Degranulation / Q000187:drug effects; D054407:Chemokine CCL4; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology*; D004533:Egtazic Acid / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000502:physiology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008027:Light; D019402:Macrophage Inflammatory Proteins; D015846:Monokines / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D037342:Pertussis Toxin; D011994:Recombinant Proteins; D012542:Scattering, Radiation; D015398:Signal Transduction / Q000187:drug effects; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
chemical_list: D000199:Actins; D054407:Chemokine CCL4; D016207:Cytokines; D019402:Macrophage Inflammatory Proteins; D015846:Monokines; D011994:Recombinant Proteins; D010566:Virulence Factors, Bordetella; D004533:Egtazic Acid; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D002118:Calcium