title: Phospholipase D mediates Fc gamma receptor activation of neutrophils and provides specificity between high-valency immune complexes and fMLP signaling pathways.
abstract: Neutrophils phagocytize high-valency immune complexes (HIC) by an Fc gamma receptor-mediated mechanism, activating an oxidative burst and initiating degranulation. In contrast, neutrophils exhibit chemotaxis to N-formylated peptides [e.g., N-formyl-methionyl-leucyl-phenylalanine (fMLP)] and secrete far fewer oxidants or granule contents than neutrophils activated by HIC. However, if neutrophils are treated with cytochalasin B (CB) or permeabilized with streptolysin O, chemoattractant-induced neutrophil secretion is increased to a level beyond that observed in response to HIC. Because priming neutrophils with CB, or permeabilizing them, also augments activation of phospholipase D (PLD) in response to fMLP, we reasoned that, in intact (i.e., nonpermeabilized) unprimed neutrophils, PLD may participate in a signaling pathway specific to phagocytic stimuli such as HIC and hence may contribute to degranulation control. PLD activity in response to HIC and fMLP correlated closely with stimulus-induced azurophilic degranulation under a wide variety of experimental conditions, including compounds that abrogated or augmented stimulus-induced PLD action. PLD activation preceded, and appeared to be necessary for, azurophilic degranulation. These results suggest that PLD may play a central role in controlling azurophilic degranulation and provide signaling specificity between pathways activated by fMLP and HIC in intact neutrophils.
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Massachusetts 02118, USA.
authors.forename: A T
authors.initials: AT
authors.lastname: Gewirtz
authors.forename: E R
authors.initials: ER
authors.lastname: Simons
mesh_terms: D000936:Antigen-Antibody Complex / Q000502:physiology*; D015550:Cell Degranulation / Q000187:drug effects / Q000502:physiology; D003571:Cytochalasin B / Q000494:pharmacology; D004789:Enzyme Activation; D006801:Humans; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology*; D018375:Neutrophil Activation / Q000187:drug effects / Q000502:physiology*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D010739:Phospholipase D / Q000378:metabolism / Q000502:physiology*; D017452:Receptors, IgG / Q000502:physiology*; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors
chemical_list: D000936:Antigen-Antibody Complex; D017452:Receptors, IgG; D003571:Cytochalasin B; D009240:N-Formylmethionine Leucyl-Phenylalanine; D010739:Phospholipase D