Transcellular prostaglandin production following mast cell activation is mediated by proximal secretory phospholipase A2 and distal prostaglandin synthase 1

Abstract

Prostaglandins mediate many biological processes. Arachidonic acid, the common precursor for all prostaglandins, is released from membrane phospholipids by both secretory and cytoplasmic forms of phospholipase A2. Free arachidonate is converted to prostaglandin H2, the common precursor to all prostanoids, by prostaglandin synthase. Both mitogen-induced prostaglandin synthesis in fibroblasts and endotoxin-induced prostaglandin synthesis in macrophages require expression of the inducible prostaglandin synthase-2; arachidonate released in these contexts is unavailable to prostaglandin synthase-1 constitutively present in fibroblasts or macrophages. In contrast to the results for fibroblasts and macrophages, prostaglandin synthesis by activated mast cells is mediated by prostaglandin synthase-1. Mast cell activation also provokes release of secretory phospholipase A2 (sPLA2). We now demonstrate that sPLA2 released from activated mast cells can mobilize arachidonate from distal Swiss 3T3 cells. This arachidonate is then used by prostaglandin synthase-1 present in 3T3 cells for prostaglandin synthesis. We thus distinguish two pathways for prostaglandin synthesis: (i) an intracellular pathway by which arachidonate released following ligand stimulation is made available only to prostaglandin synthase-2, and (ii) a transcellular pathway by which sPLA2 of proximal cells mobilizes, in distal cells, arachidonate available to prostaglandin synthase-1. Molecular and pharmacologic approaches to modulating prostaglandin-mediated events will differ for these two pathways.