1-[6-[[l 73-3-Methoxyestra-l, 3, 5 (l O)-trien-l 7-yl] amino] hexyl]-1H-pyrrole-2, 5-dione(U-731 22), an inhibitor of phospholipase C (PLC)-dependent processes in human platelets, was found to be a potent inhibitor of human polymorphonuclear neutrophil (PMN) activation by structurally unrelated receptor-specific agonists. U-731 22 caused a time-and concentration-dependent(0.1-1 zM) inhibition of myeloperoxidase and vitamin B12-binding protein release from PMNs exposed to N-formyl-methionyl-leucyl-phen-ylalanine, recombinant human C5a, leukotnene B4 and plateletactivating factor. Activation of the respiratory burst, as measured by superoxide anion production, in PMNs stimulated with these agonists was also suppressed by U-731 22. These data sug-gested that U-731 22 inhibited a component of signal transduction that was common to the mechanisms of action of these stimuli.

Production of inositol 1, 4, 5-tnsphosphate and 1, 2-diacylglycerol and the rise in the cytosolic free calcium concentration, which are early postreceptor events in PMN activation, were all suppressed in U-731 22-treated PMNs stimulated with the agonists. These signal transduction events require activation of PLC. Receptor-coupled activation of PLC in membranes isolated from PMNs was potently inhibited by U-731 22. U-731 22, however, had no direct effect on PMN protein kinase C activity. 1-[6-[[l 7fl-3-Methoxyestra-l, 3, 5 (1O)-tnen-l 7-yl] amino] hexyl]-2, 5-pyrroli-dine-dione(U-73343), a close analog of U-731 22 that does not suppress PLC activity, did not inhibit receptor-specific agonist-induced PMN responsiveness. U-731 22, therefore, is a novel reagent that is useful in investigating PLC function in receptormediated PMN activation.