Studies on the molecular mechanisms of human neutrophil Fc receptor-mediated phagocytosis. Evidence that a distinct pathway for activation of the respiratory burst results in reactive oxygen metabolite-dependent amplification of ingestion.

Human neutrophils (PMN) possess at least two distinct mechanisms for the ingestion of IgG-opsonized pathogens; one is independent of and the other is dependent on products of the respiratory burst. Oxidant-mediated ingestion is not induced by exposure to the IgG-opsonized target but requires additional stimulation by phorbol esters or cytokines. The purpose of the present work is to elucidate the signal transduction pathways underlying these two distinct phagocytic mechanisms. Both phorbol ester- and cytokine-stimulated ingestion of IgG-opsonized targets and superoxide anion production were inhibited by the protein kinase C (PKC) inhibitors TFP and H7. In contrast, neither phagocytosis nor superoxide anion generation induced by stimulation with IgG-opsonized targets alone was affected by either of these inhibitors, even when IgG opsonization was increased to generate equal levels of ingestion and superoxide anion as that observed with cytokine stimulation. Moreover, TNF-alpha and IgG-opsonized target stimulation of PMN showed marked synergy in translocation of PKC activity from the cytosol to the plasma membrane. These data indicate that a pathway for activation of the respiratory burst which is dependent on protein kinase C is involved in oxidant-mediated amplification of ingestion. Cytokine stimulation of PMN not only augments IgG-dependent ingestion and generation of superoxide anion but also changes the signaling pathway for these two IgG-dependent functions from PKC-independent to PKC-dependent. In this regard, cytokine stimulation differentiates two pathways for activation of PMN by IgG.