Article
GSK-3-beta inhibition ameliorates the course of experimental DSS-colitis in vivo
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Authors
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Mike Georg Laukötter
- Universitätsklinikum Münster, Klinik und Poliklinik für Allgemein- und Viszeralchirurgie, Münster, Deutschland
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Porfirio Nava
- Emory University, Epithelial Pathobiology Research Unit, Department of Pathology, Atlanta, GA, USA
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Charles A. Parkos
- Emory University, Epithelial Pathobiology Research Unit, Department of Pathology, Atlanta, GA, USA
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Asma Nusrat
- Emory University, Epithelial Pathobiology Research Unit, Department of Pathology, Atlanta, GA, USA
| Published: | May 17, 2010 |
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Outline
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Introduction: Intestinal barrier function is maintained by epithelial cell proliferation which is regulated by Wnt/β-catenin signaling. This canonical pathway acts through stabilization of β-catenin. In absence of Wnt, β-catenin is constantly phosphorylated by a destruction protein complex mainly consisting of glycogen synthase kinase-3β (GSK-3β). GSK-3β inhibition leads to nuclear translocation of ß-catenin and cell proliferation. We reasoned that in vivo inhibition of GSK-3β might prevent intestinal mucosal injury under inflammatory conditions.
Material and methods: Animals: C57BL/6 mice (n=10/group) were treated with 5% DSS and either the GSK-3β inhibitor (i.p.) or vehicle for 7 days, and inflammation was assessed using an established disease activity index which included daily clinical assessment of body weight, evaluation of stool consistency, and the presence of blood in the stools by a guaiac paper test. Tissue: MPO was measured in tissue from proximal to distal colon. For each animal, histological examination was performed on three samples of the distal colon. The quantification was performed in a blinded fashion using modified validated scoring systems. Alternatively, tissue samples for immunohistochemistry were snap-frozen in liquid nitrogen, and stored at –80°C.
Results: Administration of the GSK-3β inhibitor significantly reduced the disease activity index in DSS treated mice (DAI, 1.6±0.18 vs. 3.6±0.05 points on day 7, * P<0.05), but did not influence mucosal MPO activity (58.3±4.0 mU/mg vs.62.8±2.9 mU/mg tissue enzyme activity). Histologic score, which includes severity of inflammation, depth of injury, crypt damage, submucosal edema and infiltration of polymorphonuclear granulocytes in the lamina propria of DSS treated animals was significantly improved in the presence of the GSK-3β inhibitor. Ulceration and inflammation observed in DSS treated mice were significantly improved in mice co-administered the GSK-3β inhibitor.
Schlussfolgerung: Wnt/β-catenin driven epithelial cell survival may serve as a novel target for the treatment of IBD.
(This work was supported by a grant from the German Research Foundation (Deutsche Forschungsgemeinschaft-La 2359/1-1 to M.G.L.))
