Vitamin D receptor is required to control gastrointestinal immunity in IL‐10 knockout mice

Immunology Research Laboratories, The Pathobioilogy and Nutrition Graduate Programs, Department of Veterinary Science, The Pennsylvania State University, University Park, PA 16802, USA.
Immunology (Impact Factor: 3.8). 04/2006; 117(3):310-8. DOI: 10.1111/j.1365-2567.2005.02290.x
Source: PubMed


The vitamin D receptor (VDR) is a nuclear receptor expressed in a number of different cells of the immune system. This study was performed to determine the effect of VDR deficiency on immune function and inflammation of the gastrointestinal tract in a model of inflammatory bowel disease, namely interleukin-10 (IL-10) knockout mice. IL-10 knockout mice were generated which either could or could not respond to vitamin D (double IL-10/VDR knockout; DKO). The distribution and function of lymphocytes in both the primary and secondary lymphoid organs were compared and determined as a function of the severity of intestinal inflammation. DKO mice had normal thymic development and peripheral T-cell numbers at 3 weeks of age, but a week after intestinal disease was detected the thymus was dysplastic with a reduction in cellularity. The atrophy was coupled with increased apoptosis. The spleen weight of DKO mice increased as a result of the accumulation of red blood cells; however, there was a 50% reduction in the numbers of T and B cells. Conversely, the mesenteric lymph nodes were enlarged and contained increased numbers of lymphocytes. The T cells from DKO mice were of a memory phenotype and were hyporesponsive to T-cell receptor stimulation. Colitis in the DKO mice was associated with local and high expression of IL-2, interferon-gamma, IL-1beta, tumour necrosis factor-alpha and IL-12. The primary and secondary lymphoid organs in DKO mice are profoundly altered as a consequence of the fulminating inflammation in the gastrointestinal tract. VDR expression is required for the T cells and other immune cells to control inflammation in the IL-10 KO mice.

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    • "Conversely, vitamin D deficiency and/or VDR deficiency resulted in an exacerbation of experimental IBD [5]. Expression of the VDR does not affect the development of normal numbers of CD4 and CD8αβ T cells in the thymus or in the periphery [5,8,9]. VDR KO CD4+ T cells express more IL-17, and IFN-γ, proliferate more rapidly in a mixed lymphocyte reaction and induce more severe colitis than WT CD4 cells [5,10]. "
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    ABSTRACT: Vitamin D receptor (VDR) deficiency contributes to the development of experimental inflammatory bowel disease (IBD) in several different models. T cells have been shown to express the VDR, and T cells are targets of vitamin D. In this article we determined the effects of VDR expression on CD8+ T cells. VDR KO CD8+ T cells, but not WT CD8+ T cells, induced colitis in Rag KO recipients. In addition, co-transfer of VDR KO CD8+ T cells with naive CD4+ T cells accelerated colitis development. The more severe colitis was associated with rapidly proliferating naive VDR KO CD8+ T cells and increased IFN-gamma and IL-17 in the gut. VDR KO CD8+ T cells proliferated in vitro without antigen stimulation and did not downregulate CD62L and upregulate CD44 markers following proliferation that normally occurred in WT CD8+ T cells. The increased proliferation of VDR KO CD8+ cells was due in part to the higher production and response of the VDR KO cells to IL-2. Our data indicate that expression of the VDR is required to prevent replication of quiescent CD8+ T cells. The inability to signal through the VDR resulted in the generation of pathogenic CD8+ T cells from rapidly proliferating cells that contributed to the development of IBD.
    BMC Immunology 02/2014; 15(1):6. DOI:10.1186/1471-2172-15-6 · 2.48 Impact Factor
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    • "Nutrients, capable of control the pro-inflammation, are shown to be beneficial in spontaneous and induced colitis models [2]. For example, vitamin D provides significantly beneficial role in IBD via mediating the expressions of target genes, including pro-inflammatory cytokines [3]–[5]. Besides that, compelling investigations have indicated that arginine or glutamine might be a good candidate for IBD treatment with low risk [6], [7]. "
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    ABSTRACT: This study was conducted to investigate serum amino acids profile in dextran sulfate sodium (DSS)-induced colitis, and impacts of graded dose of arginine or glutamine supplementation on the colitis. Using DSS-induced colitis model, which is similar to human ulcerative colitis, we determined serum profile of amino acids at day 3, 7, 10 and 12 (5 days post DSS treatment). Meanwhile, effects of graded dose of arginine (0.4%, 0.8%, and 1.5%) or glutamine (0.5%, 1.0% and 2.0%) supplementation on clinical parameters, serum amino acids, colonic tight junction proteins, colonic anti-oxidative indicators [catalase, total superoxide dismutase (T-SOD), glutathione peroxidase (GSH-Px)], colonic pro-inflammatory cytokines [interleukin-1 beta (IL-1β), IL-6, IL-17 and tumor necrosis factor alpha (TNF-α)] in DSS-induced colitis were fully analyzed at day 7 and 12. Additionally, the activation of signal transduction pathways, including nuclear factor kappa B (NF-κB), mitogen-activated protein kinases (MAPK), phosphoinositide-3-kinases (PI3K)/PI3K-protein kinase B (Akt), and myosin light chain kinase (MLCK)- myosin light chain (MLC20), were analyzed using immunoblotting. Serum amino acids analysis showed that DSS treatment changed the serum contents of amino acids, such as Trp, Glu, and Gln (P<0.05). Dietary arginine or glutamine supplementation had significant (P<0.05) influence on the clinical and biochemical parameters (T-SOD, IL-17 and TNF-α) in colitis model. These results were associated with colonic NF-κB, PI3K-Akt and MLCK signaling pathways. In conclusion, arginine or glutamine could be a potential therapy for intestinal inflammatory diseases.
    PLoS ONE 02/2014; 9(2):e88335. DOI:10.1371/journal.pone.0088335 · 3.23 Impact Factor
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    • "Accordingly, administration of 1,25(OH) 2 D 3 to these mice inhibits the TNF-a pathway and significantly prevents disease progression and alleviates the symptoms of established IBD (Cantorna et al. 2000, 2004, Zhu et al. 2005). Additionally, work by Froicu et al. (2006) showed that VDR is required to control gastrointestinal inflammation in Il10 knockout mice, as Il10/Vdr double knockout mice develop exacerbated IBD symptoms associated with high local expression of IL2, IFN-g, IL1b, TNF-a and IL12. In line with this, 1,25(OH) 2 D 3 was shown to antagonize the NF-kB pathway and the production of IL8 in CRC cells treated with IL1b (Sun et al. 2008). "
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    ABSTRACT: The most active vitamin D metabolite, 1α,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), is a pleiotropic hormone with wide regulatory actions. Classically, vitamin D deficiency was known to alter calcium and phosphate metabolism and bone biology. In addition, recent epidemiological and experimental studies support the association of vitamin D deficiency with a large variety of human diseases, and particularly with the high risk of colorectal cancer. By regulating the expression of many genes via several mechanisms, 1,25(OH)(2)D(3) induces differentiation, controls the detoxification metabolism and cell phenotype, sensitises cells to apoptosis and inhibits the proliferation of cultured human colon carcinoma cells. Consistently, 1,25(OH)(2)D(3) and several of its analogues decrease intestinal tumourigenesis in animal models. Molecular, genetic and clinical data in humans are scarce but they suggest that vitamin D is protective against colon cancer. Clearly, the available evidence warrants new, well-designed, large-scale trials to clarify the role of vitamin D in the prevention and/or therapy of this important neoplasia.
    Endocrine Related Cancer 03/2012; 19(3):R51-71. DOI:10.1530/ERC-11-0388 · 4.81 Impact Factor
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