Efficacy of a potent and safe vitamin D receptor agonist for the treatment of inflammatory bowel disease

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• 作者：Gilles Laverny ; Giuseppe Penna ; Stefania Vetrano ; Carmen Correale ; Manuela Nebuloni ; Silvio Danese ; Luciano Adorini
• 关键词：Inflammatory bowel disease ; Vitamin D ; VDR ; TLR ; Colitis ; LPMC
• 刊名：Immunology Letters
• 出版年：2010
• 出版时间：15 June 2010
• 年：2010
• 卷：131
• 期：1
• 页码：49-58
• 全文大小：1356 K

文摘

Deficiency in 1α,25-dihydroxyvitamin D₃ (1,25D₃) has been suggested as an important environmental factor for immuno-mediated disorders including inflammatory bowel diseases (IBD), comprising Crohn's disease and ulcerative colitis, both characterized by chronic intestinal inflammation. Administration of vitamin D receptor (VDR) agonists can ameliorate spontaneous and induced animal models of colitis, but hypercalcemia is a dose-limiting adverse event. Previous work in our laboratory has identified 1α,25(OH)₂-16-ene-20-cyclopropyl-vitamin D₃ (BXL-62) as a potent anti-inflammatory VDR agonist with a low calcemic activity. In the present study, we confirm the marked anti-inflammatory properties of BXL-62 and show its capacity to induce VDR primary response genes, like CYP24A1 and CAMP, at lower concentrations than 1,25D₃, in PBMCs from IBD patients. Its higher anti-inflammatory potency compared to 1,25D₃ was demonstrated by the significantly more potent inhibition in PBMCs and in lymphocyte-enriched lamina propria mononuclear cells of the pro-inflammatory cytokines TNF-α, IL-12/23p40, IL-6 and IFN-γ, both at mRNA and protein level. The therapeutic efficacy of intra-rectal administration of BXL-62 in experimental IBD is shown by its beneficial effects, significantly higher than 1,25D₃, to induce recovery of clinical symptoms of colitis at normocalcemic doses in mice undergoing dextran sodium sulfate-induced colitis. These results confirm the therapeutic efficacy of VDR agonists in experimental colitis, and suggest BXL-62 as a promising compound for IBD treatment.