Epithelial Phosphatidylinositol-3-Kinase Signaling Is Required for β-Catenin Activation and Host Defense against Citrobacter rodentium Infection
- 1 May 2011
- journal article
- Published by American Society for Microbiology in Infection and Immunity
- Vol. 79 (5), 1863-1872
- https://doi.org/10.1128/iai.01025-10
Abstract
Citrobacter rodentium infection of mice induces cell-mediated immune responses associated with crypt hyperplasia and epithelial β-catenin signaling. Recent data suggest that phosphatidylinositol-3-kinase (PI3K)/Akt signaling cooperates with Wnt to activate β-catenin in intestinal stem and progenitor cells through phosphorylation at Ser552 (P-β-catenin 552 ). Our aim was to determine whether epithelial PI3K/Akt activation is required for β-catenin signaling and host defense against C. rodentium . C57BL/6 mice were infected with C. rodentium and treated with dimethyl sulfoxide (DMSO) (vehicle control) or with the PI3K inhibitor LY294002 or wortmannin. The effects of infection on PI3K activation and β-catenin signaling were analyzed by immunohistochemistry. The effects of PI3K inhibition on host defense were analyzed by the quantification of splenic and colon bacterial clearance, and adaptive immune responses were measured by real-time PCR (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). Increased numbers of P-β-catenin 552 -stained epithelial cells were found throughout expanded crypts in C. rodentium colitis. We show that the inhibition of PI3K signaling attenuates epithelial Akt activation, the Ser552 phosphorylation and activation of β-catenin, and epithelial cell proliferative responses during C. rodentium infection. PI3K inhibition impairs bacterial clearance despite having no impact on mucosal cytokine (gamma interferon [IFN-γ], tumor necrosis factor [TNF], interleukin-17 [IL-17], and IL-1β) or chemokine (CXCL1, CXCL5, CXCL9, and CXCL10) induction. The results suggest that the host defense against C. rodentium requires epithelial PI3K activation to induce Akt-mediated β-catenin signaling and the clearance of C. rodentium independent of adaptive immune responses.Keywords
This publication has 67 references indexed in Scilit:
- Targeting the phosphoinositide 3-kinase pathway in cancerNature Reviews Drug Discovery, 2009
- β-Catenin stabilization imparts crypt progenitor phenotype to hyperproliferating colonic epitheliaExperimental Cell Research, 2009
- Somatic mutations affect key pathways in lung adenocarcinomaNature, 2008
- Comprehensive genomic characterization defines human glioblastoma genes and core pathwaysNature, 2008
- Essential roles of PI(3)K–p110β in cell growth, metabolism and tumorigenesisNature, 2008
- AKT/PKB Signaling: Navigating DownstreamCell, 2007
- High-throughput oncogene mutation profiling in human cancerNature Genetics, 2007
- The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolismNature Reviews Genetics, 2006
- Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesisNature Reviews Cancer, 2006
- The intestinal epithelial stem cellBioEssays, 2002