Abstract
Wnt 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 β-catenin and cell proliferation. We reasoned that in vivo inhibition of GSK-3β might prevent intestinal mucosal injury under inflammatory conditions. 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. 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. Wnt/β-catenin driven epithelial cell survival may serve as a novel target for the treatment of IBD. (This work was supported by grants from the German Research Foundation – La 2359/1-1 and the NIH – DK-55679, DK-61379).
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Laukötter, M. et al. (2010). GSK-3-beta-Inhibierung lindert den Verlauf einer experimentellen DSS-Colitis in vivo . In: Gradinger, R., Menger, M., Meyer, HJ. (eds) Chirurgisches Forum und DGAV Forum 2010. Deutsche Gesellschaft für Chirurgie, vol 39. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-12192-0_88
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DOI: https://doi.org/10.1007/978-3-642-12192-0_88
Publisher Name: Springer, Berlin, Heidelberg
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