title: B cell receptor cross-linking prevents Fas-induced cell death by inactivating the IL-1 beta-converting enzyme protease and regulating Bcl-2/Bcl-x expression.
abstract: In the A20 cell line, we examined the mechanisms that modulate the Fas-mediated apoptotic pathway through the B cell receptor. As in other systems, Fas signaling activates cysteine proteases, leading to specific proteolysis of poly(ADP-ribose) polymerase (PARP) and protein kinase C (PKC) delta. We describe that PKC-epsilon and PKC-zeta proteins are two new IL-1 beta-converting enzyme (ICE) substrates; we found that ICE activation and its proteolytic effects are inhibited by surface IgG (sIgG) cross-linking. Apoptosis induced by Fas ligation is consequently abrogated after sIgG engagement, and sIgG signaling therefore interferes with the apoptotic signal upstream of ICE protease activation. Since the PKC inhibitor bisindolylmaleimide I completely abolishes the protective effect of the sIgG signal, a member of the PKC family is probably responsible for the prevention of ICE cascade activation. Direct activation of PKC by PMA partially mimics the protective effect of sIgG cross-linking against Fas-mediated death in A20 cells. Nevertheless, PMA inhibits neither ICE activation nor the subsequent proteolysis of ICE substrates, suggesting that the PKC responsible for ICE inactivation is a non-PMA-sensitive PKC. In this system, Fas ligation also triggers Bcl-2/Bcl-x down-regulation, an effect inhibited by sIgG cross-linking, the cysteine protease inhibitor acetyl-Tyr-Val-Ala-Asp-chloromethyl ketone, and PMA treatment. In A20 cells, Fas signaling may thus trigger both ICE activation and Bcl-x and Bcl-2 down-regulation. These results indicate that sIgG signaling gives rise to two pathways after PKC activation, one presumably promoted by non-PMA-sensitive PKC, which inactivates the ICE cascade, and another produced by PMA-sensitive PKC, which maintains normal Bcl-2/Bcl-x levels.
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Cientificas, Madrid, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Brás
authors.forename: C
authors.initials: C
authors.lastname: Martinez-A
authors.forename: E
authors.initials: E
authors.lastname: Baixeras
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D020170:Caspase 1; D003546:Cysteine Endopeptidases / Q000276:immunology*; D015853:Cysteine Proteinase Inhibitors / Q000276:immunology*; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D004789:Enzyme Activation / Q000187:drug effects; D007074:Immunoglobulin G / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism*; D016393:Lymphoma, B-Cell; D051379:Mice; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D011947:Receptors, Antigen, B-Cell / Q000276:immunology / Q000378:metabolism*; D013379:Substrate Specificity / Q000187:drug effects / Q000276:immunology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein; D019014:fas Receptor / Q000502:physiology*
chemical_list: D000590:Amino Acid Chloromethyl Ketones; C494812:Bcl2l1 protein, mouse; D015853:Cysteine Proteinase Inhibitors; D007074:Immunoglobulin G; D007375:Interleukin-1; C098738:N-acetyl-tyrosyl-valyl-alanyl-aspartyl chloromethyl ketone; D019253:Proto-Oncogene Proteins c-bcl-2; D011947:Receptors, Antigen, B-Cell; D051020:bcl-X Protein; D019014:fas Receptor; D003546:Cysteine Endopeptidases; D020170:Caspase 1; D013755:Tetradecanoylphorbol Acetate