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 whereby these signaling events are coupled to distal functional events in B cells is poorly understood. In this study, using anti-CD40 monoclonal antibodies which recognize different epitopes on CD40, we compare the ability to activate the stress-activated protein kinases (SAPK) such as c-Jun NH(2) terminal kinase and p38 in human B cells with CD40 function. Activation of the SAPK pathway correlated with levels of activation of Rel/NF-kappaB transcription factors, but did not appear to be associated with rescue from anti-IgM induced apoptosis by suppressing caspase (CPP32) activity. Somewhat surprisingly, in the presence of IL-4, those antibodies to CD40 which failed to activate SAPK were most active in IgE production. IgE production was augmented in the presence of wortmannin. These studies suggest that rescue from apoptosis and IgE production mediated via CD40 may be independent of SAPK activation, induction of Rel/NF-kappaB, or suppression of CPP32 and that IgE production is, at least in part, regulated by signaling pathways that are dependent on phosphatidylinositol 3-kinase.
Sakata
N
N
Division of Basic Sciences, National Jewish Medical and Research Center, Denver, CO 80206, USA.
Hamelmann
E
E
Siadak
A W
AW
Terada
N
N
Gerwins
P
P
Aruffo
A
A
Johnson
G L
GL
Gelfand
E W
EW
D000906:Antibodies; D017209:Apoptosis / Q000502:physiology; D001402:B-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D004789:Enzyme Activation; D000939:Epitopes; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology; D006801:Humans; D007073:Immunoglobulin E / Q000096:biosynthesis; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D014066:Palatine Tonsil / Q000166:cytology / Q000276:immunology; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases
D000906:Antibodies; D019013:CD40 Antigens; D000939:Epitopes; D007073:Immunoglobulin E; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases