A B-Cell Superantigen Induces the Apoptosis of Murine and Human Malignant B Cells.
B-cell superantigens (Sags) bind to conserved sites of the VH or VL regions of immunoglobulin molecules outside their complementarity-determining regions causing the apoptosis of normal cognate B cells. No attempts to investigate whether B-cell Sags are able to induce the apoptosis of cognate malignant B cells were reported. In the present study we show that protein L (PpL), secreted by Finegoldia magna, a B-cell Sag which interacts with κ+ bearing cells, induces the apoptosis of murine and human κ+ lymphoma B cells both in vitro and in vivo. Apoptosis was not altered by caspase-8 inhibitor. No alterations in the levels of Bid, Fas and Fas-L were found suggesting that PpL does not activate the extrinsic pathway of apoptosis. The involvement of the intrinsic pathway was clearly indicated by: i) alterations in mitochondrial membrane potential (ΔΨm) both in murine and human lymphoma cells exposed to PpL; ii) decreased levels of apoptosis in the presence of caspase-9 inhibitor; iii) significant increases of Bim and Bax protein levels and downregulation of Bcl-2; iv) the translocation from the cytoplasm to the mitochondria of Bax and Bim pro-apoptotic proteins and its inhibition by caspase-9 inhibitor but not by caspase-8 inhibitor and v) the translocation of Bcl-2 protein from the mitochondria to the cytosol and its inhibition by caspase-9 inhibitor but not by caspase-8 inhibitor. The possibility of a therapeutic use of Sags in lymphoma/leukemia B cell malignancies is discussed.
IMEX-CONICET, Academia Nacional de Medicina de Buenos Aires, CABA, Argentina.
Daniela
D
Lorenzo
IMEX-CONICET, Academia Nacional de Medicina de Buenos Aires, CABA, Argentina.
Alejandra
A
Duarte
IMEX-CONICET, Academia Nacional de Medicina de Buenos Aires, CABA, Argentina.
Juliana
J
Mundiñano
Fundación Instituto Leloir, IIBBA, CONICET, Buenos Aires, Argentina.
Paula
P
Berguer
IMEX-CONICET, Academia Nacional de Medicina de Buenos Aires, CABA, Argentina.
Irene
I
Nepomnaschy
IMEX-CONICET, Academia Nacional de Medicina de Buenos Aires, CABA, Argentina.
Isabel
I
Piazzon
D000293:Adolescent; D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000276:immunology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology*; D051940:B7-2 Antigen / Q000378:metabolism; D001426:Bacterial Proteins / Q000276:immunology*; D000072224:Bcl-2-Like Protein 11 / Q000378:metabolism; D002051:Burkitt Lymphoma / Q000235:genetics / Q000276:immunology / Q000473:pathology; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D061945:Caspase Inhibitors / Q000494:pharmacology; D045744:Cell Line, Tumor; D003600:Cytosol / Q000378:metabolism; D004273:DNA, Neoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000276:immunology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007075:Immunoglobulin M / Q000378:metabolism; D007145:Immunoglobulin kappa-Chains / Q000378:metabolism; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000276:immunology / Q000473:pathology*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D018089:Superantigens / Q000276:immunology*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
D017304:Annexin A5; D051940:B7-2 Antigen; D001426:Bacterial Proteins; D000072224:Bcl-2-Like Protein 11; D061945:Caspase Inhibitors; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C491901:FAS protein, human; D007075:Immunoglobulin M; D007145:Immunoglobulin kappa-Chains; C116593:L-protein, Peptococcus magnus; D012333:RNA, Messenger; D018089:Superantigens; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; D053181:Caspase 8; D053453:Caspase 9