STIMULUS-DEPENDENT SYNERGISM OF THE ANTIAPOPTOTIC TUMOR-NECROSIS-FACTOR RECEPTOR-ASSOCIATED FACTOR-2 (TRAF2) AND NUCLEAR FACTOR KAPPA-B PATHWAYS

Tumor necrosis factor (TNF) signaling leads to pleiotropic responses i n a wide range of cell types, in part by activating antiapoptotic and proapoptotic signaling pathways. Thus, although TNF can cause apoptosi s and may prove useful in the treatment of malignancies, most cells ar e resistant to TNF-induced cell death unless de novo protein synthesis is inhibited. Previous studies suggested that TNF activation of the n uclear factor (NF)-kappa B transcription factor family antagonizes the proapoptotic signals initiated by TNF-alpha. TNF receptor-associated factor (TRAF)2 has also been shown to mediate crucial antiapoptotic si gnals during TNF stimulation, yet is not essential in activation of NF -kappa B under physiologic conditions, thus raising questions about th e relationship between these antiapoptotic pathways. We report here th at inhibition of TRAF2 and NF-kappa B function in primary cells, by co expression of a constitutive repressor of multiple NF-kappa B/Rel prot eins (I kappa B alpha.DN) and a dominant negative form of TRAF2 (TRAF2 .DN), synergistically enhanced TNF-induced apoptosis. The effects were stimulus dependent, such that neither inhibitory molecule affected Fa s- and daunorubicin-induced apoptosis to the same degree as TNF-induce d death. These findings indicate that the NF-kappa B and TRAF2 pathway s activate independent antiapoptotic mechanisms which act in concert t o suppress the proapoptotic signals induced by TNF-alpha.