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, b ut the molecular mechanisms underlying induction of apoptosis remain unclea r, although the growing family of IL-1 beta-converting enzyme cysteine prot eases (caspases) are recognized to be major effecters of cellular death. Objective: We sought to delineate and compare the rescue of B-cell apoptosi s 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 Ramo s, rescue from B-cell apoptosis was compared, as were signaling pathways af ter 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, Althoug h these pathways do not overlap, they converge by preventing the anti-IgM-i nduced activation of CPP32 (caspase 3), a member of the IL-1 beta-convertin g enzyme protease family. Conclusion: These data indicate that the cAMP-protein kinase A-dependent an d CD40-signaling pathways regulate B-cell survival and converge at a common point, the inhibition of antigen receptor-induced activation of caspases.