Regulation of death receptor expression and TRAIL/Apo2L-induced apoptosis by NF-κB

TRAIL (tumour-necrosis factor-related apoptosis ligand or Apo2L) triggers apoptosis through engagement of the death receptors TRAIL-R1 (also known as DR4) and TRAIL-R2 (DR5). Here we show that the c-Rel subunit of the transcription factor NF-kappaB induces expression of TRAIL-R1 and TRAIL-R2 conversely, a transdominant mutant of the inhibitory protein I kappaB alpha or a transactivation-deficient mutant of c-Rel reduces expression of either death receptor. Whereas NF-kappaB promotes death receptor expression, cytokine-mediated activation of the RelA subunit of NF-kappaB also increases expression of the apoptosis inhibitor, Bcl-x(L), and protects cells from TRAIL. Inhibition of NF-kappaB by blocking activation of the I kappaB kinase complex reduces Bcl-x(L) expression and sensitizes tumour cells to TRAIL-induced apoptosis, The ability to induce death receptors or Bcl-x(L) may explain the dual roles of NF-kappaB as a mediator or inhibitor of cell death during immune and stress responses.