Interleukin 1β protects mice from Fas-mediated hepatocyte apoptosis and death

Background & Aims: Fas-mediated apoptosis is one of the major death processes of hepatocytes in liver diseases. The aim of this study was to determine whether interleukin (IL)-1 beta regulates the Fas-mediated apoptotic process of differentiated hepatocytes in vivo. Methods: IL-1 beta was injected into Balb/cA mice 5 hours before lethal challenge with agonistic anti-fas administration. Survival and hepatocyte apoptotic process of these mice were examined. Results: IL-1 beta pretreatment prolonged animal survival in a dose-dependent manner, and 500 ng of IL-1 beta completely protected mice from lethality. Both serum alanine aminotransferase value and hepatic DNA fragmentation were significantly suppressed by IL-1 beta pretreatment. IL-1 beta affected neither hepatic distribution of anti-fas antibody nor Fas expression levels on hepatocytes but significantly suppressed Fas-induced activation of hepatic caspase 3-like protease. Suppression of Fas-induced activation of the caspase by IL-1 beta was diminished by coadministration with D-galactosamine and reversed by coinjection with an excess amount of uridine. Conclusions: These results suggest that IL-1 beta suppresses Fas-mediated hepatocyte apoptosis by inducing molecule(s) that suppress the apoptosis control machinery upstream of caspase 3. This observation raises the possibility that IL-1 beta acts as a negative regulator of Fas-mediated hepatocyte apoptosis during liver injury.