The Amount of Keratins Matters for Stress Protection of the Colonic Epithelium

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 similar to 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.