Neurotrophic factor GDNF regulates intestinal barrier function in inflammatory bowel disease
Autor: | Sven Flemming, Jens Waschke, Hanna Ungewiß, Felix Kannapin, Marco Metzger, Michael Meir, Nicolas Schlegel, Matthias Schweinlin, Christoph-Thomas Germer, Markus E. Diefenbacher, Natalie Burkard |
---|---|
Přispěvatelé: | Publica |
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Colon MAP Kinase Signaling System p38 mitogen-activated protein kinases Inflammatory bowel disease p38 Mitogen-Activated Protein Kinases Proinflammatory cytokine Pathogenesis 03 medical and health sciences Cytokeratin Mice 0302 clinical medicine Neurotrophic factors medicine Glial cell line-derived neurotrophic factor Animals Humans Glial Cell Line-Derived Neurotrophic Factor Barrier function Desmoglein 2 biology business.industry Dextran Sulfate General Medicine medicine.disease Inflammatory Bowel Diseases Disease Models Animal 030104 developmental biology nervous system 030220 oncology & carcinogenesis Cancer research biology.protein Caco-2 Cells business Research Article |
Zdroj: | The Journal of clinical investigation. 129(7) |
ISSN: | 1558-8238 |
Popis: | Impaired intestinal epithelial barrier (IEB) function with loss of desmosomal junctional protein desmoglein 2 (DSG2) is a hallmark in the pathogenesis of inflammatory bowel disease (IBD). While previous studies have reported that glial cell line-derived neurotrophic factor (GDNF) promotes IEB function, the mechanisms are poorly understood. We hypothesized that GDNF is involved in the loss of DSG2, resulting in impaired IEB function as seen in IBD. In the inflamed intestine of patients with IBD, there was a decrease in GDNF concentrations accompanied by a loss of DSG2, changes of the intermediate filament system, and increased phosphorylation of p38 MAPK and cytokeratins. DSG2-deficient and RET-deficient Caco2 cells revealed that GDNF specifically recruits DSG2 to the cell borders, resulting in increased DSG2-mediated intercellular adhesion via the RET receptor. Challenge of Caco2 cells and enteroids with proinflammatory cytokines as well as dextran sulfate sodium-induce d (DSS-induced) colitis in C57Bl/6 mice led to impaired IEB function with reduced DSG2 mediated by p38 MAPK-dependent phosphorylation of cytokeratins. GDNF blocked all inflammation-induced changes in the IEB. GDNF attenuates inflammation-induced impairment of IEB function caused by the loss of DSG2 through p38 MAPK-dependent phosphorylation of cytokeratin. The reduced GDNF in patients with IBD indicates a disease-relevant contribution to the development of IEB dysfunction. |
Databáze: | OpenAIRE |
Externí odkaz: |