In addition to coordinating immune and inflammatory responses, NF-kappaB/Re
l transcription factors control cell survival(1). Normally, NF-kappaB dimer
s are sequestered in the cytoplasm by binding to inhibitory I kappaB protei
ns, and can be activated rapidly by signals that induce the sequential phos
phorylation and proteolysis of I kappa Bs(1). Activation of NF-kappaB antag
onizes apoptosis or programmed cell death by numerous triggers, including t
he ligand engagement of 'death receptors' such as tumour-necrosis factor (T
NF) receptor(2). The anti-apoptotic activity of NF-kappaB is also crucial t
o oncogenesis and to chemo- and radio-resistance in cancer(2). Cytoprotecti
on by NF-kappaB involves the activation of pro-survival genes(2); however,
its basis remains poorly understood. Here we report that NF-kappaB complexe
s downregulate the c-Jun aminoterminal kinase (JNK) cascade(3), thus establ
ishing a link between the NF-kappaB and the JNK pathways. This link involve
s the transcriptional upregulation of gadd45 beta /myd118 (ref. 4), which d
ownregulates JNK signalling induced by the TNF receptor (TNF-R). This NF-ka
ppaB-dependent inhibition of the JNK pathway is central to the control of c
ell death. Our findings define a protective mechanism that is mediated by N
F-kappaB complexes and establish a role for the persistent activation of JN
K in the apoptotic response to TNF-alpha.