IFN-gamma induces the apoptosis of WEHI 279 and normal pre-B cell lines by expressing direct inhibitor of apoptosis protein binding protein with low pI.
Interferon-gamma plays a crucial role in induction of Th1 response but is predominantly a negative regulator of B cell differentiation and Th2 response, so it is a key molecule in determining cellular or humoral immunity. In this study, we demonstrate that IFN-gamma induces apoptosis in WEHI 279 mouse B cells and IL-7-dependent mouse pre-B cells by disrupting mitochondrial membrane potential and cytochrome c release via down-regulation of Bcl-2 and Bcl-x(L). Furthermore, this apoptotic signal is promoted by the de novo synthesis of endogenous direct inhibitor of apoptosis protein binding protein with low pI (DIABLO) by IFN-gamma and its release from mitochondria into the cytosol. Inhibition of DIABLO expression by antisense oligonucleotide is sufficient to decrease caspase activities and DNA fragmentation, but not cytochrome c release from mitochondria, suggesting that DIABLO plays a critical role in promoting apoptotic signals downstream of mitochondrial events. Thus, these findings demonstrate a signaling pathway during B cell apoptosis induced by IFN-gamma and possible mechanisms by which B cell differentiation is negatively regulated by Th1-type cytokines.
Yoshikawa
H
H
Department of Parasitology and Immunology, Yamanashi Medical University, Yamanashi, Japan.
Nakajima
Y
Y
Tasaka
K
K
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D001402:B-Lymphocytes / Q000166:cytology* / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D001483:Base Sequence; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D003574:Cytochrome c Group / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D053938:DNA Fragmentation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D015851:Interleukin-7 / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins; D018417:Th1 Cells / Q000276:immunology; D051020:bcl-X Protein
D051017:Apoptosis Regulatory Proteins; C494812:Bcl2l1 protein, mouse; D002352:Carrier Proteins; D003574:Cytochrome c Group; C499605:Diablo protein, mouse; D015851:Interleukin-7; D024101:Mitochondrial Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D051020:bcl-X Protein; D007371:Interferon-gamma; D020169:Caspases