Keratins (K) are
intermediate filament proteins important in protection from cellular stress. K8,
K18 and K19 are the main components of
keratin filaments in colonic epithelia but their role in
intestinal diseases remains ambiguous. A function for
keratins in intestinal health is supported by the K8-knock-out (K8(-/-)) mouse which manifests an early chronic
ulcerative colitis-like
inflammatory bowel disease and epithelial hyperproliferation. We tested whether K8(-/-) mice are more susceptible to
colorectal cancer (CRC) compared to K8 wild type (K8(+/+)), and K8 heterozygote (K8(+/-)) mice showing increased proliferation but no
inflammation. K8(-/-) mice did not develop CRC spontaneously, but had dramatically increased numbers of
tumors in the distal colon in the
azoxymethane (AOM) and Apc(Min/+) CRC models while neither K8(+/+) nor K8(+/-) mice were susceptible. Upregulation of
IL-22 in combination with a complete loss of its negative regulator IL-22BP, and increased downstream STAT3-signaling in K8(-/-) and K8(-/-)Apc(Min/+) colonic epithelia confirmed that the
IL-22 pathway, important in
inflammation, proliferation and tissue regeneration, was activated. The nearly total loss of IL-22BP correlated with an activated
inflammasome leading to increased cleaved caspase-1, and the putative IL-22BP inhibitor,
IL-18, as well as a decrease in ALDH1/2. Ablation of K8 in a
colorectal cancer cell line similarly resulted in increased
IL-18 and decreased ALDH1/2. K8/
K18 co-immunoprecipitated with
pro-caspase-1, a component of the
inflammasome in the colon, which suggests that
keratins modulate
inflammasome activity and protect the colon from
inflammation and
tumorigenesis. The K8-null mouse models also provide novel epithelial-derived robust colon-specific CRC models.