Cited by 189Gastrointestinal motility and disordersInflammatory Bowel DiseaseBarrier Structure and Function Studies

Autocrine regulation of epithelial permeability by hypoxia: Role for polarized release of tumor necrosis factor α

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Taylor, Cormac T., Dzus, Andrea L., Colgan, Sean P.·1998·Gastroenterology

Abstract

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 tight junction protein expression and activating myosin light chain kinase.

    “TNF increases tight junction permeability by decreasing expression of tight junction proteins as well as by activating myosin light chain kinase (MLCK)147.”

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  1. Madara JL. Pathobiology of the intestinal epithelial barrier. Am J Pathol 1990;137:1273-1278.
  2. Colgan SP, Parkos CA, Matthews JB, D'Andrea L, Awtrey CS, Lichtman A, Delp C, Madara JL. Interferon-␥ induces a surface phenotype switch in intestinal epithelia: downregulation of ion transport and upregulation of immune accessory ligands. Am J Physiol 1994;267:C402-C410.
  3. Adams RB, Planchon SM, Roche JK. IFN-␥ modulation of epithelial barrier function: time course, reversibility, site of cytokine bind- ing. J Immunol 1993;150:2356-2363.
  4. Colgan SP, Morales VM, Madara JL, Balk SP, Blumberg RS. IFN-␥ modulates CD1d expression on intestinal epithelia. Am J Physiol 1996;271:C276-C283.
  5. DeMaeyer E, DeMaeyer-Guignard J. Interferon-gamma. Curr Opin Immunol 1992;4:321-326.
  6. McCormick BA, Colgan SP, Delp-Archer C, Miller SI, Madara JL. Salmonella typhimurium attachment to human intestinal epithe- lial monolayers: transcellular signaling to subepithelial neutro- phils. J Cell Biol 1993;123:895-907.

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Authors
Taylor, C. T., Dzus, A. L., & Colgan, S. P.
Affiliations
Brigham and Women's Hospital (US)
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
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
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › 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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