Tumor necrosis factor regulates intestinal epithelial cell migration by receptor-dependent mechanisms.

Corredor J, Yan F, Shen CC, Tong W, John SK, Wilson G, Whitehead R, Polk DB
Am J Physiol Cell Physiol. 2003 284 (4): C953-61

PMID: 12466150 · DOI:10.1152/ajpcell.00309.2002

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.

MeSH Terms (18)

Animals Antigens, CD Catalysis Cell Line Cell Movement Dose-Response Relationship, Drug Focal Adhesion Kinase 1 Focal Adhesion Protein-Tyrosine Kinases Intestinal Mucosa Mice Mice, Knockout Osmolar Concentration Protein-Tyrosine Kinases Receptors, Tumor Necrosis Factor Receptors, Tumor Necrosis Factor, Type I Receptors, Tumor Necrosis Factor, Type II src-Family Kinases Tumor Necrosis Factor-alpha

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