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Inhibition of JNK activation through NF-κB target genes

Nature volume 414, pages 313–317 (2001)Cite this article

Abstract

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.

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Figure 1: Genetic disruption of IKKβ results in sustained JNK activation by TNF-α.
Figure 2: NF-κB mediates the inhibitory effect of IKK on JNK.
Figure 3: Inhibition of JNK activation by NF-κB is specific to TNF-α signalling and involves XIAP, but not phosphatases.
Figure 4: TNF-α killing of RelA-/- fibroblasts is inhibited by a dominant negative JNKK mutant but enhanced by a constitutively active JNKK2–JNK1 fusion protein.

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Acknowledgements

We are grateful to D. Baltimore for providing us with RelA-/- fibroblasts and C. S. Duckett for the XIAP construct; M. R. Rosner for critical reading of this manuscript and suggestions; and S. Nemoto for her initial finding when she was a member of Lin laboratory. This work was supported by grants from the National Institutes of Health (NIH), the American Cancer Society (ACS) and Department of Defense to A.L. Generation of IKK-deficient cells was supported by grants from the NIH and State of California Cancer Research Program to M.K., who is the Frank and Else Schilling-ACS Research Professor.

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  1. Guilin Tang, Yuzuru Minemoto, Zhiwei Li and Michael Karin: These authors contributed equally to the work

Authors and Affiliations

  1. Ben May Institute for Cancer Research, Committee on Cancer Biology, University of Chicago, 5841 S. Maryland Avenue, Chicago, MC 6027, 60637, Illinois, USA

    Guilin Tang, Yuzuru Minemoto, Benjamin Dibling, Nicole H. Purcell & Anning Lin

  2. Department of Pharmacology, Laboratory of Gene Regulation and Signal Transduction, University of California, San Diego, 9500 Gilman Drive, La Jolla, 92093-0636, California, USA

    Zhiwei Li & Michael Karin

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  1. Guilin Tang
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Correspondence to Anning Lin.

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Tang, G., Minemoto, Y., Dibling, B. et al. Inhibition of JNK activation through NF-κB target genes. Nature 414, 313–317 (2001). https://doi.org/10.1038/35104568

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