Inhibition of JNK activation through NF-kappa B target genes

The proinflammatory cytokine tumour necrosis factor-alpha (TNF-alpha) regul ates immune responses, inflammation and programmed cell death (apoptosis)(1 -4). The ultimate fate of a cell exposed to TNF-alpha is determined by sign al integration between its different effectors, including I kappaB kinase ( IKK), c-Jun N-terminal protein kinase (JNK) and caspases(1). Activation of caspases is required for apoptotic cell death(5), whereas IKK activation in hibits apoptosis through the transcription factor NF-kappaB, whose target g enes include caspase inhibitors(1,6-10). JNK activates the transcription fa ctor c-Jun/AP-1, as well as other targets(11-16). However, the role of JNK activation in apoptosis induced by TNF-alpha is less clear(17,18). It is un known whether any crosstalk occurs between IKK and JNK, and, if so, how it affects TNF-alpha -induced apoptosis. We investigated this using murine emb ryonic fibroblasts that are deficient in either the IKK beta catalytic subu nit of the IKK complex or the RelA/p65 subunit of NF-kappaB. Here we show t hat in addition to inhibiting caspases, the IKK/NF-kappaB pathway negativel y modulates TNF-alpha -mediated JNK activation, partly through NF-kappaB-in duced X-chromosome-linked inhibitor of apoptosis (XIAP)(7,9). This negative crosstalk, which is specific to TNF-alpha signalling and does not affect J NK activation by interleukin-1 (IL-1), contributes to inhibition of apoptos is.