Original ResearchFull Report: Basic and Translational—Alimentary TractTNFR2 Activates MLCK-Dependent Tight Junction Dysregulation to Cause Apoptosis-Mediated Barrier Loss and Experimental Colitis
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Mice and Colitis Models
All experiments used C57BL/6 mice bred and maintained at the University of Chicago in accordance with Institutional Animal Care and Use Committee regulations. CD4+CD45RBhi and dextran sulfate sodium (DSS) colitis was induced in 6- to 8-week-old mice as described previously.1 For adoptive transfer colitis, CD4+ splenocytes were isolated using magnetic-activated cell sorting beads (Miltenyi Biotec, Bergisch Gladbach, Germany) and enriched for CD45RBhi lymphocytes using a MoFlo Cell Sorter
CD4+CD45RBhi Adoptive Transfer Colitis Induces Changes in Tight Junction Protein Expression and Organization That Are Similar to Human IBD
Recent studies have shown that ileal and colonic epithelial long MLCK expression and activity as well as claudin-2 expression are increased in human ulcerative colitis and Crohn’s disease.12, 13 Immunofluorescence analysis confirmed increased long MLCK expression and activity, measured as increased myosin light chain (MLC) phosphorylation, increased claudin-2 expression, and occludin endocytosis in ileal enterocytes during CD4+CD45RBhi-induced disease (Figure 1A). As expected, similar changes
Discussion
Increased intestinal permeability has been linked to a variety of autoimmune and inflammatory disorders. The case is strongest in Crohn’s disease, where reduced barrier function is a marker of impending disease reactivation.22 However, increased intestinal permeability is also increased in ulcerative colitis.23 Despite this association, intestinal barrier loss alone is insufficient to cause disease in either animal models or human subjects.1, 2, 3, 24 Nevertheless, intestinal barrier defects do
Acknowledgments
The authors thank Drs Cathryn Nagler and Warren Strober for insightful discussions and advice.
References (40)
- et al.
Targeted epithelial tight junction dysfunction causes immune activation and contributes to development of experimental colitis
Gastroenterology
(2009) - et al.
Unique role of junctional adhesion molecule-a in maintaining mucosal homeostasis in inflammatory bowel disease
Gastroenterology
(2008) - et al.
Epithelial barrier defects in ulcerative colitis: characterization and quantification by electrophysiological imaging
Gastroenterology
(2001) - et al.
Antibodies against tumor necrosis factor (TNF) induce T-cell apoptosis in patients with inflammatory bowel diseases via TNF receptor 2 and intestinal CD14(+) macrophages
Gastroenterology
(2011) - et al.
IFN-gamma-induced TNFR2 expression is required for TNF-dependent intestinal epithelial barrier dysfunction
Gastroenterology
(2006) - et al.
Role of tumor necrosis factor receptor 2 (TNFR2) in colonic epithelial hyperplasia and chronic intestinal inflammation in mice
Gastroenterology
(2002) - et al.
Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution
Gastroenterology
(2005) - et al.
Epithelial myosin light chain kinase expression and activity are upregulated in inflammatory bowel disease
Lab Invest
(2006) - et al.
Dedicated myosin light chain kinases with diverse cellular functions
J Biol Chem
(2001) - et al.
A differentiation-dependent splice variant of myosin light chain kinase, MLCK1, regulates epithelial tight junction permeability
J Biol Chem
(2004)
Intestinal permeability and the prediction of relapse in Crohn's disease
Lancet
The sugar permeability test reflects disease activity in children and adolescents with inflammatory bowel disease
J Pediatr
A membrane-permeant peptide that inhibits MLC kinase restores barrier function in invitro models of intestinal disease
Gastroenterology
LIGHT signals directly to intestinal epithelia to cause barrier dysfunction via cytoskeletal and endocytic mechanisms
Gastroenterology
Epithelial myosin light chain kinase activation induces mucosal interleukin-13 expression to alter tight junction ion selectivity
J Biol Chem
Endoscopic and histological healing with infliximab anti-tumor necrosis factor antibodies in Crohn's disease: a European multicenter trial
Gastroenterology
Infliximab as rescue therapy in severe to moderately severe ulcerative colitis: a randomized, placebo-controlled study
Gastroenterology
TNF receptor type I-dependent activation of innate responses to reduce intestinal damage-associated mortality
Gastroenterology
Distinct temporal-spatial roles for rho kinase and myosin light chain kinase in epithelial purse-string wound closure
Gastroenterology
JAM-A regulates permeability and inflammation in the intestine in vivo
J Exp Med
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Author names in bold designate shared co-first authorship.
Conflicts of interest The authors disclose no conflicts.
Funding Supported by the National Institutes of Health (R01DK61931, R01DK68271, P01D067887, P30DK042086, P30CA14599, UL1RR024999, T32HL007237, K01DK09238, R01DK77905), Department of Defense (W81XWH-09-1-0341), the Broad Medical Research Foundation (IBD-022), the Crohn’s and Colitis Foundation of America, the Chicago Biomedical Consortium (with support from The Searle Funds at The Chicago Community Trust), and the National Natural Science Foundation of China (30900670, 81272749).
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Authors share co-first authorship.