INHIBITION OF MATURE IL-1-BETA PRODUCTION IN MURINE MACROPHAGES AND AMURINE MODEL OF INFLAMMATION BY WIN-67694, AN INHIBITOR OF IL-1-BETA CONVERTING-ENZYME

The proinflammatory cytokine IL-1 beta is synthesized by activated mon ocytes and macrophages as a 31-kDa, biologically inactive precursor th at is proteolytically processed to the biologically active 17-kDa matu re molecule by the IL-1 beta converting enzyme (ICE). WIN 67694, Z-Val -Ala-Asp-CH2O(CO)[2,6-(Cl-2)]Ph, is a potent, selective inhibitor of h uman ICE. In activated murine peritoneal macrophages, WIN 67694 inhibi ted the release of mature IL-1 beta with an IC50 of 1.8 mu M without a ny effect on the release of IL-1 alpha, IL-6, or TNF-alpha. The effect was specific to mature IL-1 beta release; the ICE inhibitor did not e ffect IL-1 beta RNA levels or precursor protein synthesis. In vivo, WI N 67694 was also able to inhibit selectively the release of IL-1 beta in a dose-dependent manner in a subcutaneous tissue chamber implant mo del of inflammation. IL-1 beta levels in tissue chamber fluid were inh ibited 35 and 55% at 10 and 100 mg/kg, respectively. IL-1 alpha, IL-6, and TNF-alpha levels were not affected. The ability to selectively in hibit mature IL-1 beta release in vivo with ICE inhibitors will allow for detailed studies of the role of IL-1 beta and ICE in inflammatory diseases.