The amount of keratins matters for stress protection of the colonic epithelium

PLoS One. 2015 May 22;10(5):e0127436. doi: 10.1371/journal.pone.0127436. eCollection 2015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Colitis / chemically induced
  • Colitis / metabolism
  • Colon / metabolism*
  • Dextran Sulfate
  • Inflammation / metabolism
  • Intestinal Mucosa / metabolism*
  • Ion Transport / genetics
  • Keratin-7 / genetics
  • Keratin-7 / metabolism*
  • Keratin-8 / genetics
  • Keratin-8 / metabolism*
  • Mice
  • Mice, Knockout
  • Reactive Oxygen Species / metabolism

Substances

  • Keratin-7
  • Keratin-8
  • Reactive Oxygen Species
  • Dextran Sulfate

Grant support

This work was supported by funding from the Academy of Finland #140759/126161 and 266582 to DMT, http://www.aka.fi/en-GB/A/; Sigrid Juselius Foundation to DMT, http://www.sigridjuselius.fi/foundation/contact-info/; Liv och Hälsa foundation to DMT, http://www.livochhalsa.fi/; European Union Framework 7 International Reintegration Grant to DMT, http://ec.europa.eu/research/mariecurieactions/about-mca/actions/cig/index_en.htm; The Finnish Diabetes Research Foundation to DMT, http://www.diabetestutkimus.fi/en; Åbo Akademi University Center of Excellence on Cell Stress and Molecular Aging to DMT, http://www.abo.fi/fakultet/en/Content/Document/document/26585; Turku Doctoral Programme for Biomedical Sciences to MNA, http://www.tubs.utu.fi/; Åbo Akademi University Doctoral Network in Molecular Biosciences to ISKL and JSGS, http://www.abo.fi/forskning/doctoralnetworkmolecularbiosciences; Swedish Cultural foundation to IAKL, http://www.kulturfonden.fi/en/; Finnish Cultural Foundation to CA, https://www.skr.fi/en; and Victoriastiftelsen-foundation to TOH, http://victoriastiftelsen.fi/start/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.