The vitamin D analog TX527 ameliorates disease symptoms in a chemically induced model of inflammatory bowel disease

The vitamin D system plays a critical role in inflammatory bowel disease as evidenced by the finding that both vitamin D deficient mice and vitamin D receptor knockout mice are extremely sensitive to dextran sodium sulfate (DSS)-induced colitis. Moreover, the active form of vitamin D, 1 alpha,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3] is an important immunomodulator that ameliorates the pathogenesis of inflammatory bowel disease. However, therapeutic application of 1,25(OH)(2)D-3 is hampered by its calcemic activity. Previous work illustrated that the analog 1 alpha,25(OH)(2)-19-nor-14,20-bisepi-23-yne-vitamin D-3 (TX527) has potent antiproliferative effects with limited calcemic activity. In the present study we demonstrated that TX527 ameliorated disease symptoms in a DSS-induced model of inflammatory bowel disease. TX527 significantly attenuated disease scores, by suppressing bleeding and diarrhea. Colon length was significantly elevated at the end of the experiment. Histological examination indicated that TX527 diminished mucosal damage and crypt loss and suppressed the infiltration of immune cells in DSS-induced colitis mice. Furthermore, transcript levels of inflammatory cytokines such as IL-1, IL-6, IFN-gamma and TNF-alpha were significantly down-regulated in colonic mucosa of mice with colitis. Moreover, transcript levels of the gastrointestinal glutathione peroxidase 2, which acts as a radical scavenger, were significantly down-regulated after TX527 treatment in DSS-colitis mice. These results indicate that TX527 may have a therapeutic value in the setting of inflammatory bowel disease. This article is part of a Special Issue entitled 'Vitamin D Workshop'. (C) 2012 Elsevier Ltd. All rights reserved.