A SYNTHETIC INHIBITOR OF INTERLEUKIN-1-BETA CONVERTING-ENZYME PREVENTS ENDOTOXIN-INDUCED INTERLEUKIN-1-BETA PRODUCTION IN-VITRO AND IN-VIVO

A potent, reversible, tetrapeptide inhibitor of interleukin-1 beta con verting enzyme (ICE), L-709,049, has been shown to suppress the in vit ro production of mature IL-1 beta. We now report that this inhibitor a lso effectively suppresses the production of mature IL-1 beta in a mur ine model of endotoxic shock. Intraperitoneal administration of L-709, 049 reduced the elevations of IL-1 beta in the plasma and peritoneal f luid of mice treated with LPS in a dose-related manner (ED(50) = 2 +/- 0.9 mg/kg). LPS-induced elevations in IL-1 alpha and IL-6 in these mi ce were unaffected, indicating that the inhibitor specifically affecte d IL-1 beta production. Immunoblot analysis of plasma and peritoneal f luid indicated that L-709,049 suppressed the formation of mature IL-1 beta production in vivo, When mouse blood was incubated in vitro with LPS, IL-1 beta was released into the plasma, This assay was used to de termine ex vivo the activity of an ICE inhibitor in the blood followin g its administration to mice. Blood obtained 15 minutes after ip admin istration of 10 mg/kg of L-709,049 to mice produced 80% less IL-1 beta than control blood, and IL-1 beta production returned to control leve ls in blood obtained 30 minutes after injection of this inhibitor. In addition, the capacity of the blood plasma obtained from these animals to prevent the cleavage of a synthetic substrate by ICE disappeared w ithin 1 h of ip administration of 50 mg/kg of inhibitor.