Enterocyte STAT5 promotes mucosal wound healing via suppression of myosin light chain kinase-mediated loss of barrier function and inflammation.

Abstract

Epithelial myosin light chain kinase (MLCK)-dependent barrier dysfunction contributes to the pathogenesis of inflammatory bowel diseases (IBD). We reported that epithelial GM-CSF-STAT5 signalling is essential for intestinal homeostatic response to gut injury. However, mechanism, redundancy by STAT5 or cell types involved remained foggy. We here generated intestinal epithelial cell (IEC)-specific STAT5 knockout mice, these mice exhibited a delayed mucosal wound healing and dysfunctional intestinal barrier characterized by elevated levels of NF-κB activation and MLCK, and a reduction of zonula occludens expression in IECs. Deletion of MLCK restored intestinal barrier function in STAT5 knockout mice, and facilitated mucosal wound healing. Consistently, knockdown of stat5 in IEC monolayers led to increased NF-κB DNA binding to MLCK promoter, myosin light chain phosphorylation and tight junction (TJ) permeability, which were potentiated by administration of tumour necrosis factor-α (TNF-α), and prevented by concurrent NF-κB knockdown. Collectively, enterocyte STAT5 signalling protects against TJ barrier dysfunction and promotes intestinal mucosal wound healing via an interaction with NF-κB to suppress MLCK. Targeting IEC STAT5 signalling may be a novel therapeutic approach for treating intestinal barrier dysfunction in IBD.

• Authors: Shila Gilbert, Rongli Zhang, Lee Denson, Richard Moriggl, Kris Steinbrecher, Noah Shroyer, James Lin, Xiaonan Han
• Journal: EMBO molecular medicine (EMBO Mol Med) Vol. 4 Issue 2 Pg. 109-24 (Feb 2012) ISSN: 1757-4684 [Electronic] England
• PMID: 22228679 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 EMBO Molecular Medicine.

Chemical References

• STAT5 Transcription Factor
• Tumor Necrosis Factor-alpha
• Myosin-Light-Chain Kinase

Topics

• Animals
• Epithelial Cells (metabolism)
• Female
• Immunohistochemistry
• Inflammation (metabolism)
• Intestinal Mucosa (metabolism)
• Male
• Mice
• Mice, Knockout
• Myosin-Light-Chain Kinase (genetics, metabolism)
• STAT5 Transcription Factor (genetics, metabolism)
• Tumor Necrosis Factor-alpha (genetics, metabolism)
• Wound Healing