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Epithelial-cell-intrinsic IKK-β expression regulates intestinal immune homeostasis

Nature volume 446, pages 552–556 (2007)Cite this article

Abstract

Intestinal epithelial cells (IECs) provide a primary physical barrier against commensal and pathogenic microorganisms in the gastrointestinal (GI) tract, but the influence of IECs on the development and regulation of immunity to infection is unknown1. Here we show that IEC-intrinsic IκB kinase (IKK)-β-dependent gene expression is a critical regulator of responses of dendritic cells and CD4+ T cells in the GI tract. Mice with an IEC-specific deletion of IKK-β show a reduced expression of the epithelial-cell-restricted cytokine thymic stromal lymphopoietin in the intestine and, after infection with the gut-dwelling parasite Trichuris, fail to develop a pathogen-specific CD4+ T helper type 2 (TH2) response and are unable to eradicate infection. Further, these animals show exacerbated production of dendritic-cell-derived interleukin-12/23p40 and tumour necrosis factor-α, increased levels of CD4+ T-cell-derived interferon-γ and interleukin-17, and develop severe intestinal inflammation. Blockade of proinflammatory cytokines during Trichuris infection ablates the requirement for IKK-β in IECs to promote CD4+ TH2 cell-dependent immunity, identifying an essential function for IECs in tissue-specific conditioning of dendritic cells and limiting type 1 cytokine production in the GI tract. These results indicate that the balance of IKK-β-dependent gene expression in the intestinal epithelium is crucial in intestinal immune homeostasis by promoting mucosal immunity and limiting chronic inflammation.

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Figure 1: IKK-β-dependent NF-κB activation in IECs is required for adaptive immunity to Trichuris.
Figure 2: Dysregulated dendritic cell responses in Ikkb ΔIEC mice after infection with Trichuris are associated with defective TSLP expression.
Figure 3: IkkbΔIEC mice show exacerbated pathogen-specific IFN-γ and IL-17 responses and severe intestinal inflammation after infection with Trichuris.
Figure 4: IEC-intrinsic IKK-β is required for limiting proinflammatory cytokine responses in the GI tract.

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Acknowledgements

We thank C. A. Hunter, E. J. Pearce and E. H. Wilson for critical reading of the manuscript, and J. N. Ihle for the Tpte2-/- mice. This work was supported by the NIH (D.A., L.E. and M.K.), the pilot feasibility program of the NIDDK Diseases Centre (D.A.), and NIAID (A.E.T.) and NCRR (L.D.B.-B.) NIH training grants. M.K. is an American Cancer Society Research Professor. C.Z. is a recipient of a fellowship from the Irvington Institute for Immunological Research. D.A. is the recipient of the Crohn’s and Colitis Foundation of America’s William and Shelby Modell Family Foundation Research Award.

Author Contributions C.Z., A.E.T., B.C.T., F.R.G., L.E., M.K. and D.A. designed the research. C.Z., A.E.T., B.C.T., L.D.B.-B., K.J.G., Y.D., E.A.Y. and D.A. performed the research. F.R.G., L.E., A.D.G., M.J.M. and M.K. contributed new reagents. C.Z., A.E.T., B.C.T., F.R.G, L.E., M.J.M, M.K. and D.A. analysed the data. C.Z. and D.A. wrote the paper.

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  1. Florian R. Greten

    Present address: Present address: Second Department of Medicine, Technical University Munich, 81675 Munich, Germany.,

Authors and Affiliations

  1. Department of Pathobiology and,,

    Colby Zaph, Amy E. Troy, Betsy C. Taylor, Lisa D. Berman-Booty, Katherine J. Guild, Yurong Du, Evan A. Yost & David Artis

  2. Department of Animal Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA,

    Michael J. May

  3. Department of Veterinary Pathology, Free University Berlin, 14163 Berlin, Germany,

    Achim D. Gruber

  4. Department of Pharmacology, Laboratory of Gene Regulation and Signal Transduction, and,

    Florian R. Greten & Michael Karin

  5. Department of Medicine, University of California San Diego, La Jolla, California 92093, USA,

    Lars Eckmann

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Correspondence to David Artis.

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Supplementary information

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The supplementary information contains Supplementary Figures 1-5 and Legends, Supplementary Methods and Supplementary Notes. Supplementary Figure S1 shows the relative mRNA expression level of IL-4 in mLN of infected IkkbF/F and IkkbΔIEC mice and photomicrographs of histological sections of the caecum of infected IkkbF/F and IkkbΔIEC mice stained for goblet cell mucins. Supplementary Figure S2 shows that barrier function is intact in IkkbF/F and IkkbΔIEC mice. Supplementary Figure S3 shows the activation status of dendritic cell subsets in the mLN of naïve IkkbF/F and IkkbΔIEC mice. Supplementary Figure S4 shows the relative mRNA expression levels of CCL6, CCL20 and CCL28 in naïve or infected IkkbF/F and IkkbΔIEC mice. Supplementary Figure S5 shows photomicrographs of histological sections of the caecum stained for goblet cell mucins and levels of secreted RELMΔ in infected IkkbF/F mice and control immunoglobulin or anti-IL-12/23p40/IFN-Δ treated IkkbΔIEC mice. The Supplementary Methods provide details on the experimental procedures. Supplementary Notes contain additional references. (PDF 2431 kb)

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Zaph, C., Troy, A., Taylor, B. et al. Epithelial-cell-intrinsic IKK-β expression regulates intestinal immune homeostasis. Nature 446, 552–556 (2007). https://doi.org/10.1038/nature05590

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