Tumor necrosis factor (TNF) and phorbol ester induce TNF-related apoptosis-inducing ligand (TRAIL) under critical involvement of NF-κB essential modulator (NEMO)/IKKγ

We show that tumor necrosis factor (TNF) and phorbol 12-myristate 13-acetate (PMA) induce TNF-related apoptosis-inducing ligand (TRAIL) in T cells. In cells deficient for NF-kappaB essential modulator (NEMO)/IKK gamma, an essential component of the NF-kappaB-inducing I-kappaB kinase (IKK) complex, induction of TRAIL expression was completely abrogated but was recovered in cells restored for IKK gamma expression. In cells deficient for receptor-interacting protein expression TNF, but not PMA-induced TRAIL expression was blocked. Inhibition of protein synthesis with cycloheximide blocked PMA, but not TNF-induced up-regulation of TRAIL. As both TNF and PMA rapidly induce NF-kappaB activation this suggests that NEMO/IKK gamma -dependent activation of the NF-kappaB pathway is necessary but not sufficient for up-regulation of TRAIL in T cells. The capability of the NF-kappaB pathway to induce the potent death ligand TRAIL may explain the reported proapoptotic features of this typically antiapoptotic pathway.