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2-Integrin-Mediated Adhesion and Synthesis of Leukotriene C4 in Eosinophils1
* Section of Pulmonary and Critical Care Medicine, Department of Medicine, and
Department of Neurobiology Pharmacology and Physiology and Committees on Molecular Medicine, Clinical Pharmacology, and Cell Physiology, The University of Chicago, Chicago, Illinois 60637; and
Department of Chemistry, University of Illinois, Chicago, IL 60607
We examined the mechanism by which secretory group V phospholipase A2 (gVPLA2) secreted from stimulated epithelial cells activates eosinophil adhesion to ICAM-1 surrogate protein and secretion of leukotriene (LT)C4. Exogenous human group V PLA2 (hVPLA2) caused an increase in surface CD11b expression and focal clustering of this integrin, which corresponded to increased 
2 integrin-mediated adhesion. Human IIaPLA2, a close homolog of hVPLA2, or W31A, an inactive mutant of hVPLA2, did not affect these responses. Exogenous lysophosphatidylcholine but not arachidonic acid mimicked the 2 integrin-mediated adhesion caused by hVPLA2 activation. Inhibition of hVPLA2 with MCL-3G1, a mAb against gVPLA2, or with LY311727, a global secretory phospholipase A2 (PLA2) inhibitor, attenuated the activity of hVPLA2; trifluoromethylketone, an inhibitor of cytosolic group IVA PLA2 (gIVA-PLA2), had no inhibitory effect on hVPLA2-mediated adhesion. Activation of 2 integrin-dependent adhesion by hVPLA2 did not cause ERK1/2 activation and was independent of gIVA-PLA2 phosphorylation. In other studies, eosinophils cocultured with epithelial cells were stimulated with FMLP/cytochalasin B (FMLP/B) and/or endothelin-1 (ET-1) before LTC4 assay. FMLP/B alone caused release of LTC4 from eosinophils, which was augmented by coculture with epithelial cells activated with ET-1. Addition of MCL-3G1 to cocultured cells caused 
50% inhibition of LTC4 secretion elicited by ET-1, which was blocked further by trifluoromethylketone. Our data indicate that hVPLA2 causes focal clustering of CD11b and 2 integrin adhesion by a novel mechanism that is independent of arachidonic acid synthesis and gIVA-PLA2 activation. We also demonstrate that gVPLA2, endogenously secreted from activated epithelial cells, promotes secretion of LTC4 in cocultured eosinophils.
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