1,25(OH)(2)D(3) Deficiency Induces Colon Inflammation via Secretion of Senescence-Associated Inflammatory Cytokines

Epidemiological studies showed that 1,25-Dihydroxyvitamin D[1,25(OH)(2)D(3)] insufficiency appears to be associated with aging and colon cancer while underlying biological mechanisms remain largely unknown. Inflammatory bowel disease is one of the risk factors for colon cancer. In this study, we investigated whether 1,25(OH)(2)D(3) deficiency has an impact on the colon of 25-hydroxyvitamin D 1α-hydroxylase knockout [Cyp27b1(−/−)] mice fed on a rescue diet (high calcium, phosphate, and lactose) from weaning to 10 months of age. We found that 1,25(OH)(2)D(3) deficient mice displayed significant colon inflammation phenotypes including shortened colon length, thinned and disordered mucosal structure, and inflammatory cell infiltration. DNA damage, cellular senescence and the production of senescence-associated inflammatory cytokines were also increased significantly in the colon of Cyp27b1(−/−)mice. Furthermore, the levels of ROS in the colon were increased significantly, whereas the expression levels of antioxidative genes were down-regulated dramatically in the colon of Cyp27b1(−/−)mice. Taken together, our results demonstrated that 1,25(OH)(2)D(3) deficiency could induce colon inflammation, which may result from increased oxidative stress and DNA damage, subsequently, induced cell senescence and overproduction of senescence-associated secretory factors. Therefore, our findings suggest that 1,25(OH)(2)D(3) may play an important role in preventing the development and progression of colon inflammation and colon cancer.