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Interferon-gamma induces internalization of epithelial tight junction proteins via a macropinocytosis-like process

Matthias Bruewer1, Markus Utech, Andrei I Ivanov

  • 1Epithelial Pathobiology Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia 30322, USA.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|June 1, 2005
PubMed

Insights

Interferon-gamma (IFN-gamma) increases epithelial permeability by triggering macropinocytosis of tight junction proteins. This process disrupts the epithelial barrier during inflammation.

Area of Science:

  • Cell Biology
  • Immunology
  • Gastroenterology

Background:

  • Inflammatory conditions increase epithelial permeability.
  • The precise mechanisms by which mediators like interferon-gamma (IFN-gamma) disrupt epithelial barriers are not fully understood.
  • IFN-gamma is known to induce tight junction (TJ) disassembly.

Purpose of the Study:

  • To investigate whether endocytosis of junctional proteins mediates TJ disassembly induced by IFN-gamma.
  • To identify the specific endocytic pathway involved in IFN-gamma-induced TJ disruption in intestinal epithelial cells.

Main Methods:

  • Utilized selective inhibitors and pathway markers to analyze endocytosis in IFN-gamma-treated intestinal epithelial cells.
  • Examined the role of clathrin-mediated endocytosis, caveolar-mediated endocytosis, and macropinocytosis.
  • Assessed the localization of TJ proteins and macropinocytosis markers (dextran, phosphatidylinositol-3,4,5-trisphosphate).

Main Results:

  • Clathrin- and caveolar-mediated endocytosis were not involved in IFN-gamma-induced internalization of TJ proteins.
  • Inhibitors of macropinocytosis effectively blocked the internalization of TJ proteins.
  • TJ proteins colocalized with macropinocytosis markers and were found in early and recycling endosomes.

Conclusions:

  • IFN-gamma induces epithelial barrier dysfunction by promoting macropinocytosis of TJ proteins.
  • This study identifies macropinocytosis as a key mechanism in IFN-gamma-mediated epithelial leakiness.
  • The findings provide novel insights into the molecular pathways governing inflammatory epithelial permeability.

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