Tumor necrosis factor α‐induced activation of c‐jun N‐terminal kinase is mediated by TRAF2

Tumor necrosis factor α (TNFα) a pro‐inflammatory cytokine is an endogenous mediator of septic shock, inflammation, anti‐viral responses and apoptotic cell death. TNFα elicits its complex biological responses through the individual or cooperative action of two TNF receptors of mol. wt 55 kDa (TNF‐RI) and mol. wt 75 kDa (TNF‐RII). To determine signaling events specific for TNF‐RII we fused the extracellular 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 (JNK); (ii) TRAF2, a molecule that binds TNF‐RII and associates indirectly with TNF–RI, is sufficient to activate JNK upon overexpression; (iii) dominant‐negative TRAF2 blocks TNFα‐mediated JNK activation and (iv) TRAF2 signals the activation of JNK and NF‐κB through different pathways. Our findings suggest that TNFα‐mediated JNK activation in fibroblasts is independent of the cell death pathway and that TRAF2 occupies a key role in TNF receptor signaling to JNK.