LIPOXIN A(4) AND B-4 INHIBIT LEUKOTRIENE-STIMULATED INTERACTIONS OF HUMAN NEUTROPHILS AND ENDOTHELIAL-CELLS

Lipoxins are bioactive eicosanoids that are generated within the vascu lar lumen by leukocytes and transcellular biosynthetic routes during m ulticellular responses. Polymorphonuclear neutrophils (PMN) and endoth elial cells express high affinity receptors for lipoxins, engagement o f which invokes profiles of signaling events that differ from other li pid mediators. In this work, we report that lipoxins are potent inhibi tors of PMN-endothelial cell interactions triggered by leukotrienes vi a dual-pronged actions with PMN and endothelial cells. Both lipoxin A( 4) (LXA(4)) and B-4 (LXB(4)) blocked PMN migration stimulated by leuko triene B-4 (LTB(4)), a well established agonist for PMN recruitment, i n a transmigration assay in vitro. Lipoxins were almost as effective i n this regard as the pharmacologic LTB, receptor antagonist, ONO 4057, and the blocking anti-CD18 mAb, R15.7. LXA(4) and LXB(4) blunted PMN transmigration, in part, by inhibiting beta(2) integrin-dependent PMN adhesion. These modulatory actions of lipoxins were evident at subnano molar concentrations, rapid in onset, and attenuated by prior exposure of PMN to a tyrosine kinase inhibitor, genistein. The peptidoleukotri enes, leukotriene C-4 (LTC(4)) and leukotriene D-4 (LTD(4)), also prov oked PMN-endothelial cell adhesion, but via a different mechanism than LTB(4). Both LTC(4) and LTD(4) enhanced endothelial adhesiveness for PMN, in part, by stimulating mobilization of P-selectin from intracell ular Weibel-Palade bodies. LXA(4) and LXB(4), but not other lipoxygena se products, blocked P-selectin mobilization induced by peptidoleukotr ienes 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, an d are potential endogenous lipid-derived modulators of PMN trafficking in host defense, inflammation, and other vascular events.