CD38 induces apoptosis of a murine pro-B leukemic cell line by a tyrosine kinase-dependent but ADP-ribosyl cyclase- and NAD glycohydrolase-independent mechanism

• Published in: International immunology Vol. 18; no. 7; pp. 1029 - 1042
• Main Authors: Lund, Frances E., Muller-Steffner, Hélène, Romero-Ramirez, Héctor, Moreno-García, Miguel E., Partida-Sánchez, Santiago, Makris, Melissa, Oppenheimer, Norman J., Santos-Argumedo, Leopoldo, Schuber, Francis
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01-07-2006; Oxford Publishing Limited (England)
• Subjects: ADP-ribosyl Cyclase - antagonists & inhibitors; ADP-ribosyl Cyclase - immunology; ADP-ribosyl Cyclase - metabolism; ADP-ribosyl Cyclase 1 - antagonists & inhibitors; ADP-ribosyl Cyclase 1 - immunology; ADP-ribosyl Cyclase 1 - metabolism; Animals; apoptosis; Apoptosis - drug effects; Apoptosis - immunology; B lymphocytes; B-Lymphocytes - enzymology; B-Lymphocytes - immunology; Calcium - metabolism; Calcium Signaling - drug effects; Calcium Signaling - immunology; Cell Differentiation - drug effects; Cell Differentiation - immunology; Cell Line, Tumor; Cell Proliferation - drug effects; cell-surface molecules; Cyclic ADP-Ribose - immunology; Cyclic ADP-Ribose - metabolism; Enzyme Inhibitors - pharmacology; Hematopoietic Stem Cells - immunology; Hematopoietic Stem Cells - metabolism; Immunologic Capping - drug effects; Immunologic Capping - immunology; Leukemia, B-Cell - immunology; Leukemia, B-Cell - metabolism; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Membrane Microdomains - enzymology; Membrane Microdomains - immunology; Mice; NAD - analogs & derivatives; NAD - pharmacology; signal transduction
• ISSN: 0953-8178; 1460-2377
• DOI: 10.1093/intimm/dxl037

Cross-linking of CD38 on hematopoietic cells induces activation, proliferation and differentiation of mature T and B cells and mediates apoptosis of myeloid and lymphoid progenitor cells. In addition to acting as a signaling receptor, CD38 is also an enzyme capable of producing several calcium-mobilizing metabolites, including cyclic adenosine diphosphate ribose (cADPR). It has been previously postulated that the calcium-mobilizing metabolites produced by CD38 may regulate its receptor-based activities. To test this hypothesis, we examined whether the enzyme activity of CD38 controls the apoptosis of an anti-CD38-stimulated leukemic B cell. We show that anti-CD38-induced apoptosis of Ba/F3 cells, a murine pro-B cell line, is not affected by blocking the calcium-mobilizing activity of cADPR or by inhibiting intracellular or extracellular calcium mobilization. In addition, we demonstrate that blocking CD38 enzyme activity with 2′-deoxy-2′-fluoro-nicotinamide arabinoside adenine dinucleotide has no effect on apoptosis and that Ba/F3 cells expressing catalytically inactive mutant forms of CD38 still undergo apoptosis upon CD38 cross-linking. Instead, we find that anti-CD38-induced apoptosis is dependent on tyrosine kinase and caspase activation, and that this process appears to be potentiated by the presence of membrane microdomains. Thus, the receptor-mediated functions of CD38 can be separated from its enzyme activity in a murine leukemic cell line, suggesting that CD38 plays multiple, but independent, biologic roles.