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The many faces of tumor necrosis factor signaling in the intestinal epithelium

Genes & Immunity volume 20, pages 609–626 (2019)Cite this article

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Abstract

The intestinal epithelium represents an exquisite complex combination of specialized cellular components, structural organization, as well as fine-tuned maintenance and renewal mechanisms that ensure its barrier and absorptive function. Defects in one or more of these components can lead to devastating consequences for the organisms, and when chronic, even develop into inflammatory diseases, such as Crohn’s disease or ulcerative colitis. In these scenarios, the cytokine TNF (Tumor Necrosis Factor α) appears to be a major inflammation-promoting and tissue damage-promoting effector molecule. Besides its role in inflammation and cell death, TNF presents a wide range of pleiotropic activities with implications in various cellular processes, including proliferation and differentiation. Moreover, more recent evidences suggest an anti-inflammatory role of TNF, mostly via the induction of local glucocorticoids synthesis in the intestinal epithelium. Thus, the outcome of TNF receptor signaling largely depends on various factors, like the TNFR composition and the precise cellular context or tissue type, which will determine the cellular fate. In this review, we discuss the molecular mechanisms and their potential crosstalk that regulate the different TNF-initiated cellular outcomes in the intestine, as well as possible applications for pharmacological interventions in the treatment of inflammatory disorders of the intestinal mucosa.

Highlights

  • TNF stimulation leads to survival, inflammation, apoptosis and necroptosis induction, depending on the cellular background and the disruption of specific checkpoints.

  • The intestinal epithelium is exquisitely sensitive to TNF-induced cell death.

  • TNF signaling involves early NF-κB-independent, as well as late NF-κB-dependent checkpoints.

  • TNF-induced cell death is often associated with intestinal immunopathologies, such as inflammatory bowel disease.

  • TNF induces local intestinal glucocorticoid synthesis, which regulates immune homeostasis in the intestinal mucosa.

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Acknowledgements

This work was supported by Grants from the German Science Foundation to TB. MED received an Independent Research Grant from the University of Konstanz “Zukunftskolleg”.

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MED and TB designed and discussed the manuscript. MED wrote the text, while TB edited it.

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  1. Chair of Biochemical Pharmacology, Department of Biology, University of Konstanz, Konstanz, Germany

    M. Eugenia Delgado & Thomas Brunner

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  1. M. Eugenia Delgado
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Delgado, M.E., Brunner, T. The many faces of tumor necrosis factor signaling in the intestinal epithelium. Genes Immun 20, 609–626 (2019). https://doi.org/10.1038/s41435-019-0057-0

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