期刊
IMMUNITY
卷 32, 期 3, 页码 392-402出版社
CELL PRESS
DOI: 10.1016/j.immuni.2010.03.001
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资金
- National Institutes of Health [DK72564, DK61379, DK79392, DK53202, DK55679, DK59888, DK64399]
- Crohn's and Colitis Foundation of America
- German Research Foundation (Deutsche Forschungsgemeinschaft, Bonn, Germany) [La 2359/1-1]
- Crohn's & Colitis Foundation of America [2634] Funding Source: researchfish
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 Wing-less-Int (Wnt)-beta-catenin signaling pathways. Shortterm 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 (INF-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.
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