A Crucial Role for the Vitamin D Receptor in Experimental Inflammatory Bowel Diseases

Abstract

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 receptor expression by the lung micro-environment is required for maximal induction of lung inflammation

“…It has been shown in the multiple sclerosis model (experimental autoimmune encephalomyelitis) that vitamin D deficiency accelerates and VDR deficiency prevents symptom development [24,26]. Conversely, in models of inflammatory bowel disease, disease development is more severe in vitamin D deficiency and VDR deficiency [25,27].…”

Optimal vitamin D levels in Crohn's disease: a review

“…Vitamin D deficiency increased symptoms of several experimental models of IBD (68) and VDR deficiency increased susceptibility of mice to colitis (69,70) .…”

“…Conversely treatment with 1,25(OH) 2 D improves IBD symptoms and blocks the progression of colitis in mice (65,70,71) Vitamin D may also function on the epithelial barrier. Epithelial cells are connected by intercellular junctions, comprising tight junctions and adherens junctions (72) .…”

The paradoxical effects of vitamin D on type 1 mediated immunity

“…Induction of T reg and suppression of Th1 cells by 1,25(OH) 2 D 3 has been correlated with suppression of experimental autoimmunity. In addition, the VDR deficient host is more susceptible to experimental IBD in a number of different models (Froicu et al 2003;Froicu et al 2007). The immune system of VDR KO mice has normal CD4+, CD8+, and NK cell numbers.…”

“…The immune system of VDR KO mice has normal CD4+, CD8+, and NK cell numbers. However, CD4+ T cells from VDR KO mice overproduce IFN-γ, have a strong mixed lymphocyte reaction that is Th1 mediated and are lacking NKT cells (Froicu et al 2003;Froicu et al 2006;Yu et al 2008). iNKT cells are early innate regulatory cells that can alter the outcome of autoimmunity .…”