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Toll-like Receptor-4 Inhibits Enterocyte Proliferation via Impaired Beta-catenin Signaling in Necrotizing Enterocolitis

Necrotizing Enterocolitis (NEC) is characterized by impaired enterocyte migration through unknown mechanisms and exaggerated TLR4 signaling. In many cell types, proliferation is regulated through the beta-catenin signaling pathway. We have demonstrated that TLR4 activation in our murine NEC model and in intestinal epithelial cells (IEC6) significantly impairs enterocyte migration. We demonstrated that TLR4 activation phosphorylates the upstream inhibitory kinase GSK-3beta and causes beta catenin degradation. Strikingly, the inhibition of enterocyte beta-catenin signaling in NEC could be reversed, and enterocyte proliferation can be restored via an adenoviral-mediated inhibition of TLR4 in the intestinal mucosa.
 
As shown above, inhibition of enterocyte TLR4 signaling in mice with NEC restores enterocyte proliferation and reverses the changes in _-catenin andGSK3_ expression. (A to C) Newborn mice were either breast fed (black bars) or were induced to develop NEC and administered adenoviruses expressing GFP (dark gray bars), GFP–wild-type TLR4 (white bars), or GFP–dominant-negative TLR4 by enteral gavage (gray bars). The expression by quantitative RT-PCR of pCNA (A), _-catenin (B), and GSK3_ (C) in mucosal scrapings in each group is shown; *P _ .005 versus breast-fed mice,**P _ .001 versus both NEC mice administered adeno-GFP and adeno-GFP–wild-type-TLR4, ANOVA. Representative of 5 separate experiments with _5 mice per group (Di–v) Confocal micrographs showing GFP (green), actin (red), and nuclei (blue) in untreated (“control”) mice or mice treated by gavage with the indicated adenovirus. (v) RT-PCR of pCNA in TLR4 mutant mice that were administered GFP (dark gray bars), GFP–wild-type TLR4 (white bars), GFP–dominant-negative TLR4 (gray bars) or control (black bars) and LPS as indicated. Representative of 3 separate experiments.
 
 
Schematic showing mechanism by which TLR4 inhibits enterocyte proliferation.
 
Authors
Sodhi CP, Shi XH, Richardson WM, Grant ZS, Shapiro RA, Prindle T Jr, Branca M, Russo A, Gribar SC, Ma C, Hackam DJ
Gastroenterology
2009 Sep 25
 
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Last Update
January 22, 2011
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Last Update
January 22, 2011
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