title: Two signaling mechanisms for activation of alphaM beta2 avidity in polymorphonuclear neutrophils.
abstract: Circulating polymorphonuclear neutrophils (PMN) are quiescent, nonadherent cells that rapidly activate at sites of inflammation, where they develop the capacity to perform a repertoire of functions that are essential for host defense. Induction of integrin-mediated adhesion, which requires an increase in integrin avidity, is critical for the development of these effector functions. Although a variety of stimuli can activate integrins in PMN, the signaling cascades involved are unclear. Phosphatidylinositol (PI) 3-kinase has been implicated in integrin activation in a variety of cells, including PMN. In this work, we have examined activation of the PMN integrin alphaM beta2, assessing both adhesion and generation of the epitope recognized by the activation-specific antibody CBRM1/5. We have found that PI 3-kinase has a role in activation of alphaM beta2 by immune complexes, but we have found no role for it in alphaM beta2 activation by ligands for trimeric G protein-coupled receptors, including formylmethionylleucylphenylalanine (fMLP), interleukin-8, and C5a. Cytochalasin D inhibition suggests a role for the actin cytoskeleton in immune complex activation of alphaM beta2, but cytochalasin has no effect on fMLP-induced activation. Similarly, immune complex activation of the Rac/Cdc42-dependent serine/threonine kinase Pak1 is blocked by PI 3-kinase inhibitors, but fMLP-induced activation is not. These results demonstrate that two signaling pathways exist in PMN for activation of alphaM beta2. One, induced by FcgammaR ligation, is PI 3-kinase-dependent and requires the actin cytoskeleton. The second, initiated by G protein-linked receptors, is PI 3-kinase-independent and cytochalasin-insensitive. Pak1 may be in a final common pathway leading to activation of alphaM beta2.
authors.affiliation: Division of Infectious Diseases, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Jones
authors.forename: U G
authors.initials: UG
authors.lastname: Knaus
authors.forename: G M
authors.initials: GM
authors.lastname: Bokoch
authors.forename: E J
authors.initials: EJ
authors.lastname: Brown
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects; D004789:Enzyme Activation; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D016177:Macrophage-1 Antigen / Q000276:immunology / Q000378:metabolism*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011961:Receptors, Fc / Q000378:metabolism; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015854:Up-Regulation; D054462:p21-Activated Kinases
chemical_list: D019204:GTP-Binding Proteins; D016177:Macrophage-1 Antigen; D009240:N-Formylmethionine Leucyl-Phenylalanine; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011961:Receptors, Fc; D013755:Tetradecanoylphorbol Acetate; D054462:p21-Activated Kinases; C515903:PAK1 protein, human