Critical role for mitochondria in B cell receptor-mediated apoptosis.
Antigen-induced apoptosis of B cells serves to deplete the immune repertoire of anti-self specificities leading to central and peripheral B cell tolerance. However, the mechanism of B cell receptor (BCR)-mediated apoptosis is widely unknown. By using the human Burkitt lymphoma cell line BL60 as a model system for human germinal center B cells we show here that BCR-mediated apoptosis requires transcriptional activity but, in contrast to activation-induced T cell apoptosis, is neither mediated via known death receptor systems nor does it involve initial activation of caspase-8. Moreover, during BCR-induced apoptosis cytochrome c release and mitochondrial permeability transition (PT) precedecaspase activation. Although caspase inhibition after BCR stimulation blocks cleavage of caspase substrates and DNA fragmentation it does not prevent mitochondrial PT, cytochrome c release and cell death. Thus, BCR-mediated apoptosis is initiated by the caspase-independent induction of mitochondrial PT resulting in release of cytochrome c and subsequent activation of caspase-9, downstream caspases and apoptosis.
Bouchon
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A
Tumor Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany. bouchon@bii.ch
Krammer
P H
PH
Walczak
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H
D015703:Antigens, CD / Q000502:physiology; D017209:Apoptosis; D001402:B-Lymphocytes / Q000502:physiology*; D020169:Caspases / Q000502:physiology; D003574:Cytochrome c Group / Q000378:metabolism; D006801:Humans; D008564:Membrane Potentials; D008928:Mitochondria / Q000502:physiology*; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D053219:Receptors, Tumor Necrosis Factor, Member 25; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000502:physiology
D015703:Antigens, CD; D003574:Cytochrome c Group; D011947:Receptors, Antigen, B-Cell; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053219:Receptors, Tumor Necrosis Factor, Member 25; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C105190:TNFRSF10A protein, human; C505639:TNFRSF10B protein, human; C506033:TNFRSF25 protein, human; D019014:fas Receptor; D020169:Caspases