THE BIOSYNTHESIS OF ENDOTHELIN-1 BY HUMAN POLYMORPHONUCLEAR LEUKOCYTES

Human polymorphonuclear leukocytes (PMNs) converted human big endothelin (bET; 2 μM) to an endothelin-1 (ET-1) like contractile factor, as assessed by bioassay. The generation of this ET-1 like activity was rapid (minutes), time-dependent and more pronounced in non-activated cells, suggesting a partial degradation by activated PMNs. Phosphoramidon (54 μg/ml) inhibited the formation of this contractile factor, whereas phenylmethylsulfonylfluoride (PMSF; 25 μg/ml), pepstatin A (1 μg/ml) or epoxysuccinyl-L-leucylamido-(guanidino)butane (E-64; 10 μg/ml) did not. Incubations of activated PMNs with PMSF significantly potentiated the generation of ET-1 like activity and selectively inhibited the degradation of [125I]ET-1 by activated PMNs. These findings indicate that human PMNs contain and/or release neutral proteases, which can both rapidly produce and degrade ET-1, an observation which may have important (patho)physiologic implications. © 1991.