1. Ben May Institute for Cancer Research, Committee on Cancer Biology, University of Chicago, 5841 S. Maryland Avenue, MC 6027, Chicago, Illinois 60637, USA
2. Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0636, USA
3. These authors contributed equally to the work

Correspondence to: Anning Lin¹ Correspondence and requests for materials should be addressed to A.L. (email: Email: alin@huggins.bsd.uchicago.edu).

The proinflammatory cytokine tumour necrosis factor- (TNF-) regulates immune responses, inflammation and programmed cell death (apoptosis)^{1, 2, 3, 4}. The ultimate fate of a cell exposed to TNF- is determined by signal integration between its different effectors, including IB 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-B, whose target genes include caspase inhibitors^{1, 6, 7, 8, 9, 10}. JNK activates the transcription factor c-Jun/AP-1, as well as other targets^{11, 12, 13, 14, 15, 16}. However, the role of JNK activation in apoptosis induced by TNF- is less clear^{17, 18}. It is unknown whether any crosstalk occurs between IKK and JNK, and, if so, how it affects TNF--induced apoptosis. We investigated this using murine embryonic fibroblasts that are deficient in either the IKK catalytic subunit of the IKK complex or the RelA/p65 subunit of NF-B. Here we show that in addition to inhibiting caspases, the IKK/NF-B pathway negatively modulates TNF--mediated JNK activation, partly through NF-B-induced X-chromosome-linked inhibitor of apoptosis (XIAP)^{7, 9}. This negative crosstalk, which is specific to TNF- signalling and does not affect JNK activation by interleukin-1 (IL-1), contributes to inhibition of apoptosis.