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Analyzing Beneficial Effects of Nutritional Supplements on Intestinal Epithelial Barrier Functions During Experimental Colitis
Published on: January 5, 2017
Activated notch signaling pathway protects the intestinal barrier in DSS-induced colitis by regulating tight
Tingting Li1,2, Chong Geng3, Xiao Li2
1Department of Gastroenterology, First Affiliated Hospital of Soochow University, Suzhou, China.
Background And Aims:
Studies have suggested that the activation of Notch pathway may provide protection to the intestinal mucosal barrier. However, the underlying mechanism remains to be elucidated.
Methods:
In vivo experiments, the dextran sulfate sodium (DSS)-induced colitis mice were used and LY411,575, a γ-secretase inhibitor, was orally administered for Notch signaling inhibition. In vitro experiments, we modulated Notch signaling by either activating or inhibiting it through the overexpression of Hes1 or LY411,575, respectively. The tight junction (TJ) and relevant myosin light chain kinase (MLCK) pathway were systematically investigated. To elucidate the mechanism underlying Notch activation, we conducted a comprehensive analysis of ligands and receptors associated with the Notch pathway in Caco-2 cells.
Results:
Compared to DSS-colitis mice, inhibition of Notch activation by LY411,575 led to severe exacerbation of colitis, accompanied by TJ deterioration and concurrent activation of MLCK pathway. In vitro experiments confirmed the Notch signaling's regulatory effect on TJ function, with MLCK inhibitor ML-7 effectively mitigating the TJ dysfunction induced by LY411,575. Additionally, TNF-α-treated Caco-2 cells exhibited significantly increased expression of Jag1, Notch1, and Hes1. Silencing Jag1 using siRNA resulted in reduced NICD1 and Hes1 expression.
Conclusions:
Activation of Jag1/Notch1/Hes1 signaling pathway protects the intestinal mucosal barrier from inflammatory injury by abrogating MLCK-dependent TJ dysregulation.
Insights
The Notch pathway protects the intestinal barrier by regulating tight junctions (TJ) and the myosin light chain kinase (MLCK) pathway. Activating Jag1/Notch1/Hes1 signaling prevents inflammatory injury and TJ dysfunction.
Area of Science:
- Gastroenterology
- Cell Biology
- Immunology
Background:
- The Notch pathway's role in intestinal mucosal barrier protection is suggested but not fully understood.
- Elucidating the molecular mechanisms is crucial for understanding inflammatory bowel diseases.
Purpose of the Study:
- To investigate the protective mechanism of Notch pathway activation on the intestinal mucosal barrier.
- To determine the relationship between Notch signaling, tight junctions, and the MLCK pathway.
Main Methods:
- Utilized dextran sulfate sodium (DSS)-induced colitis mouse models and Caco-2 cell cultures.
- Inhibited Notch signaling with LY411,575 and activated it via Hes1 overexpression.
- Analyzed tight junction integrity and myosin light chain kinase (MLCK) pathway activation.
- Investigated Notch ligands and receptors in TNF-α-treated Caco-2 cells.
Main Results:
- Notch inhibition exacerbated colitis, TJ deterioration, and MLCK activation in vivo.
- In vitro, Notch signaling regulated TJ function; MLCK inhibition (ML-7) ameliorated LY411,575-induced TJ dysfunction.
- TNF-α increased Jag1, Notch1, and Hes1 expression; Jag1 silencing reduced NICD1 and Hes1.
Conclusions:
- The Jag1/Notch1/Hes1 signaling pathway protects the intestinal mucosal barrier against inflammatory injury.
- This protection is achieved by preventing MLCK-dependent tight junction dysregulation.
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