B cell apoptosis triggered by antigen receptor ligation proceeds via a novel caspase-dependent pathway.
In contrast to positive signaling leading to proliferation, the mechanisms involved in negative signaling culminating in apoptosis after B cell Ag receptor (BCR) ligation have received little study. We find that apoptosis induced by BCR cross-linking on EBV-negative mature and immature human B cell lines involves the following sequential, required events: a cyclosporin A-inhibitable, likely calcineurin-mediated step; and activation of caspase-2, -3, and -9. Caspase-2 is activated early and plays a major role in the apoptotic pathway, while caspase-9 is activated later in the apoptotic pathway and most likely functions to amplify the apoptotic signal. Caspase-8 and -1, which are activated by ligation of the CD95 and TNF-R1 death receptors, are not involved. Apoptosis induced by BCR ligation thus proceeds via a previously unreported intracellular signaling pathway.
Chen
W
W
H. Lee Moffitt Cancer Center and Research Institute, Department of Pharmacology and Therapeutics, University of South Florida, Tampa 33612, USA.
Wang
H G
HG
Srinivasula
S M
SM
Alnemri
E S
ES
Cooper
N R
NR
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D001402:B-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D020170:Caspase 1 / Q000378:metabolism; D053143:Caspase 2; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism / Q000502:physiology; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D016393:Lymphoma, B-Cell; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D011947:Receptors, Antigen, B-Cell / Q000276:immunology* / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D014407:Tumor Cells, Cultured
D061945:Caspase Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011947:Receptors, Antigen, B-Cell; D016572:Cyclosporine; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; C505410:Casp3 protein, rat; C505528:Casp8 protein, rat; C506435:Casp9 protein, rat; D053143:Caspase 2; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D020170:Caspase 1