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

Shila Gilbert; Rongli Zhang; Lee Denson; Richard Moriggl; Kris Steinbrecher; Noah Shroyer; James Lin; Xiaonan Han

doi:10.1002/emmm.201100192

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

Journal article

Peer reviewed

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

Shila Gilbert, Rongli Zhang, Lee Denson, Richard Moriggl, Kris Steinbrecher, Noah Shroyer, James Lin and Xiaonan Han

EMBO molecular medicine, Vol.4(2), pp.109-124

02/2012

DOI: 10.1002/emmm.201100192

PMID: 22228679

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Abstract

Epithelial myosin light chain kinase (MLCK)-dependent barrier dysfunction contributes to the pathogenesis of inflammatory bowel diseases (IBD). We reported that epithelial GM-CSFSTAT5 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-?B 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-?B DNA binding to MLCK promoter, myosin light chain phosphorylation and tight junction (TJ) permeability, which were potentiated by administration of tumour necrosis factor-a (TNF-a), and prevented by concurrent NF-?B knockdown. Collectively, enterocyte STAT5 signalling protects against TJ barrier dysfunction and promotes intestinal mucosal wound healing via an interaction with NF-?B to suppress MLCK. Targeting IEC STAT5 signalling may be a novel therapeutic approach for treating intestinal barrier dysfunction in IBD.

Life Sciences & Biomedicine

Medicine, Research & Experimental

Research & Experimental Medicine

Science & Technology

Details

Title: Subtitle: Enterocyte STAT5 promotes mucosal wound healing via suppression of myosin light chain kinase-mediated loss of barrier function and inflammation
Creators: Shila Gilbert - Cincinnati Children's Hospital Medical Center
Rongli Zhang - Peking University
Lee Denson - Cincinnati Children's Hospital Medical Center
Richard Moriggl - Ludwig Boltzmann Institute for Cancer Research
Kris Steinbrecher - Cincinnati Children's Hospital Medical Center
Noah Shroyer - Cincinnati Children's Hospital Medical Center
James Lin - Cincinnati Children's Hospital Medical Center
Xiaonan Han - Cincinnati Children's Hospital Medical Center
Resource Type: Journal article
Publication Details: EMBO molecular medicine, Vol.4(2), pp.109-124
DOI: 10.1002/emmm.201100192
PMID: 22228679
ISSN: 1757-4676
eISSN: 1757-4684
Publisher: Wiley
Number of pages: 16
Grant note: KL2 RR026315 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA SFB F28 / Austrian Science Funds (FWF); Austrian Science Fund (FWF) University of California, Los Angeles; University of California System Crohns and Colitis Foundation of America Cincinnati Children's Hospital Medical Center (CCHMC) P30 DK078392 / Cincinnati Children's Hospital Research Foundation Digestive Health Center (PHS); United States Department of Health & Human Services; United States Public Health Service F 2807 / Austrian Science Fund (FWF)
Language: English
Date published: 02/2012
Academic Unit: Orthopedics and Rehabilitation
Record Identifier: 9985237500702771

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