Intracellular IL-1beta is an inhibitor of Fas-mediated apoptosis.
Fas-mediated apoptosis has been shown to be mediated by the IL-1beta converting enzyme (ICE) pathway. To determine the relationship between ICE and its substrate IL-1beta, 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-1beta mRNA was highly expressed only in HL-60 cells. Acetyl-Tyr-Val-Ala-Asp-chloromethylketone, 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-1beta 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-1beta transfectant clones using SKW6.4 cells. We demonstrated that stably transfected SKW6.4 cells expressing precursor IL-1beta, 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-1beta to mature IL-1beta. These results suggest that Fas-mediated apoptosis is mediated by ICE cleavage of proteolytic substrates other than IL-1beta and that IL-1beta is an endogenous inhibitor of Fas-mediated apoptosis.
Tatsuta
T
T
Sankyo Company, Ltd., Tokyo, Japan.
Cheng
J
J
Mountz
J D
JD
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology*; D001402:B-Lymphocytes / Q000473:pathology; D002051:Burkitt Lymphoma / Q000473:pathology; D020170:Caspase 1; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000502:physiology*; D004790:Enzyme Induction; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D007424:Intracellular Fluid / Q000378:metabolism; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D011498:Protein Precursors / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000473:pathology; D014162:Transfection; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000502:physiology*
D000590:Amino Acid Chloromethyl Ketones; D007375:Interleukin-1; C098738:N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone; D009842:Oligopeptides; D011480:Protease Inhibitors; D011498:Protein Precursors; D011993:Recombinant Fusion Proteins; C099158:acetyl-aspartyl-glutamyl-valyl-aspartal; D019014:fas Receptor; D003546:Cysteine Endopeptidases; D020170:Caspase 1