title: Responses of neutrophils to anti-integrin antibodies depends on costimulation through low affinity Fc gamma Rs: full activation requires both integrin and nonintegrin signals.
abstract: The relative contribution of integrin and nonintegrin signals to neutrophil activation is incompletely understood. Immobilized anti-integrin Abs were previously shown to induce robust activation of neutrophils without any additional stimulus, suggesting that cross-linking of integrins is sufficient for full activation of the cells. However, the possible contribution from other receptors has not been tested in this system. In this study, we show that neutrophil responses to anti-integrin Abs requires costimulation through low-affinity Fc gamma Rs. Murine neutrophils lacking the FcR gamma-chain or Fc gamma RIII failed to respond to immobilized Abs against beta(1), beta(2), or beta(3) integrins and the activation of wild-type cells could be prevented by blocking Abs against Fc gamma RII/III. Plate-bound anti-CD18 Abs initiated a respiratory burst from human neutrophils, but this response was abrogated when the F(ab')(2) of the same Abs were used or the cells were preincubated with Fc gamma RIIA-blocking Abs. Lack of Fc gamma RIII or administration of Fc gamma R-blocking Abs had no effect on responses of TNF-stimulated cells plated on fibrinogen or rICAM-1. TNF restored the respiratory burst of Fc gamma RIII-deficient neutrophils plated on anti-CD18 mAbs. The p38 MAPK inhibitor SB203580 attenuated the responses of neutrophils to anti-CD18 mAbs or TNF stimulation on a fibrinogen surface. Taken together, these results indicate that activation of low-affinity Fc gamma Rs is required for neutrophil responses induced by anti-integrin Abs and suggest that a second coactivation signal (e.g., through TNF or FcR ligation) is indispensable for full integrin-mediated activation of neutrophils. These second signals are interchangeable and they may converge on the p38 MAPK.
authors.affiliation: Department of Physiology, Semmelweis University School of Medicine, Budapest, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Jakus
authors.forename: Giorgio
authors.initials: G
authors.lastname: Berton
authors.forename: Erzsébet
authors.initials: E
authors.lastname: Ligeti
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Lowell
authors.forename: Attila
authors.initials: A
authors.lastname: Mócsai
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005340:Fibrinogen / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D039641:Integrin beta Chains / Q000276:immunology / Q000502:physiology*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D009504:Neutrophils / Q000187:drug effects*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D011940:Receptor Aggregation; D017452:Receptors, IgG / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D016897:Respiratory Burst / Q000187:drug effects; D015398:Signal Transduction / Q000502:physiology*; D013481:Superoxides / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D000911:Antibodies, Monoclonal; D004791:Enzyme Inhibitors; C485701:Fcgr1 protein, mouse; C499172:Fcgr2b protein, mouse; C485700:Fcgr3 protein, mouse; D007093:Imidazoles; D039641:Integrin beta Chains; D011725:Pyridines; D017452:Receptors, IgG; D011994:Recombinant Proteins; D013481:Superoxides; D018799:Intercellular Adhesion Molecule-1; D005340:Fibrinogen; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580