Basic–alimentary tractIFN-γ-Induced TNFR2 Expression Is Required for TNF-Dependent Intestinal Epithelial Barrier Dysfunction
Section snippets
CD4+CD45RBhi-Adoptive Transfer
C57BL/6 and RAG1−/− mice were obtained from Jackson Laboratories (Bar Harbor, ME) and maintained in a specific pathogen-free facility. All experiments were carried out in accordance with National Institutes of Health guidelines under protocols approved by the Institutional Animal Care and Use Committee at the University of Chicago. CD4+CD45RBhi lymphocytes were isolated from C57BL/6 splenocytes using a MO-FLO sorter (Dako, Carpinteria, CA) after staining with allophycocyanin-conjugated anti-CD4
Experimental Immune-Mediated Inflammatory Bowel Disease Is Associated With Increased MLCK Expression, Increased MLC Phosphorylation, and Tight Junction Disruption In Vivo
Several studies using in vitro2, 5, 18 and acute in vivo4 models have shown that MLCK-mediated MLC phosphorylation is central to TNF-induced epithelial tight junction disruption and barrier dysfunction. In the setting of chronic disease, it has recently been reported that intestinal epithelial MLCK expression and MLC phosphorylation are increased in patients with active inflammatory bowel disease and that the magnitude of these changes correlates with the grade of disease activity.6 However,
Discussion
Compromised intestinal barrier function is a common feature of inflammatory, infectious, ischemic, and immune-mediated intestinal disease,35 and abundant data suggest that compromised intestinal barrier function may be a critical pathogenic event in these processes.36, 37, 38, 39, 40 For example, in patients with inactive Crohn’s disease, barrier loss predicts disease reactivation.41, 42 The degree of barrier dysfunction also parallels expression of activation markers on circulating lymphocytes.
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Supported by the National Institutes of Health (DK61931 and DK68271), the Crohn’s Colitis Foundation of America, The University of Chicago Digestive Disease Center (DK42086), and The University of Chicago Cancer Center (CA14599).
- 1
F.W. and B.T.S. contributed equally to this work.