Epithelial-cell-intrinsic IKK-β expression regulates intestinal immune homeostasis
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 unknown. Here we show that IEC-intrinsic IkappaB kinase (IKK)-beta-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-beta 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 (T(H)2) response and are unable to eradicate infection. Further, these animals show exacerbated production of dendritic-cell-derived interleukin-12/23p40 and tumour necrosis factor-alpha, increased levels of CD4+ T-cell-derived interferon-gamma and interleukin-17, and develop severe intestinal inflammation. Blockade of proinflammatory cytokines during Trichuris infection ablates the requirement for IKK-beta in IECs to promote CD4+ T(H)2 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-beta-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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Conditional deletion of the NF-κB pathway in intestinal epithelial cells in mice leads to an increased susceptibility to colitis, similar to that of mice expressing homozygous mutant HIF1α.
“It is notable that conditional deletion of the NF-κB pathway in intestinal epithelial cells in mice leads to an increased susceptibility to colitis50, similar to that of the mice expressing homozygous mutant HIF1α13.”
From Hypoxia: an alarm signal during intestinal inflammation (2010) · cites this paper as [50]
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- Authors
- Zaph, C., Troy, A. E., Taylor, B. C., Berman-Booty, L. D., Guild, K. J., Du, Y., Yost, E. A., Gruber, A. D., May, M. J., Greten, F. R., Eckmann, L., Karin, M., & Artis, D.
- Affiliations
- University of Pennsylvania (US)
- Freie Universität Berlin (DE)
- Technical University of Munich (DE)
- University of California San Diego (US)
- Corresponding author
- Artis, David
- ORCID
- Venue
- Nature
- Published
- 2007-02-25
- Volume
- 446
- Issue
- 7135
- Pages
- 552-556
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2041607290
- Cited by
- 496
- References
- 28
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 11 · 2023: 10 · 2022: 11 · 2021: 13 · 2020: 7 · 2019: 14 · 2018: 18 · 2017: 22 · 2016: 16 · 2015: 28 · 2014: 29 · 2013: 18 · 2012: 41
- FWCI
- 24.77
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- IKKβ, intestinal epithelial cells, intestinal immune homeostasis, thymic stromal lymphopoietin, dendritic cells, NF-κB, TNF-α, interferon-gamma, IL-17, intestinal inflammation, mucosal immunity, inflammatory cytokines
- MeSH terms
- Thymic Stromal Lymphopoietin, Animals, Dendritic Cells, Epithelial Cells, Homeostasis, Interferon-gamma, Intestines, Trichuris, CD4-Positive T-Lymphocytes, Gene Expression Regulation, Enzymologic, Cytokines, NF-kappa B, Immunity, Mucosal, Interleukin-17, Mice, I-kappa B Kinase
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