The active form of vitamin D (1,25D3) suppressed the development of animal models of human autoimmune diseases including experimental inflammatory bowel disease (IBD). The vitamin D receptor (VDR) is required for all known biologic effects of vitamin D. Here we show that VDR deficiency (knockout, KO) resulted in severe inflammation of the gastrointestinal tract in two different experimental models of IBD. In the CD45RB transfer model of IBD, CD4+/CD45RBhigh T cells from VDR KO mice induced more severe colitis than wild-type CD4+/CD45RBhigh T cells. The second model of IBD used was the spontaneous colitis that develops in IL-10 KO mice. VDR/IL-10 double KO mice developed accelerated IBD and 100% mortality by 8 wk of age. At 8 wk of age, all of the VDR and IL-10 single KO mice were healthy. Rectal bleeding was observed in every VDR/IL-10 KO mouse. Splenocytes from the VDR/IL-10 double KO mice cells transferred IBD symptoms. The severe IBD in VDR/IL-10 double KO mice is a result of the immune system and not a result of altered calcium homeostasis, or gastrointestinal tract function. The data establishes an essential role for VDR signaling in the regulation of inflammation in the gastrointestinal tract.

Vitamin D is a potent immune system regulator. The active form of vitamin D (1,25(OH)(2)D(3)) suppresses the development of animal models of human autoimmune diseases. 1,25(OH)(2)D(3) decreased the proliferation of all T helper (h) cells and decreased the production of IFN-gamma, IL-2, and IL-5. In Th2 cells 1,25(OH)(2)D(3) increased the production of IL-4. Quiescent CD4+ T cells express vitamin D receptors but only at a low level, which increased five-fold following activation. 1,25(OH)(2)D(3) treatment of Th0 cells, but not Th1 or Th2 cells, induced the expression of the transcription factor GATA-3. Microarray technology identified over 102 targets of 1,25(OH)(2)D(3) in CD4+ T cells. Of the 102 genes, 57 genes were down-regulated and 45 were up-regulated by 1,25(OH)(2)D(3) treatment of the CD4+ T cells. Two of the identified genes are regulators of NFkB. Other genes of interest included the IL-2Rbeta gene and IgE binding factor. Th2 and Th0 cells produced more IgE binding factor after treatment with 1,25(OH)(2)D(3) while Th1 cell IgE binding factor expression was unaffected by 1,25(OH)(2)D(3) addition. It is unclear why some of the genes identified are expressed in CD4+ T cells and furthermore why 1,25(OH)(2)D(3) regulates the expression of these genes. Clearly CD4+ T cells can be direct targets of vitamin D. The targets of vitamin D in CD4+ T cells depend on the state of activation and differentiation status of the cells.

inflammatory bowel disease ͉ mucosal immunity ͉ regulatory T cell

The active metabolite of vitamin D (1,25-dihydroxyvitamin D3 (1,25(OH)2D3)) is known to modulate the immune response in Th1 cell-directed diseases. To investigate the role of vitamin D in Th2 cell-directed diseases, experimental allergic asthma was induced in vitamin D receptor (VDR) knockout and in wild-type (WT) mice. As expected, WT mice developed symptoms of airway inflammation with an influx of eosinophils, elevated Th2 cytokine levels, mucous production, and airway hyperresponsiveness. The administration of 1,25(OH)2D3 had no effect on asthma severity. The only discernable effect of 1,25(OH)2D3 on experimental allergic asthma in WT mice was an increased expression of two Th2-related genes (soluble CD23 and GATA-3) in lungs of BALB/c mice exposed to Ag through the nasal route only. By contrast, asthma-induced VDR knockout mice failed to develop airway inflammation, eosinophilia, or airway hyperresponsiveness, despite high IgE concentrations and elevated Th2 cytokines. The data suggest that although 1,25(OH)2D3 induced these Th2-type genes, the treatment failed to have any affect on experimental asthma severity. However, VDR-deficient mice failed to develop experimental allergic asthma, suggesting an important role for the vitamin D endocrine system in the generation of Th2-driven inflammation in the lung.

OBJECTIVES:Low vitamin D status may be associated with Crohn's disease. A pilot study was performed in patients with mild-to-moderate Crohn's disease to determine the dose of vitamin D needed to raise serum vitamin D levels above 40 ng/ml.METHODS:Patients were evaluated for severity of symptoms using the Crohn's disease activity index (CDAI) and patients with mild-to-moderate (150–400 CDAI scores) Crohn's disease were entered into the study (n=18). Vitamin D3 oral therapy was initiated at 1,000 IU/d and after 2 weeks, the dose was escalated incrementally until patients' serum concentrations reached 40 ng/ml 25(OH)D3 or they were taking 5,000 IU/d. Patients continued on the vitamin D supplements for 24 weeks. CDAI, quality of life measures, bone mineral density, dietary analyses, cytokines, parathyroid hormone, calcium, and several other laboratory measurements were evaluated at baseline and after 24 weeks supplementation.RESULTS:Fourteen of eighteen patients required the maximal vitamin D supplement of 5,000 IU/d. Vitamin D oral supplementation significantly increased serum 25(OH)D3 levels from 16±10 ng/ml to 45±19 ng/ml (P<0.0001) and reduced the unadjusted mean CDAI scores by 112±81 points from 230±74 to 118±66 (P<0.0001). Quality-of-life scores also improved following vitamin D supplementation (P=0.0004). No significant changes in cytokine or other laboratory measures were observed.CONCLUSIONS:Twenty-four weeks supplementation with up to 5,000 IU/d vitamin D3 effectively raised serum 25(OH)D3 and reduced CDAI scores in a small cohort of Crohn's patients suggesting that restoration of normal vitamin D serum levels may be useful in the management of patients with mild–moderate Crohn's disease.