Cytokine-induced Wnt/beta-catenin Signaling in Intestinal Stem Cells in Inflammatory Bowel Disease

Inflammatory stimuli have recently been suggested to promote dedifferentiation of intestinal epithelial cells (IEC) and acquisition of stem-like properties. Data indicate that Wnt/beta-catenin, a key signaling pathway in intestinal stem cell (ISC) homeostasis, is activated during mucosal inflammation. However, the mechanism by which inflammatory milieu regulates Wnt/beta-catenin remains unknown. In these studies, several aspects of inflammation-mediated beta-catenin regulation were investigated: the role of 1) tumor necrosis factor 2) Nox1 and 3) PI3K in beta-catenin activation.;Using ex vivo enteroid culture, transgenic and knockout mouse models, and data from human patients, we demonstrate that TNF directly provides mitogenic signal and confers stem properties to IEC through beta-catenin signaling. Anti-TNF therapy reduced IEC proliferative response in Crohn's disease patients independent of inflammation, and blockade of TNF in IL-10-/- mice prevented dysplasia development. We discovered an opposing role of IFN-gamma which suppressed ISC gene expression and induced IEC apoptosis.;We further provide evidence for Nox1-mediated PI3K activation as a link between TNF and beta-catenin. Stem/progenitor cell (ISC/PC) isolation by CD44+ sorting revealed higher Nox1 expression in ISC/PC compared to mature cells in upper crypt. Mucosal inflammation increased Nox1 expression in a TNF-dependent manner, and Nox1-/- mice have reduced expression of ISC genes. To explore the role of PI3K in mediating beta-catenin, epithelial specific deletion of the regulatory subunit p85alpha was achieved in VilCre-p85alphaf/f mice. VilCre-p85alphaf/f mice exhibited increased mortality due to impaired epithelial regeneration.;Data suggest that inefficient anti-TNF therapy may impair mucosal healing by reducing ISC/PC activation in patients with persistent mucosal inflammation. Additionally, an attractive implication is that the early use of anti-TNF therapy in a "top-down" approach would reduce the risk of CAC. Furthermore, given that Nox1 expression is restricted to IEC within the intestine, Nox1 inhibition may be an effective therapy for reducing the risk of CAC without global immunosuppression.