Differential Mitogen-Activated Protein Kinase Stimulation by Fcγ Receptor IIa and Fcγ Receptor IIIb Determines the Activation Phenotype of Human Neutrophils

Abstract

FcγRs mediate immune complex-induced tissue injury. The hypothesis that FcγRIIa and FcγRIIIb control neutrophil responses by activating mitogen-activated protein kinases was examined. Homotypic and heterotypic cross-linking of FcγRIIa and/or FcγRIIIb resulted in a rapid, transient increase in ERK and p38 activity, with maximal stimulation between 1 and 3 min. FcγRIIa and FcγRIIIb stimulated distinct patterns of ERK and p38 activity, and heterotypic cross-linking failed to stimulate synergistic activation of either ERK or p38 activity. Both FcγRIIa and FcγRIIIb required activation of a nonreceptor tyrosine kinase and phosphatidylinositol 3-kinase for stimulation of ERK and p38. Inhibition of ERK activation with PD98059 enhanced H2O2 production stimulated by homotypic and heterotypic FcγR cross-linking. Inhibition of p38 with SB203580 attenuated H2O2 production stimulated by FcγRIIIb or heterotypic cross-linking, but had no effect on FcγRIIa-stimulated H2O2 production. On the other hand, PD98059 inhibited actin polymerization stimulated by FcγR cross-linking, while SB203580 had no effect. Inhibition of actin polymerization with cytochalasin D enhanced p38 activity stimulated by either FcγRIIa or FcγRIIIb, but cytochalasin D only enhanced H2O2 production stimulated by FcγRIIIb. Our data indicate that FcγRIIa and FcγRIIIb independently activate ERK and p38. The two receptors demonstrate different efficacies for ERK and p38 activation, and they do not act cooperatively. ERK and p38 provide stimulatory and inhibitory signals for neutrophil responses to immune complexes. In addition, these data indicate that actin reorganization may play a role in mediating p38-dependent activation of respiratory burst upon stimulation of FcγRIIIb in neutrophils.