Interferon-gamma regulates intestinal epithelial homeostasis through converging beta-catenin signaling pathways

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.
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.