Inhibition of JNK activation through NF-κB target genes

The proinflammatory cytokine tumour necrosis factor-α (TNF-α) regulates immune responses, inflammation and programmed cell death (apoptosis)1,2,3,4. The ultimate fate of a cell exposed to TNF-α is determined by signal integration between its different effectors, including IκB kinase (IKK), c-Jun N-terminal protein kinase (JNK) and caspases1. Activation of caspases is required for apoptotic cell death5, whereas IKK activation inhibits apoptosis through the transcription factor NF-κB, whose target genes include caspase inhibitors1,6,7,8,9,10. JNK activates the transcription factor c-Jun/AP-1, as well as other targets11,12,13,14,15,16. However, the role of JNK activation in apoptosis induced by TNF-α is less clear17,18. It is unknown whether any crosstalk occurs between IKK and JNK, and, if so, how it affects TNF-α-induced apoptosis. We investigated this using murine embryonic fibroblasts that are deficient in either the IKKβ catalytic subunit of the IKK complex or the RelA/p65 subunit of NF-κB. Here we show that in addition to inhibiting caspases, the IKK/NF-κB pathway negatively modulates TNF-α-mediated JNK activation, partly through NF-κB-induced X-chromosome-linked inhibitor of apoptosis (XIAP)7,9. This negative crosstalk, which is specific to TNF-α signalling and does not affect JNK activation by interleukin-1 (IL-1), contributes to inhibition of apoptosis.