1. The Gwen Knapp Center for Lupus and Immunology Research, and The Ben May Institute for Cancer Research, The University of Chicago, 924 East 57th Street, Chicago, Illinois 60637, USA

Correspondence to: Guido Franzoso Correspondence and requests for materials should be addressed to G.F. (e-mail: Email: gfranzos@midway.uchicago.edu).

In addition to coordinating immune and inflammatory responses, NF-B/Rel transcription factors control cell survival¹. Normally, NF-B dimers are sequestered in the cytoplasm by binding to inhibitory IB proteins, and can be activated rapidly by signals that induce the sequential phosphorylation and proteolysis of IBs¹. Activation of NF-B antagonizes apoptosis or programmed cell death by numerous triggers, including the ligand engagement of 'death receptors' such as tumour-necrosis factor (TNF) receptor². The anti-apoptotic activity of NF-B is also crucial to oncogenesis and to chemo- and radio-resistance in cancer². Cytoprotection by NF-B involves the activation of pro-survival genes²; however, its basis remains poorly understood. Here we report that NF-B complexes downregulate the c-Jun amino-terminal kinase (JNK) cascade³, thus establishing a link between the NF-B and the JNK pathways. This link involves the transcriptional upregulation of gadd45/myd118 (ref. 4), which downregulates JNK signalling induced by the TNF receptor (TNF-R). This NF-B-dependent inhibition of the JNK pathway is central to the control of cell death. Our findings define a protective mechanism that is mediated by NF-B complexes and establish a role for the persistent activation of JNK in the apoptotic response to TNF-.