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Rs: Full Activation Requires Both Integrin and Nonintegrin Signals1
* Department of Physiology, Semmelweis University School of Medicine, Budapest, Hungary;
Department of Pathology, Section of General Pathology, University of Verona, Verona, Italy; and
Department of Laboratory Medicine, University of California, San Francisco, CA 94143
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
Rs. Murine neutrophils lacking the FcR -chain or FcRIII failed to respond to immobilized Abs against 
1, 2, or 3 integrins and the activation of wild-type cells could be prevented by blocking Abs against FcRII/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 FcRIIA-blocking Abs. Lack of FcRIII or administration of FcR-blocking Abs had no effect on responses of TNF-stimulated cells plated on fibrinogen or rICAM-1. TNF restored the respiratory burst of FcRIII-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 FcRs 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.
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