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The two faces of IKK and NF-κB inhibition: prevention of systemic inflammation but increased local injury following intestinal ischemia-reperfusion

Nature Medicine volume 9, pages 575–581 (2003)Cite this article

Abstract

We studied the role of NF-κB in acute inflammation caused by gut ischemia-reperfusion through selective ablation of IκB kinase (IKK)-β, the catalytic subunit of IKK that is essential for NF-κB activation. Ablation of IKK-β in enterocytes prevented the systemic inflammatory response, which culminates in multiple organ dysfunction syndrome (MODS) that is normally triggered by gut ischemia-reperfusion. IKK-β removal from enterocytes, however, also resulted in severe apoptotic damage to the reperfused intestinal mucosa. These results show the dual function of the NF-κB system, which is responsible for both tissue protection and systemic inflammation, and underscore the caution that should be exerted in using NF-κB and IKK inhibitors.

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Figure 1: Gut ischemia-reperfusion results in TNF-α–dependent lung inflammation and failure.
Figure 2: Induction of inflammation-associated genes and IKK and NF-κB activation in lungs of mice subjected to gut ischemia-reperfusion.
Figure 3: IKK-β–dependent IKK and NF-κB activation in intestinal mucosa.
Figure 4: Enterocyte-specific deletion of IKK-β reduces TNF-α release.
Figure 5: Enterocyte-specific ablation of IKK-β prevents systemic inflammation and MODS.
Figure 6: Enterocyte-specific ablation of IKK-β results in damage to the intestinal mucosa after ischemia-reperfusion.

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References

  1. Ghosh, S., May, M.J. & Kopp, E.B. NF-κB and Rel proteins: evolutionarily conserved mediators of immune responses. Ann. Rev. Immunol. 16, 225–260 (1998).

    Article  CAS  Google Scholar 

  2. Ghosh, S. & Karin, M. Missing pieces in the NF-κB puzzle. Cell 109, S81–S96 (2002).

    Article  CAS  Google Scholar 

  3. Barnes, P.J. & Karin, M. NF-κB—a pivotal transcription factor in chronic inflammatory diseases. N. Engl. J. Med. 336, 1066–1071 (1997).

    Article  CAS  Google Scholar 

  4. Bohrer, H. et al. Role of NF-κB in the mortality of sepsis. J. Clin. Invest. 100, 972–985 (1997).

    Article  CAS  Google Scholar 

  5. Arnalich, F. et al. Predictive value of NF-κB activity and plasma cytokine levels in patients with sepsis. Infect. Immun. 68, 1942–1945 (2000).

    Article  CAS  Google Scholar 

  6. Pennington, C., Dunn, J., Li, C., Ha, T. & Browder, W. NF-κB activation in acute appendicitis: a molecular marker for extent of disease? Am. J. Surg. 66, 914–918 (2000).

    CAS  Google Scholar 

  7. Lawrence, T., Gilroy, D.W., Colville-Nash, P.R. & Willoughby, D.A. Possible new role for NF-κB in the resolution of inflammation. Nat. Med. 7, 1291–1297 (2001).

    Article  CAS  Google Scholar 

  8. Gerondakis, S., Grossmann, M., Nakamura, Y., Pohl, T. & Grumont, R. Genetic approaches in mice to understand Rel/NF-κB and IκB function: transgenics and knockouts. Oncogene 18, 6888–6895 (1999).

    Article  CAS  Google Scholar 

  9. Rothwarf, D.M. & Karin, M. The NF-κB activation pathway: a paradigm in information transfer from membrane to nucleus. Sci. STKE 1999 (5), RE1 (1999).

    Google Scholar 

  10. Li, Q., Van Antwerp, D., Mercurio, F., Lee, K.-F. & Verma, I.M. Severe liver degeneration in mice lacking the IκB kinase 2 gene. Science 284, 321–325 (1999a).

    Article  CAS  Google Scholar 

  11. Park, J.M., Greten, F.R., Li, Z.-W. & Karin, M. Macrophage apoptosis by anthrax lethal factor and p38 MAP kinase inhibition. Science 297, 2048–2051 (2002).

    Article  CAS  Google Scholar 

  12. Balk, R.A. Pathogenesis and management of multiple organ dysfunction or failure in severe sepsis and septic shock. Crit. Care Clin. 16, 337–352 (2000).

    Article  CAS  Google Scholar 

  13. Schmeling, D.J., Caty, M.G., Oldham, K.T., Guice, K.S. & Hinshaw, D.B. Evidence for neutrophil-related acute lung injury after intestinal ischemia-reperfusion. Surgery 106, 201–202 (1989).

    Google Scholar 

  14. Carden, D.L. & Granger, D.N. Pathophysiology of ischaemia-reperfusion injury. J. Pathol. 190, 255–266 (2000).

    Article  CAS  Google Scholar 

  15. Fukatsu, K. et al. Enteral nutrition prevents remote organ injury and death after a gut ischemic insult. Ann. Surg. 233, 660–668 (2001).

    Article  CAS  Google Scholar 

  16. Caty, M.G., Guice, K.S., Oldham, K.T., Remick, D.G. & Kunkel, S.I. Evidence for tumor necrosis factor-induced pulmonary microvascular injury after intestinal ischemia-reperfusion injury. Ann. Surg. 212, 694–700 (1990).

    Article  CAS  Google Scholar 

  17. Pfeffer, K. et al. Mice deficient for the 55 kD tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection. Cell 73, 457–467 (1993).

    Article  CAS  Google Scholar 

  18. DiDonato, J.A., Hayakawa, M., Rothwarf, D.M., Zandi, E. & Karin, M. A cytokine-responsive IκB kinase that activates the transcription factor NF-κB. Nature 388, 548–554 (1997).

    Article  CAS  Google Scholar 

  19. McCord, J.M. Oxygen-derived free radicals in postischemic tissue injury. N. Engl. J. Med. 312, 159–163 (1985).

    Article  CAS  Google Scholar 

  20. Li, Z.-W. et al. The IKKβ subunit of IκB kinase (IKK) is essential for NF-κB activation and prevention of apoptosis. J. Exp. Med. 189, 1839–1845 (1999).

    Article  CAS  Google Scholar 

  21. Imbert, V. et al. Tyrosine phosphorylation of IκBα activates NF-κB without proteolytic degradation of IκBα. Cell 86, 787–798 (1996).

    Article  CAS  Google Scholar 

  22. Li, Z.-W., Omori, S.A., Labuda, T., Karin, M. & Rickert, R.C. IKKβ is required for peripheral B cell proliferation and survival. J. Immunol. (in the press).

  23. Pinto, D., Robine, S., Jaisser, F., El Marjou, F.E. & Louvard, D. Regulatory sequences of the mouse villin gene that efficiently drive transgenic expression in immature and differentiated epithelial cells of small and large intestines. J. Biol. Chem. 274, 6476–6482 (1999).

    Article  CAS  Google Scholar 

  24. Nakajima, A. et al. Endogenous PPARγ mediates anti-inflammatory activity in murine ischemia-reperfusion injury. Gastroenterology 120, 460–469 (2001).

    Article  CAS  Google Scholar 

  25. Song, Y. et al. A low level of TNFα mediates hemorrhage-induced acute lung injury via p55 TNF receptor. Am. J. Physiol. Lung Cell. Mol. Physiol. 281, L677–L684 (2001).

    Article  CAS  Google Scholar 

  26. Makris, C. et al. Female mice heterozygote for IKKγ/NEMO deficiencies develop a genodermatosis similar to the human X-linked disorder incontinentia pigmenti. Mol. Cell 15, 969–979 (2000).

    Article  Google Scholar 

  27. Lewis, S.E. & Konradi, C. Analysis of DNA-protein interactions in the nervous system using the electrophoretic mobility shift assay. Methods 10, 301–311 (1996).

    Article  CAS  Google Scholar 

  28. Hu, Y. et al. Abnormal morphogenesis but intact IKK activation in mice lacking the IKKα subunit of the IκB kinase. Science 284, 316–320 (1999).

    Article  CAS  Google Scholar 

  29. Senftleben, U. et al. Activation by IKKα of a second, evolutionary conserved, NF-κB signaling pathway. Science 293, 1495–1499 (2001).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank S. Robine and D. Louvard (Institut Curie) for providing the Vil gene promoter. Z.W.L. and F.R.G. were supported by postdoctoral fellowships from the Cancer Research Institute and the German Research Foundation (D.F.G.). Grant support came from the National Science Council of Taiwan (L.W.C.), Kaohsiung Veterans General Hospital (L.W.C.), National Institutes of Health (M.K. and M.F.K.), Superfund Basic Research Program (M.K.), Cystic Fibrosis Foundation (M.F.K.), State of California Cancer Research Program (M.K.) and an award to M.K. from the Sandler Family Supporting Foundation. M.K. is a Frank and Else Schilling American Cancer Society Research Professor.

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Authors and Affiliations

  1. Department of Pharmacology, Laboratory of Gene Regulation and Signal Transduction, University of California, San Diego, California, USA

    Lee-Wei Chen, Zhi-Wei Li, Florian R. Greten & Michael Karin

  2. Department of Medicine, Laboratory of Mucosal Immunology, University of California, San Diego, California, USA

    Laurence Egan & Martin F. Kagnoff

  3. Department of Surgery, Kaohsiung Veterans General Hospital, National Yang-Ming Medical University, Taipei, Republic of China

    Lee-Wei Chen

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Correspondence to Michael Karin.

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Chen, LW., Egan, L., Li, ZW. et al. The two faces of IKK and NF-κB inhibition: prevention of systemic inflammation but increased local injury following intestinal ischemia-reperfusion. Nat Med 9, 575–581 (2003). https://doi.org/10.1038/nm849

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