CD40 and adenosine A2 receptor agonist-cyclic adenosine monophosphate rescue B-cell antigen receptor-induced apoptosis through independent pathways and converge to prevent caspase activation.
BACKGROUND
Antigen receptor ligation induces apoptosis of B lymphocytes, but the molecular mechanisms underlying induction of apoptosis remain unclear, although the growing family of IL-1beta-converting enzyme cysteine proteases (caspases) are recognized to be major effectors of cellular death.


OBJECTIVE
We sought to delineate and compare the rescue of B-cell apoptosis through CD40 ligand-CD40 interaction and cyclic adenosine monophosphate (cAMP)-dependent protein kinase A in human B cells.


METHODS
By using tonsillar B cells and the B-lymphoblastoid cell line Ramos, rescue from B-cell apoptosis was compared, as were signaling pathways after activation of cells through CD40 and the adenosine A2 receptor.


RESULTS
Both CD40 ligand-CD40 interaction and activation of intracellular cAMP rescue B cells from apoptosis after antigen receptor ligation. Although these pathways do not overlap, they converge by preventing the anti-IgM-induced activation of CPP32 (caspase 3), a member of the IL-1beta-converting enzyme protease family.


CONCLUSIONS
These data indicate that the cAMP-protein kinase A-dependent and CD40-signaling pathways regulate B-cell survival and converge at a common point, the inhibition of antigen receptor-induced activation of caspases.
Sakata
N
N
Division of Basic Sciences, Department of Pediatrics, Program in Molecular Signal Transduction, National Jewish Medical and Research Center, Denver, CO, USA.
Kawasome
H
H
Terada
N
N
Johnson
G L
GL
Gelfand
E W
EW
D000906:Antibodies / Q000494:pharmacology; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000166:cytology; D003994:Bucladesine; D019013:CD40 Antigens / Q000276:immunology / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism*; D000242:Cyclic AMP / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D058906:Purinergic P1 Receptor Agonists; D011947:Receptors, Antigen, B-Cell / Q000037:antagonists & inhibitors / Q000502:physiology*; D014407:Tumor Cells, Cultured
D000906:Antibodies; D000888:Antibodies, Anti-Idiotypic; D019013:CD40 Antigens; D015853:Cysteine Proteinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D058906:Purinergic P1 Receptor Agonists; D011947:Receptors, Antigen, B-Cell; C044203:anti-IgM; D003994:Bucladesine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020169:Caspases