title: The vitamin D analog TX527 ameliorates disease symptoms in a chemically induced model of inflammatory bowel disease.
abstract: 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, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] is an important immunomodulator that ameliorates the pathogenesis of inflammatory bowel disease. However, therapeutic application of 1,25(OH)2D3 is hampered by its calcemic activity. Previous work illustrated that the analog 1α,25(OH)2-19-nor-14,20-bisepi-23-yne-vitamin D3 (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-γ and TNF-α 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'.
authors.affiliation: Laboratorium voor Klinische en Experimentele Endocrinologie, KU Leuven, Herestraat 49, bus 902, 3000 Leuven, Belgium. lieve.verlinden@med.kuleuven.be
authors.forename: Lieve
authors.initials: L
authors.lastname: Verlinden
authors.forename: Carlien
authors.initials: C
authors.lastname: Leyssens
authors.forename: Ine
authors.initials: I
authors.lastname: Beullens
authors.forename: Suzanne
authors.initials: S
authors.lastname: Marcelis
authors.forename: Chantal
authors.initials: C
authors.lastname: Mathieu
authors.forename: Pierre
authors.initials: P
authors.lastname: De Clercq
authors.forename: Annemieke
authors.initials: A
authors.lastname: Verstuyf
mesh_terms: D000480:Alkynes / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000097:blood; D002762:Cholecalciferol / Q000494:pharmacology*; D003092:Colitis / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D016207:Cytokines / Q000235:genetics; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D005979:Glutathione Peroxidase / Q000235:genetics; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress / Q000187:drug effects
chemical_list: D000480:Alkynes; D016207:Cytokines; C409043:inecalcitol; D002762:Cholecalciferol; D016264:Dextran Sulfate; C492172:Gpx2 protein, mouse; D005979:Glutathione Peroxidase; D002118:Calcium