Inhibition of Mature IL-1 Beta Production in Murine Macrophages and a Murine Model of Inflammation by WIN 67694, an Inhibitor of IL-1 Beta Converting Enzyme

The proinflammatory cytokine IL-1 beta is synthesized by activated monocytes and macrophages as a 31-kDa, biologically inactive precursor that is proteolytically processed to the biologically active 17-kDa mature molecule by the IL-1 beta converting enzyme (ICE). WIN 67694, Z-Val-Ala-Asp-CH2O(CO)[2,6-(CI2)]Ph, is a potent, selective inhibitor of human ICE. In activated murine peritoneal macrophages, WIN 67694 inhibited the release of mature IL-1 beta with an IC50 of 1.8 microM without any 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 effect IL-1 beta RNA levels or precursor protein synthesis. In vivo, WIN 67694 was also able to inhibit selectively the release of IL-1 beta in a dose-dependent manner in a subcutaneous tissue chamber implant model of inflammation. IL-1 beta levels in tissue chamber fluid were inhibited 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 inhibit 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.