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Interferon-gamma regulates intestinal epithelial homeostasis through converging beta-catenin signaling pathways
Epithelial Pathobiology Unit, Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Epithelial Pathobiology Unit, Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
Epithelial Pathobiology Unit, Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA; Department of General Surgery, Universitaet Muenster, Muenster, Germany.
Epithelial Pathobiology Unit, Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
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2010 (English)In: Immunity, ISSN 1074-7613, E-ISSN 1097-4180, Vol. 32, no 3, 392-402 p.Article in journal (Refereed) Published
Abstract [en]

Inflammatory cytokines have been proposed to regulate epithelial homeostasis during intestinal inflammation. We report here that interferon-gamma (IFN-gamma) regulates the crucial homeostatic functions of cell proliferation and apoptosis through serine-threonine protein kinase AKT-beta-catenin and Wingless-Int (Wnt)-beta-catenin signaling pathways. Short-term exposure of intestinal epithelial cells to IFN-gamma resulted in activation of beta-catenin through AKT, followed by induction of the secreted Wnt inhibitor Dkk1. Consequently, we observed an increase in Dkk1-mediated apoptosis upon extended IFN-gamma treatment and reduced proliferation through depletion of the Wnt coreceptor LRP6. These effects were enhanced by tumor necrosis factor-alpha (TNF-alpha), suggesting synergism between the two cytokines. Consistent with these results, colitis in vivo was associated with decreased beta-catenin-T cell factor (TCF) signaling, loss of plasma membrane-associated LRP6, and reduced epithelial cell proliferation. Proliferation was partially restored in IFN-gamma-deficient mice. Thus, we propose that IFN-gamma regulates intestinal epithelial homeostasis by sequential regulation of converging beta-catenin signaling pathways.

Place, publisher, year, edition, pages
Cambridge, United States: Cell Press , 2010. Vol. 32, no 3, 392-402 p.
Keyword [en]
Animals, Apoptosis, Cell Line, Cell Proliferation, Colitis/genetics/immunology/metabolism/pathology, Epithelial Cells/cytology/*immunology/metabolism, *Homeostasis, Interferon-gamma/deficiency/*immunology/metabolism, Intestines/*immunology/metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Proto-Oncogene Proteins c-akt/metabolism, *Signal Transduction, Wnt Proteins/metabolism, beta Catenin/*metabolism
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-141666DOI: 10.1016/j.immuni.2010.03.001ISI: 000276125400012PubMedID: 20303298Scopus ID: 2-s2.0-77949937466ISBN: 1097-4180 (Electronic) 1074-7613 (Linking) OAI: oai:DiVA.org:liu-141666DiVA: diva2:1149703
Note

Nava, Porfirio Koch, Stefan Laukoetter, Mike G Lee, Winston Y Kolegraff, Keli Capaldo, Christopher T Beeman, Neal Addis, Caroline Gerner-Smidt, Kirsten Neumaier, Irmgard Skerra, Arne Li, Linheng Parkos, Charles A Nusrat, Asma eng R01 DK059888-09/DK/NIDDK NIH HHS/ R01 DK079392/DK/NIDDK NIH HHS/ R01 DK061379-08/DK/NIDDK NIH HHS/ DK55679/DK/NIDDK NIH HHS/ R29 DK055679/DK/NIDDK NIH HHS/ T32 GM008169/GM/NIGMS NIH HHS/ DK72564/DK/NIDDK NIH HHS/ DK64399/DK/NIDDK NIH HHS/ R01 DK072564/DK/NIDDK NIH HHS/ R01 DK055679-12/DK/NIDDK NIH HHS/ DK53202/DK/NIDDK NIH HHS/ R24 DK064399/DK/NIDDK NIH HHS/ R24 DK064399-019003/DK/NIDDK NIH HHS/ DK59888/DK/NIDDK NIH HHS/ DK79392/DK/NIDDK NIH HHS/ R01 DK055679/DK/NIDDK NIH HHS/ R01 DK079392-07/DK/NIDDK NIH HHS/ R24 DK064399-019002/DK/NIDDK NIH HHS/ R01 DK061379/DK/NIDDK NIH HHS/ R01 DK059888/DK/NIDDK NIH HHS/ DK61379/DK/NIDDK NIH HHS/ R01 DK072564-15/DK/NIDDK NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't 2010/03/23 06:00 Immunity. 2010 Mar 26;32(3):392-402. doi: 10.1016/j.immuni.2010.03.001. Epub 2010 Mar 18.

Available from: 2017-10-16 Created: 2017-10-16 Last updated: 2017-10-24Bibliographically approved

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