TNF receptor-associated factor-3 signaling mediates activation of p38 and Jun N-terminal kinase, cytokine secretion, and Ig production following ligation of CD40 on human B cells.
CD40 engagement induces a variety of functional outcomes following association with adaptor molecules of the TNF receptor-associated factor (TRAF) family. Whereas TRAF2, -5, and -6 initiate NF-kappaB activation, the outcomes of TRAF3-initiated signaling are less characterized. To delineate CD40-induced TRAF3-dependent events, Ramos B cells stably transfected with a dominant negative TRAF3 were stimulated with membranes expressing recombinant CD154/CD40 ligand. In the absence of TRAF3 signaling, activation of p38 and control of Ig production were abrogated, whereas Jun N-terminal kinase activation and secretion of IL-10, lymphotoxin-alpha, and TNF-alpha were partially blocked. By contrast, induction of apoptosis, activation of NF-kappaB, generation of granulocyte-macrophage CSF, and up-regulation of CD54, MHC class II, and CD95 were unaffected by the TRAF3 dominant negative. Together, these results indicate that TRAF3 initiates independent signaling pathways via p38 and JNK that are associated with specific functional outcomes.
Harold C. Simmons Arthritis Research Center, University of Texas Southwestern Medical Center, Dallas 75235-8884, USA.
A C
AC
Grammer
J L
JL
Swantek
R D
RD
McFarland
Y
Y
Miura
T
T
Geppert
P E
PE
Lipsky
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001402:B-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D002051:Burkitt Lymphoma; D019013:CD40 Antigens / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D023201:CD40 Ligand; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis*; D048031:JNK Mitogen-Activated Protein Kinases; D008024:Ligands; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases; D011506:Proteins / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D048008:TNF Receptor-Associated Factor 3; D014162:Transfection / Q000276:immunology; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
D019013:CD40 Antigens; D016207:Cytokines; D007136:Immunoglobulins; D008024:Ligands; D008562:Membrane Glycoproteins; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor; D048008:TNF Receptor-Associated Factor 3; D023201:CD40 Ligand; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases