De rol van de 1,25(OH)2D3 signalisatiecascade en 1,25(OH)2D3-analogen tijdens inflammatoire darmziekten

Inflammatory bowel disease (IBD) represents a group of idiopathic, chronic diseases of the gastro-intestinal tract including both Crohn’s disease (CD) and ulcerative colitis (UC). The exact etiology of IBD is still largely unknown, however, it is generally accepted that an excessive host immune response towards luminal bacteria plays a major role. A genetic predisposition, environmental factors as well as the epithelial barrier itself are also involved in the pathogenesis of IBD. Vitamin D3 deficiency is common in IBD patients, as measured by 25(OH)D serum levels. Low vitamin D3 levels are associated with a decrease in health related quality of life and with a more severe disease activity in IBD patients. Most vitamin D3 is generated in human skin under the influence of sunlight. To obtain the biologically active form 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), vitamin D3 undergoes two subsequent hydroxylations in the liver and kidneys. 1,25(OH)2D3 then binds the vitamin D receptor (VDR) that functions as a transcription factor to modulate gene expression. Both in vitro and in vivo studies have shown that 1,25(OH)2D3 can influence all major players during IBD development such as the epithelial barrier function, the immune system and bacterial composition in the gut. Moreover, systemic deletion of the Vdr in mouse models aggravates experimental colitis symptoms. 1,25(OH)2D3 treatment of experimental colitis ameliorates the IBD-associated symptoms but is hampered by its calcemic side effects when given in high doses. Therefore, vitamin D3 analogs such as TX527 have been developed that maintain their non-classical effects without eliciting calcemic side effects. In the first part of this project we investigated the effects of rectal 1,25(OH)2D3 or TX527 treatment in a model of acute experimental colitis. Moreover, by using transgenic mice with a intestinal- or myeloid-specific VDR deletion we studied the importance of VDR expression in intestinal epithelial cells and myeloid cells (macrophages and granulocytes) during intestinal inflammation. In the final part of this project, epithelial cells isolated from human non-inflamed biopsies of healthy volunteers and IBD patients were cultured with 1,25(OH)2D3 in order to investigate the effects of local 1,25(OH)2D3 on the expression of vitamin D3-metabolizing genes.status: publishe