The Amount of Keratins Matters for Stress Protection of the Colonic Epithelium |
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Authors: | M. Nadeem Asghar Jonas S. G. Silvander Terhi O. Helenius Iris A. K. L?hdeniemi Catharina Alam Lina E. Fortelius Rickard O. Holmsten Diana M. Toivola |
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Affiliation: | Cell Biology, Biosciences, Faculty of Science and Engineering, Åbo Akademi University, and Turku Center for Disease Modeling, Turku, Finland;RWTH Aachen, GERMANY |
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Abstract: | Keratins (K) are important for epithelial stress protection as evidenced by keratin mutations predisposing to human liver diseases and possibly inflammatory bowel diseases. A role for K8 in the colon is supported by the ulcerative colitis-phenotype with epithelial hyperproliferation and abnormal ion transport in K8-knockout (K8−/−) mice. The heterozygote knockout (K8+/−) colon appears normal but displays a partial ion transport-defect. Characterizing the colonic phenotype we show that K8+/− colon expresses ~50% less keratins compared to K8 wild type (K8+/+) but de novo K7 expression is observed in the top-most cells of the K8+/− and K8−/− crypts. The K8+/− colonic crypts are significantly longer due to increased epithelial hyperproliferation, but display no defects in apoptosis or inflammation in contrast to K8−/−. When exposed to colitis using the dextran sulphate sodium-model, K8+/− mice showed higher disease sensitivity and delayed recovery compared to K8+/+ littermates. Therefore, the K8+/− mild colonic phenotype correlates with decreased keratin levels and increased sensitivity to experimental colitis, suggesting that a sufficient amount of keratin is needed for efficient stress protection in the colonic epithelia. |
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