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 proinfla mmatory properties; however, its physiological substrate is not identi fied. Although inactive toward intact cells, sPLA(2) hydrolyzed phosph olipids in membrane microvesicles shed from Ca2+-loaded erythrocytes a s well as from platelets and from whole blood cells challenged with in flammatory stimuli. sPLA(2) was stimulated upon degradation of sphingo myelin (SPH) and produced lysophosphatidic acid (LPA), which induced p latelet 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 phosph olipid asymmetry, cell-derived microvesicles provide a preferential su bstrate for sPLA(2). SPH hydrolysis, which is provoked by various cyto kines, regulates sPLA(2) activity, and the novel lipid mediator LPA ca n be generated by this pathway.