FcγRI-triggered generation of arachidonic acid and eicosanoids requires iPLA2 but not cPLA2 in human monocytic cells

Abstract

Aggregation of receptors for immunoglobulin G (FcγRs) on myeloid cells activates a series of events that are key in the inflammatory response and that can ultimately lead to targeted cell killing by antibody-directed cellular cytotoxicity. Generation of lipid-derived proinflammatory mediators is an important component of the integrated cellular response mediated by receptors for the constant region of immunoglobulins (Fc). We have demonstrated previously that, in interferon-γ-primed U937 cells, the high affinity receptor for IgG, FcγRI, is coupled to a novel intracellular signaling pathway that involves the sequential activation of phospholipase D, sphingosine kinase, calcium transients, and protein kinase C isoforms, leading to the activation of the NADPH-oxidative burst. Here, we investigate the nature of the phospholipase that regulates arachidonic acid and eicosanoid production. Our data show that FcγRI couples to iPLA2β for the release of arachidonic acid and the generation of leukotriene B4 and prostaglandin E2. Activation of iPLA2β was protein kinase C-dependent; on the other hand, platelet-activating factor triggered cPLA2α by means of the mitogen-activated protein kinase pathway. These studies demonstrate that intracellular PLA2s can be selectively regulated by different stimuli and suggest a critical role for iPLA2β in the intracellular signaling cascades initiated by FcγRI and its functional role in the generation of key inflammatory mediators.