Lipoxins are bioactive eicosanoids that are generated within the vascular lumen by leukocytes and transcellular biosynthetic routes during multicellular responses. Polymorphomuclear neutrophils (PMN) and endothelial cells express high affinity receptors for lipoxins, engagement of which invokes profiles of signaling events that differ from other lipid mediators. In this work, we report that lipoxins are potent inhibitors of PMN-endothelial cell interactions triggered by leukotrienes via dual-pronged actions with PMN and endothelial cells. Both lipoxin A4(LXA4) and B4(LXB4) blocked PMN migration stimulated by leukotriene B4 (LTB4), a well established agonist for PMN recruitment, a transmigration assay in vitro. Lipoxins were almost as effective in this regard as the pharmacologic LTB4 receptor antagonist, ONO 4057, and the blocking anti-CD18 mAb, R15.7. LXA4 and LXB4 blunted PMN transmigration, in part by inhibiting beta 2 integrin-dependent PMN adhesion. These modulatory actions of lipoxins were evident at subnanomolar concentrations, rapid in onset, and attenuated by prior exposure of PMN to a tyrosine kinase inhibitor, genistein. The peptidoleukotrienes, leukotriene C4 (LTC4) and leukotriene D4 (LTD4) also provoked PMN-endothelial cell adhesion, but via a different mechanism than LTB4. Both LTC4 and LTD4 enhanced endothelial adhesiveness for PMN, in part, by stimulating mobilization of P-selectin from intracellular Weibel-Palade bodies. LXA4 and LXB4, but not other lipoxygenase products, blocked P-selectin mobilization induced by peptidoleukotrienes and attenuated P-selectin-mediated PMN-endothelial cell adhesion. These results indicate that lipoxins attenuate PMN-endothelial cell interactions supported by selectins and beta 2 integrins in vitro, and are potential endogenous lipid-derived modulators of PMN trafficking in host defense, inflammation, and other vascular events.

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