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(The FASEB Journal. 2005;19:923-933.)
© 2005 FASEB

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

Matthias Bruewer*,{dagger},1, Markus Utech*,{dagger}, Andrei I. Ivanov*, Ann M. Hopkins*, Charles A. Parkos* and Asma Nusrat*,2

* Epithelial Pathobiology Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA; and
{dagger} Department of General Surgery, University of Münster, Münster, Germany

2Correspondence: Department of Pathology and Laboratory Medicine, Emory University, Whitehead Research Building, Room 105E, 615 Michael St., Atlanta, GA 30322, USA. E-mail: anusrat{at}emory.edu

Increased epithelial permeability is observed in inflammatory states. However, the mechanism by which inflammatory mediators such as IFN-{gamma} increase epithelial permeability is unknown. We recently observed that IFN-{gamma} induces disassembly of tight junctions (TJ); in this study we asked whether such TJ disassembly is mediated by endocytosis of junctional proteins. The role of three major internalization pathways in disruption of TJ in IFN-{gamma}-treated intestinal epithelial cells was analyzed using selective inhibitors and markers of the pathways. No role for the clathrin- and caveolar-mediated endocytosis in the IFN-{gamma}-induced internalization of TJ proteins was observed. However, inhibitors of macropinocytosis blocked internalization of TJ proteins and junctional proteins colocalized with macropinocytosis markers, dextran and phosphatidylinositol-3,4,5-trisphosphate. Internalized TJ proteins were identified in early and recycling endosomes but not in late endosomes/lysosomes. These results for the first time suggest that IFN-{gamma} produces a leaky epithelial barrier by inducing macropinoytosis of TJ proteins.—Bruewer, M., Utechm M., Ivanov, A. I., Hopkins, A. M., Parkos, C. A., Nusrat, A. Interferon-{gamma} induces internalization of epithelial tight junction proteins via a macropinocytosis-like process.


Key Words: cytokines • inflammation • mucosa




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