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

Abstract
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.
AuthorsT Tatsuta, J Cheng, J D Mountz
JournalJournal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 157 Issue 9 Pg. 3949-57 (Nov 01 1996) ISSN: 0022-1767 [Print] United States
PMID8892627 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Amino Acid Chloromethyl Ketones
  • Interleukin-1
  • N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone
  • Oligopeptides
  • Protease Inhibitors
  • Protein Precursors
  • Recombinant Fusion Proteins
  • acetyl-aspartyl-glutamyl-valyl-aspartal
  • fas Receptor
  • Cysteine Endopeptidases
  • Caspase 1
Topics
  • Amino Acid Chloromethyl Ketones (pharmacology)
  • Apoptosis (physiology)
  • B-Lymphocytes (pathology)
  • Burkitt Lymphoma (pathology)
  • Caspase 1
  • Cysteine Endopeptidases (genetics, physiology)
  • Enzyme Induction
  • HL-60 Cells
  • HeLa Cells
  • Humans
  • Interleukin-1 (pharmacology)
  • Intracellular Fluid (metabolism)
  • Leukemia-Lymphoma, Adult T-Cell (pathology)
  • Lymphoma, Large B-Cell, Diffuse (pathology)
  • Oligopeptides (pharmacology)
  • Protease Inhibitors (pharmacology)
  • Protein Precursors (metabolism)
  • Recombinant Fusion Proteins (metabolism)
  • Signal Transduction
  • T-Lymphocytes (pathology)
  • Transfection
  • Tumor Cells, Cultured
  • fas Receptor (physiology)

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