B cell receptor triggering sensitizes human B cells to TRAIL-induced apoptosis.
TRAIL is known to cause death in tumor cells, but physiological regulation of its activity remains poorly characterized. We demonstrate that BCR triggering sensitizes transformed centroblast-like BL cells and peripheral blood memory B cells to TRAIL-mediated apoptosis. The sensitization correlated with surface down-regulation and intracellular retention of TRAIL-R4, along with changes in the expression of several Bcl-2 protein family members. Although enhancing FAS-mediated cell death, CD40 activation protected B cells from TRAIL-induced apoptosis. Combination of Ig cross-linking with CD40 ligation did not prevent TRAIL-R4 down-regulation but induced changes in the mitochondria-regulated pathway of apoptosis that are known to be associated with resistance to TRAIL. Human CD5(+) B cells, presumably stimulated by reactivity to self without immunological help, exhibited very high ex vivo sensitivity to TRAIL. Our results define the first B-lymphocyte-specific physiological signal that increases cellular sensitivity to TRAIL. This may be important for our understanding of TRAIL involvement in the control of B cell responses and aid in designing TRAIL-based therapies for B cell lymphomas.
Guerreiro-Cacais
Andre Ortlieb
AO
Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD 21205, USA.
Levitskaya
Jelena
J
Levitsky
Victor
V
D000918:Antibody Specificity; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology / Q000502:physiology; D018929:Cell Culture Techniques; D002460:Cell Line; D015536:Down-Regulation; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D006801:Humans; D007156:Immunologic Memory; D011947:Receptors, Antigen, B-Cell / Q000235:genetics* / Q000502:physiology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D051020:bcl-X Protein / Q000235:genetics
D051017:Apoptosis Regulatory Proteins; D019013:CD40 Antigens; D011947:Receptors, Antigen, B-Cell; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha; D051020:bcl-X Protein