Autocrine regulation of epithelial permeability by hypoxia: role for polarized release of tumor necrosis factor alpha

Gastroenterology. 1998 Apr;114(4):657-68. doi: 10.1016/s0016-5085(98)70579-7.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cell Hypoxia*
  • Cell Polarity
  • Cells, Cultured
  • Interferon-gamma / pharmacology
  • Intestinal Mucosa / metabolism*
  • Ischemia / metabolism
  • Permeability
  • Receptors, Tumor Necrosis Factor / analysis
  • Thalidomide / pharmacology
  • Tumor Necrosis Factor-alpha / metabolism*


  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha
  • Thalidomide
  • Interferon-gamma