Intracellular IL-1 beta is an inhibitor of Fas-mediated apoptosis

Fas-mediated apoptosis has been shown to be mediated by the IL-1 beta converting enzyme (ICE) pathway, To determine the relationship between ICE and its substrate IL-1 beta, we examined six human cell lines for susceptibility to Fas-mediated apoptosis and Fas induction of ICE-like activity. The human B lymphoblastoid cell line SKW6.4 and the human T lymphoma cell lines jurkat, CEM-6, H-9, and MOLT4 were susceptible to Fas-mediated apoptosis, whereas the human promyelocytic leukemia cell line HL-60 was resistant to Fas-mediated apoptosis, ICE mRNA was highly expressed in SKW6.4, H-9, and HL-60 cells, and ICE-like activity increased during Fas-mediated apoptosis in SKW6.4 cells. In contrast, IL-1 beta mRNA was highly expressed only in HL-60 cells. Acetyl-Tyr-Val-Ala-Asp-chloromethylketon a tetrapeptidyl inhibitor of ICE, prevented Fas-mediated apoptosis strongly in SKW6.4 and H-9 cells but weakly or marginally in other cells. To examine whether intracellular IL-1 beta is a proteolytic substrate or an endogenous competitive inhibitor against other substrates for Fas-ICE-mediated apoptosis in SKW6.4 cells, we established precursor IL-1 beta transfectant clones using SKW6.4 cells. We demonstrated that stably transfected SKW6.4 cells expressing precursor IL-1 beta, but not cells transfected with the empty vector, exhibited resistance to Fas-mediated apoptosis due to competitive inhibition of ICE-like activity, which was associated with increased cleavage of precursor IL-1 beta to mature IL-1 beta. These results suggest that Fas-mediated apoptosis is mediated by ICE cleavage of proteolytic substrates other than IL-1 beta and that IL-1 beta is an endogenous inhibitor of Fas-mediated apoptosis.