Immunity (Cambridge, Mass.), 2010-03, Vol.32 (3), p.392-402
2010
Details
- Autor(en) / Beteiligte
- Titel
- Interferon-γ Regulates Intestinal Epithelial Homeostasis through Converging β-Catenin Signaling Pathways
- Ist Teil von
- Immunity (Cambridge, Mass.), 2010-03, Vol.32 (3), p.392-402
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2010
- Link zum Volltext
- Quelle
- EZB-FREE-00999 freely available EZB journals
- Beschreibungen/Notizen
- 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. [Display omitted] ► IFN-γ induces AKT-β-catenin transcriptional activity in intestinal epithelium ► Phosphorylation of β-catenin by AKT is essential to induce Dkk1 expression ► Dkk1 enhances epithelial apoptosis by inhibiting Wnt-β-catenin signaling ► Regulation of β-catenin by AKT and Dkk1 is important for epithelial homeostasis
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1074-7613, 1097-4180eISSN: 1097-4180DOI: 10.1016/j.immuni.2010.03.001Titel-ID: cdi_swepub_primary_oai_DiVA_org_liu_141666
- Format
- –
- Schlagworte
- Animals, Apoptosis, beta Catenin - metabolism, Cell Line, Cell Proliferation, CELLIMMUNO, Colitis - genetics, Colitis - immunology, Colitis - metabolism, Colitis - pathology, Colitis/genetics/immunology/metabolism/pathology, Epithelial Cells - cytology, Epithelial Cells - immunology, Epithelial Cells - metabolism, Epithelial Cells/cytology/immunology/metabolism, Homeostasis, Inbred C57BL, Interferon-gamma - deficiency, Interferon-gamma - immunology, Interferon-gamma - metabolism, Interferon-gamma/deficiency/immunology/metabolism, Intestines - immunology, Intestines - metabolism, Intestines/immunology/metabolism, Knockout, Mice, Mice, Inbred C57BL, Mice, Knockout, MOLIMMUNO, Proto-Oncogene Proteins c-akt - metabolism, Signal Transduction, Wnt Proteins - metabolism