TNF RECEPTOR-ASSOCIATED FACTOR-3 SIGNALING MEDIATES ACTIVATION OF P38AND 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 ass ociation with adaptor molecules of the TNF receptor-associated factor (TRAF) family. Whereas TRAF2, -5, and -6 initiate NF-kappa B activatio n, the outcomes of TRAF3-initiated signaling are less characterized. T o delineate CD40-induced TRAF3-dependent events, Ramos B cells stably transfected with a dominant negative TRAF3 were stimulated with membra nes expressing recombinant CD154/CD40 ligand, In the absence of TRAM s ignaling, activation of p38 and control of Ig production were abrogate d, whereas Jun N-terminal kinase activation and secretion of IL-10, ly mphotoxin-alpha, and TNF-alpha were partially blocked. By contrast, in duction of apoptosis, activation of NF-kappa B, generation of granuloc yte-macrophage CSF, and up-regulation of CD54, MHC class II, and CD95 were unaffected by the TRAF3 dominant negative. Together, these result s indicate that TRAF3 initiates independent signaling pathways via p38 and JNK that are associated with specific functional outcomes.