Tumor necrosis factor regulates intestinal epithelial cell migration by receptor-dependent mechanisms.
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.
Corredor
Julissa
J
Department of Pediatrics, Division of Gastroenterology and Nutrition, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2576, USA.
Yan
Fang
F
Shen
Christopher C
CC
Tong
Wei
W
John
Sutha K
SK
Wilson
Guinn
G
Whitehead
Robert
R
Polk
D Brent
DB
D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D002384:Catalysis; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D007413:Intestinal Mucosa / Q000166:cytology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D009994:Osmolar Concentration; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000502:physiology*; D019061:src-Family Kinases / Q000378:metabolism
D015703:Antigens, CD; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496051:Ptk2 protein, mouse; D019061:src-Family Kinases