title: Death signals from the B cell antigen receptor target mitochondria, activating necrotic and apoptotic death cascades in a murine B cell line, WEHI-231.
abstract: B cell antigen receptor (BCR)-mediated cell death has been proposed as a mechanism for purging the immune repertoire of anti-self specificities during B cell differentiation in bone marrow. Mitochondrial alterations and activation of caspases are required for certain aspects of apoptotic cell death, but how the mitochondria and caspases contribute to BCR-mediated cell death is not well understood. In the present study, we used the mouse WEHI-231 B cell line to demonstrate that mitochondrial alterations and activation of caspases are indeed participants in BCR-mediated cell death. The peptide inhibitor of caspases, N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (z-VAD-fmk), blocked cleavage of poly(ADP-ribose) polymerase and various manifestation of nuclear apoptosis such as nuclear fragmentation, hypodiploidy and DNA fragmentation, indicating that signals from the BCR induced the activation of caspases. In addition, z-VAD-fmk delayed apoptosis-associated changes in cellular reduction-oxidation potentials as determined by hypergeneration of superoxide anion, as well as exposure of phosphatidylserine residues in the outer plasma membrane. By contrast, although z-VAD-fmk retarded cytolysis, it was incapable of preventing disruption of the plasma membrane even under the same condition in which it completely blocked nuclear apoptosis. Mitochondrial membrane potential loss was also not blocked by z-VAD-fmk. Bongkrekic acid, a specific inhibitor of mitochondrial permeability transition pores, suppressed not only the mitochondrial membrane potential but also the change of plasma membrane permeability. Overexpression of Bcl-xL prevented mitochondrial dysfunction, nuclear apoptosis and membrane permeability cell death triggered by BCR signal transduction. These observations indicate that death signals from BCR may first cause mitochondrial alterations followed by activation of both necrotic and apoptotic cascades.
authors.affiliation: Department of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Doi
authors.forename: N
authors.initials: N
authors.lastname: Motoyama
authors.forename: A
authors.initials: A
authors.lastname: Tokunaga
authors.forename: T
authors.initials: T
authors.lastname: Watanabe
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D017209:Apoptosis / Q000276:immunology*; D001402:B-Lymphocytes / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D001865:Bongkrekic Acid / Q000494:pharmacology; D016923:Cell Death / Q000276:immunology; D002463:Cell Membrane Permeability; D002467:Cell Nucleus / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004789:Enzyme Activation / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D007425:Intracellular Membranes / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000276:immunology* / Q000378:metabolism*; D009336:Necrosis; D010718:Phosphatidylserines / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D011947:Receptors, Antigen, B-Cell / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D000888:Antibodies, Anti-Idiotypic; C494812:Bcl2l1 protein, mouse; D015853:Cysteine Proteinase Inhibitors; D007075:Immunoglobulin M; D010718:Phosphatidylserines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011947:Receptors, Antigen, B-Cell; C044203:anti-IgM; D051020:bcl-X Protein; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D001865:Bongkrekic Acid; D011065:Poly(ADP-ribose) Polymerases