Interferon-γ Regulates Intestinal Epithelial Homeostasis through Converging β-Catenin Signaling Pathways

Porfirio Nava, Stefan Koch, Mike G. Laukoetter, Winston Y. Lee, Keli Kolegraff, Christopher T. Capaldo, Neal Beeman, Caroline Addis, Kirsten Gerner-Smidt, Irmgard Neumaier, Arne Skerra, Linheng Li, Charles A. Parkos, Asma Nusrat

Research output: Contribution to journalArticlepeer-review

253 Scopus citations

Abstract

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

Original languageEnglish
Pages (from-to)392-402
Number of pages11
JournalImmunity
Volume32
Issue number3
DOIs
StatePublished - Mar 2010

Keywords

  • CELLIMMUNO
  • MOLIMMUNO

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