Secretory phospholipase A2 generates the novel lipid mediator lysophosphatidic acid in membrane microvesicles shed from activated cells

Abstract Nonpancreatic secretory phospholipase A 2 (sPLA 2 ) displays proinflammatory properties; however, its physiological substrate is not identified. Although inactive toward intact cells, sPLA 2 hydrolyzed phospholipids in membrane microvesicles shed from Ca 2+ -loaded erythrocytes as well as from platelets and from whole blood cells challenged with inflammatory stimuli. sPLA 2 was stimulated upon degradation of sphingomyelin (SPH) and produced lysophosphatidic acid (LPA), which induced platelet aggregation. Finally, lysophospholipid-containing vesicles and sPLA 2 were detected in inflammatory fluids in relative proportions identical to those used in vitro. We conclude that upon loss of phospholipid asymmetry, cell-derived microvesicles provide a preferential substrate for sPLA 2 . SPH hydrolysis, which is provoked by various cytokines, regulates sPLA 2 activity, and the novel lipid mediator LPA can be generated by this pathway.