SECRETORY PHOSPHOLIPASE A(2) GENERATES THE NOVEL LIPID MEDIATOR LYSOPHOSPHATIDIC ACID IN MEMBRANE MICROVESICLES SHED FROM ACTIVATED CELLS

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 Ca2+-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.