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Autocrine regulation of epithelial permeability by hypoxia: Role for polarized release of tumor necrosis factor α
Open accessAbstract
Background & aims The intestinal mucosa is lined by a monolayer of protective epithelial cells. This barrier is regulated by immune-derived factors such as interferon gamma (IFN-gamma). Because of the high volume of blood flow, the intestine is a primary target for hypoxic damage. We hypothesize that epithelial cytokine responses are regulated by hypoxia.Methods T84 intestinal epithelial cells were used to assess alterations in permeability, major histocompatibility complex class II induction, cytokine receptor expression, and cytokine release in response to combinations of IFN-gamma and cellular hypoxia.Results Hypoxia potentiated the influence of IFN-gamma on epithelial barrier function. Such responses were conferrable in a >/=10-kilodalton conditioned media fraction from hypoxic epithelia. Subsequent experiments identified this factor as epithelium-derived tumor necrosis factor alpha (TNF-alpha). Add-back of recombinant TNF-alpha in combination with IFN-gamma to normoxic epithelia recapitulated hypoxia and identified basolaterally polarized TNF-alpha receptor types I and II on intestinal epithelia. A similar pattern of TNF-alpha-receptor expression was observed on native intestinal epithelia. Specific inhibition of TNF-alpha using neutralizing antibody or alpha-N-phthalimidoglutarimide (thalidomide) resulted in reversal of the hypoxia-evoked responses.Conclusions These studies indicate that during hypoxia, epithelium-derived mediators such as TNF-alpha have the potential to regulate permeability through autocrine pathways.
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“TNF increases tight junction permeability by decreasing expression of tight junction proteins as well as by activating myosin light chain kinase (MLCK)147.”
From The gut microbiome and liver cancer: mechanisms and clinical translation (2017) · cites this paper as [147]
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Metadata
- Authors
- Taylor, C. T., Dzus, A. L., & Colgan, S. P.
- Affiliations
- Brigham and Women's Hospital (US)
- ORCID
- Taylor, Cormac T.
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 1998-04
- Volume
- 114
- Issue
- 4
- Pages
- 657-668
- ISSN
- 0016-5085 (ISSN-L)
- OpenAlex
- W2042606716
- Cited by
- 188
- References
- 58
- Citations by year
- 2026: 1 · 2024: 3 · 2023: 5 · 2022: 4 · 2021: 6 · 2020: 5 · 2019: 6 · 2018: 4 · 2017: 6 · 2016: 4 · 2015: 11 · 2014: 9 · 2013: 7 · 2012: 9
- FWCI
- 9.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (F32DK009699, DK09699, DK-50189)
- Topics
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- intestinal epithelial permeability, hypoxia, TNF-α, autocrine regulation, interferon-gamma, intestinal barrier function, thalidomide, MHC class II induction, cytokine receptor expression, T84 cells
- MeSH terms
- Cells, Cultured, Interferon-gamma, Intestinal Mucosa, Ischemia, Permeability, Thalidomide, Tumor Necrosis Factor-alpha, Cell Hypoxia, Cell Polarity, Receptors, Tumor Necrosis Factor
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