Differential regulation of CD40-mediated human B cell responses by antibodies directed against different CD40 epitopes

Ligation of CD40 using anti-CD40 or soluble CD40-ligand activates numerous intracellular kinases which transduce signals to the nucleus. The nature wh ereby these signaling events are coupled to distal functional events in B c ells is poorly understood. In this study, using anti-CD40 monoclonal antibo dies which recognize different epitopes on CD40, we compare the ability to activate the stress-activated protein kinases (SAPK) such as c-Jun NH2 term inal kinase and p38 in human B cells with CD40 function. Activation of the SAPK pathway correlated with levels of activation of Rel/NF-kappa B transcr iption factors, but did not appear to be associated with rescue from anti-I gM induced apoptosis by suppressing caspase (CPP32) activity. Somewhat surp risingly, in the presence of IL-4, those antibodies to CD40 which failed to activate SAPK were most active in IgE production. IgE production was augme nted in the presence of wortmannin. These studies suggest that rescue from apoptosis and IgE production mediated via CD40 may be independent of SAPK a ctivation, induction of Rel/NF-kappa B, or suppression of CPP32 and that Ig E production is, at least in part, regulated by signaling pathways that are dependent on phosphatidylinositol 3-kinase. (C) 2000 Academic Press.