CD27 and CD40 inhibit p53-independent mitochondrial pathways in apoptosis of B cells induced by B cell receptor ligation.
B cells in the germinal center are known to undergo apoptosis after B cell receptor (BCR) ligation, a process relevant to immunological tolerance. Human CD27 is a B cell co-stimulatory molecule. The aim of this study was to compare the effects of CD27 and CD40 signals on BCR-mediated apoptosis of B cells. BCR ligation activated mitochondrial apoptotic pathways including down-regulation of Bcl-X(L), dissipation of mitochondrial transmembrane potential, release of cytochrome c, and activation of caspase-9. Each of these effects was significantly inhibited by CD27 and CD40. Bik expression was weakly but significantly down-regulated by CD27 but up-regulated by CD40. BCR ligation resulted in p53 activation including its phosphorylation at Ser(15), nuclear translocation, and target gene p53AIP1 induction. CD27 and CD40 clearly suppressed these processes. Analyses that used dominant-negative p53 variants revealed a low but still substantial level of BCR-mediated apoptosis and intact mitochondria-mediated apoptotic pathway. These pathways were further inhibited by CD27 and CD40, although the cells showed no p53 phosphorylation or p53AIP1 expression. Our results suggested that, at the mitochondrial level, CD27 and CD40 co-stimulatory signals regulated the p53-amplified apoptotic pathway in B cells through the inhibition of p53-independent apoptotic pathway primarily induced by BCR ligation.
D017209:Apoptosis; D001402:B-Lymphocytes / Q000473:pathology*; D015153:Blotting, Western; D019013:CD40 Antigens / Q000096:biosynthesis*; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D015536:Down-Regulation; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D005799:Genes, Dominant; D006801:Humans; D015151:Immunoblotting; D008564:Membrane Potentials; D008928:Mitochondria / Q000378:metabolism*; D010766:Phosphorylation; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000378:metabolism; D013997:Time Factors; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000096:biosynthesis*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation
D019013:CD40 Antigens; D003574:Cytochrome c Group; D011947:Receptors, Antigen, B-Cell; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D016159:Tumor Suppressor Protein p53; D012694:Serine; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases