TUMOR-NECROSIS-FACTOR ALPHA-INDUCED ACTIVATION OF C-JUN N-TERMINAL KINASE IS MEDIATED BY TRAF2

Tumor necrosis factor alpha (TNF alpha) a pro-inflammatory cytokine is an endogenous mediator of septic shock, inflammation, anti-viral resp onses and apoptotic cell death. TNF alpha elicits its complex biologic al responses through the individual or cooperative action of two TNF r eceptors of mol. wt 55 kDa (TNF-RI) and mol. wt 75 kDa (TNF-RII). To d etermine signaling events specific for TNF-RII we fused the extracellu lar domain of the mouse CD4 antigen to the intracellular domain of TNF -RII. Crosslinking of the chimeric receptor using anti-CD4 antibodies initiates exclusively TNF-RII-mediated signals. Our findings show that : (i) TNF-RII is able to activate two members of the MAP kinase family : extracellular regulated kinase (ERK) and c-jun N-terminal kinase (JN K); (ii) TRAF2, a molecule that binds TNF-RII and associates indirectl y with TNF-RI, is sufficient to activate JNK upon overexpression; (iii ) dominant-negative TRAF2 blocks TNF alpha-mediated JNK activation and (iv) TRAF2 signals the activation of JNK and NF-kappa B through diffe rent pathways. Our findings suggest that TNF alpha-mediated JNK activa tion in fibroblasts is independent of the cell death pathway and that TRAF2 occupies a key role in TNF receptor signaling to JNK.