U-73122 - A POTENT-INHIBITOR OF HUMAN POLYMORPHONUCLEAR NEUTROPHIL ADHESION ON BIOLOGICAL SURFACES AND ADHESION-RELATED EFFECTOR FUNCTIONS

We have reported that U-73122 (1-[6-[[17 10)trien-17-yl]amino]hexyl]-1 H-pyrrole-2,5-dione), an inhibitor of phospholipase C-dependent proces ses in human polymerphonuclear neutrophils (PMN) and platelets, potent ly suppresses the responsiveness of suspended PMN and platelets to rec eptor agonists. We demonstrate here that U-73122 caused a concenr trat ion-dependent (10-800 nM) inhibition of N-formyl-methionyl-leucyl-phen ylalanine, tumor necrosis factor-alpha (TNF alpha), interleukin-8, and phorbol myristate acetate (PMA)-triggered PMN adhesion on fibronectin , fetal bovine serum or keyhole limpet hemocyanin-coated microliter pl ates. U-73122 also inhibited PMN adherence to and transmigration throu gh TNF alpha-activated endothelium (IC50 < 50 nM). Further, U-73122 su ppressed interleukin-8, N-formylmethionyl-leucyl-phenylalanine and PMA -stimulated up-regulation of the beta(2)-integrin, Mac-1 (CD11b/CD18), on the PMN surface (IC50 < 1.3 mu M). U-73122 also caused a time- (15 -120 min) and concentration-dependent inhibition (IC50 = 25-100 nM) of the N-formyl-methionyl-leucyl-phenylalanine-, TNF alpha- and PMA-elic ited adhesion-dependent oxidative burst, measured as hydrogen peroxide (H2O2) production, in PMN. The CD18-dependent extracellular release o f lactoferrin from PMN activated with these stimuli was also suppresse d by U-73122. U-73343 (1-[6-[[17 0)-trien-17-yl]amino]hexyl]-2,5-pyrro lidinedione), a close analog of U-73122, did not affect PMN responsive ness.