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-lik e 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 t o Fas-mediated apoptosis, whereas the human promyelocytic leukemia cel l line HL-60 was resistant to Fas-mediated apoptosis, ICE mRNA was hig hly expressed in SKW6.4, H-9, and HL-60 cells, and ICE-like activity i ncreased during Fas-mediated apoptosis in SKW6.4 cells. In contrast, I L-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 aga inst other substrates for Fas-ICE-mediated apoptosis in SKW6.4 cells, we established precursor IL-1 beta transfectant clones using SKW6.4 ce lls. We demonstrated that stably transfected SKW6.4 cells expressing p recursor IL-1 beta, but not cells transfected with the empty vector, e xhibited resistance to Fas-mediated apoptosis due to competitive inhib ition of ICE-like activity, which was associated with increased cleava ge of precursor IL-1 beta to mature IL-1 beta. These results suggest t hat Fas-mediated apoptosis is mediated by ICE cleavage of proteolytic substrates other than IL-1 beta and that IL-1 beta is an endogenous in hibitor of Fas-mediated apoptosis.