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1.
J Clin Invest ; 114(9): 1272-80, 2004 Nov.
Article in English | MEDLINE | ID: mdl-15520859

ABSTRACT

TNF plays a pathogenic role in inflammatory bowel diseases (IBDs), which are characterized by altered cytokine production and increased intestinal epithelial cell apoptosis. In vitro studies suggest that kinase suppressor of Ras-1 (KSR1) is an essential regulatory kinase for TNF-stimulated survival pathways in intestinal epithelial cell lines. Here we use a KSR1-deficient mouse model to study the role of KSR1 in regulating intestinal cell fate during cytokine-mediated inflammation. We show that KSR1 and its target signaling pathways are activated in inflamed colon mucosa. Loss of KSR1 increases susceptibility to chronic colitis and TNF-induced apoptosis in the intestinal epithelial cell. Furthermore, disruption of KSR1 expression enhances TNF-induced apoptosis in mouse colon epithelial cells and is associated with a failure to activate antiapoptotic signals including Raf-1/MEK/ERK, NF-kappaB, and Akt/protein kinase B. These effects are reversed by WT, but not kinase-inactive, KSR1. We conclude that KSR1 has an essential protective role in the intestinal epithelial cell during inflammation through activation of cell survival pathways.


Subject(s)
Apoptosis , Cytokines/metabolism , Inflammation/pathology , Intestinal Mucosa/pathology , Protein Kinases/physiology , Animals , Blotting, Western , Caspase 3 , Caspases/metabolism , Cell Line, Tumor , Cell Nucleus/metabolism , Cell Survival , Colon/pathology , Epithelial Cells/cytology , Genetic Predisposition to Disease , Immunohistochemistry , Immunoprecipitation , In Situ Nick-End Labeling , Intestines/cytology , Mice , Mice, Inbred BALB C , Mice, Transgenic , Platelet Endothelial Cell Adhesion Molecule-1/biosynthesis , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-akt , Signal Transduction , Time Factors
2.
Am J Physiol Cell Physiol ; 284(4): C953-61, 2003 Apr.
Article in English | MEDLINE | ID: mdl-12466150

ABSTRACT

Altered mucosal integrity and increased cytokine production, including tumor necrosis factor (TNF), are the hallmarks of inflammatory bowel disease (IBD). In this study, we addressed the role of TNF receptors (TNFR) on intestinal epithelial cell migration in an in vitro wound closure model. With mouse TNFR1 or TNFR2 knockout intestinal epithelial cells, gene transfection, and pharmacological inhibitors, we show a concentration-dependent receptor-mediated regulation of intestinal cell migration by TNF. A physiological TNF level (1 ng/ml) enhances migration through TNFR2, whereas a pathological level (100 ng/ml) inhibits wound closure through TNFR1. Increased rate of wound closure by TNFR2 or inhibition by TNFR1 cannot be explained by either increased proliferation or apoptosis, respectively. Furthermore, inhibiting Src tyrosine kinase decreases TNF-induced focal adhesion kinase (FAK) tyrosine phosphorylation and cellular migration. We therefore conclude that TNFR2 activates a novel Src-regulated pathway involving FAK tyrosine phosphorylation that enhances migration of intestinal epithelial cells.


Subject(s)
Antigens, CD/physiology , Intestinal Mucosa/physiology , Receptors, Tumor Necrosis Factor/physiology , Tumor Necrosis Factor-alpha/physiology , Animals , Catalysis , Cell Line , Cell Movement/drug effects , Cell Movement/physiology , Dose-Response Relationship, Drug , Focal Adhesion Kinase 1 , Focal Adhesion Protein-Tyrosine Kinases , Intestinal Mucosa/cytology , Mice , Mice, Knockout/genetics , Osmolar Concentration , Protein-Tyrosine Kinases/metabolism , Receptors, Tumor Necrosis Factor, Type I , Receptors, Tumor Necrosis Factor, Type II , Tumor Necrosis Factor-alpha/administration & dosage , src-Family Kinases/metabolism
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