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Epithelial NEMO links innate immunity to chronic intestinal inflammation


Deregulation of intestinal immune responses seems to have a principal function in the pathogenesis of inflammatory bowel disease1,2,3,4. The gut epithelium is critically involved in the maintenance of intestinal immune homeostasis—acting as a physical barrier separating luminal bacteria and immune cells, and also expressing antimicrobial peptides3,5,6. However, the molecular mechanisms that control this function of gut epithelial cells are poorly understood. Here we show that the transcription factor NF-κB, a master regulator of pro-inflammatory responses7,8, functions in gut epithelial cells to control epithelial integrity and the interaction between the mucosal immune system and gut microflora. Intestinal epithelial-cell-specific inhibition of NF-κB through conditional ablation of NEMO (also called IκB kinase-γ (IKKγ)) or both IKK1 (IKKα) and IKK2 (IKKβ)—IKK subunits essential for NF-κB activation7,8,9—spontaneously caused severe chronic intestinal inflammation in mice. NF-κB deficiency led to apoptosis of colonic epithelial cells, impaired expression of antimicrobial peptides and translocation of bacteria into the mucosa. Concurrently, this epithelial defect triggered a chronic inflammatory response in the colon, initially dominated by innate immune cells but later also involving T lymphocytes. Deficiency of the gene encoding the adaptor protein MyD88 prevented the development of intestinal inflammation, demonstrating that Toll-like receptor activation by intestinal bacteria is essential for disease pathogenesis in this mouse model. Furthermore, NEMO deficiency sensitized epithelial cells to tumour-necrosis factor (TNF)-induced apoptosis, whereas TNF receptor-1 inactivation inhibited intestinal inflammation, demonstrating that TNF receptor-1 signalling is crucial for disease induction. These findings demonstrate that a primary NF-κB signalling defect in intestinal epithelial cells disrupts immune homeostasis in the gastrointestinal tract, causing an inflammatory-bowel-disease-like phenotype. Our results identify NF-κB signalling in the gut epithelium as a critical regulator of epithelial integrity and intestinal immune homeostasis, and have important implications for understanding the mechanisms controlling the pathogenesis of human inflammatory bowel disease.

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Figure 1: Intestinal epithelium-specific NEMO ablation causes severe spontaneous colitis.
Figure 2: Inflammation in the colon of NEMO IEC-KO mice.
Figure 3: Compromised epithelial integrity and bacterial translocation in the colon of NEMO IEC-KO mice.
Figure 4: NF-κB inhibition in intestinal epithelial cells causes inflammatory colitis that depends on TNFRI and MyD88 signalling. a,
Figure 5: NEMO-mediated NF-κB activation in intestinal epithelial cells is essential for the maintenance of epithelial barrier integrity and immune homeostasis in the colon.


  1. Bouma, G. & Strober, W. The immunological and genetic basis of inflammatory bowel disease. Nature Rev. Immunol. 3, 521–533 (2003)

    CAS  Article  Google Scholar 

  2. Hanauer, S. B. Inflammatory bowel disease: epidemiology, pathogenesis, and therapeutic opportunities. Inflamm. Bowel Dis. 12, (suppl. 1)S3–S9 (2006)

    Article  Google Scholar 

  3. Macdonald, T. T. & Monteleone, G. Immunity, inflammation, and allergy in the gut. Science 307, 1920–1925 (2005)

    ADS  CAS  Article  Google Scholar 

  4. Neurath, M. F., Finotto, S. & Glimcher, L. H. The role of Th1/Th2 polarization in mucosal immunity. Nature Med. 8, 567–573 (2002)

    CAS  Article  Google Scholar 

  5. Abreu, M. T., Fukata, M. & Arditi, M. TLR signaling in the gut in health and disease. J. Immunol. 174, 4453–4460 (2005)

    CAS  Article  Google Scholar 

  6. Wehkamp, J., Fellermann, K., Herrlinger, K. R., Bevins, C. L. & Stange, E. F. Mechanisms of disease: defensins in gastrointestinal diseases. Nature Clin. Pract. Gastroenterol. Hepatol. 2, 406–415 (2005)

    CAS  Article  Google Scholar 

  7. Karin, M. & Greten, F. R. NF-κB: linking inflammation and immunity to cancer development and progression. Nature Rev. Immunol. 5, 749–759 (2005)

    CAS  Article  Google Scholar 

  8. Li, Q. & Verma, I. M. NF-κB regulation in the immune system. Nature Rev. Immunol. 2, 725–734 (2002)

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  10. Schmidt-Supprian, M. et al. NEMO/IKKγ-deficient mice model incontinentia pigmenti. Mol. Cell 5, 981–992 (2000)

    CAS  Article  Google Scholar 

  11. Madison, B. B. et al. Cis elements of the villin gene control expression in restricted domains of the vertical (crypt) and horizontal (duodenum, cecum) axes of the intestine. J. Biol. Chem. 277, 33275–33283 (2002)

    CAS  Article  Google Scholar 

  12. Becker, C. et al. TGF-β suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling. Immunity 21, 491–501 (2004)

    CAS  Article  Google Scholar 

  13. Rudolph, D. et al. Severe liver degeneration and lack of NF-κB activation in NEMO/IKKγ-deficient mice. Genes Dev. 14, 854–862 (2000)

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Makris, C. et al. Female mice heterozygous for IKKγ/NEMO deficiencies develop a dermatopathy similar to the human X-linked disorder incontinentia pigmenti. Mol. Cell 5, 969–979 (2000)

    CAS  Article  Google Scholar 

  15. Darmoul, D. & Ouellette, A. J. Positional specificity of defensin gene expression reveals Paneth cell heterogeneity in mouse small intestine. Am. J. Physiol. 271, G68–G74 (1996)

    CAS  PubMed  Google Scholar 

  16. Lan, J. G. et al. Different cytokine response of primary colonic epithelial cells to commensal bacteria. World J. Gastroenterol. 11, 3375–3384 (2005)

    CAS  Article  Google Scholar 

  17. Fellermann, K. et al. A chromosome 8 gene-cluster polymorphism with low human β-defensin 2 gene copy number predisposes to Crohn disease of the colon. Am. J. Hum. Genet. 79, 439–448 (2006)

    CAS  Article  Google Scholar 

  18. Greten, F. R. et al. IKKβ links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118, 285–296 (2004)

    CAS  Article  Google Scholar 

  19. Pasparakis, M. et al. TNF-mediated inflammatory skin disease in mice with epidermis-specific deletion of IKK2. Nature 417, 861–866 (2002)

    ADS  CAS  Article  Google Scholar 

  20. Li, Q., Estepa, G., Memet, S., Israel, A. & Verma, I. M. Complete lack of NF-κB activity in IKK1 and IKK2 double-deficient mice: additional defect in neurulation. Genes Dev. 14, 1729–1733 (2000)

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Gareus, R. et al. Normal epidermal differentiation but impaired skin barrier formation upon keratinocyte-restricted IKK1 ablation. Nature Cell Biol. doi:10.1038/ncb1560 (in the press).

  22. Kawai, T. & Akira, S. TLR signaling. Cell Death Differ. 13, 816–825 (2006)

    CAS  Article  Google Scholar 

  23. Targan, S. R. et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor α for Crohn’s disease. Crohn’s Disease cA2 Study Group. N. Engl. J. Med. 337, 1029–1035 (1997)

    CAS  Article  Google Scholar 

  24. Luedde, T. et al. Deletion of NEMO/IKKγ in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma. Cancer Cell 11, 119–132 (2007)

    CAS  Article  Google Scholar 

  25. Pasparakis, M., Alexopoulou, L., Episkopou, V. & Kollias, G. Immune and inflammatory responses in TNFα-deficient mice: a critical requirement for TNFα in the formation of primary B cell follicles, follicular dendritic cell networks and germinal centers, and in the maturation of the humoral immune response. J. Exp. Med. 184, 1397–1411 (1996)

    CAS  Article  Google Scholar 

  26. 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)

    CAS  Article  Google Scholar 

  27. Kawai, T., Adachi, O., Ogawa, T., Takeda, K. & Akira, S. Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 11, 115–122 (1999)

    CAS  Article  Google Scholar 

  28. Becker, C. et al. Constitutive p40 promoter activation and IL-23 production in the terminal ileum mediated by dendritic cells. J. Clin. Invest. 112, 693–706 (2003)

    CAS  Article  Google Scholar 

  29. Becker, C. et al. In vivo imaging of colitis and colon cancer development in mice using high resolution chromoendoscopy. Gut 54, 950–954 (2005)

    CAS  Article  Google Scholar 

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We thank K. Pfeffer and S. Akira for providing TNFRI-deficient and MyD88-deficient mice, respectively. This work was supported by grants from the German Research Council to C.B. and M.F.N., and by EU-FP6 grants MUGEN and IMDEMI to M.P.; A.W. received a research fellowship from the Alexander von Humboldt Foundation.

Author Contributions A. Nenci, C.B., A.W., R.G, G.v.L, M.F.N and M.P. designed the research. A. Nenci, C.B, A.W, R.G, G.v.L, S.D., M.H., A. Nikolaev and C.N. performed the research. B.M. and D.G. contributed new reagents. A. Nenci, C.B., A.W., R.G, M.F.N and M.P. analysed the data and wrote the paper. M.F.N. and M.P share senior authorship.

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Correspondence to Manolis Pasparakis.

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Nenci, A., Becker, C., Wullaert, A. et al. Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446, 557–561 (2007).

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