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.
    Full-text · Article · Feb 2014 · BMC Immunology
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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.
    Full-text · Article · Feb 2014 · PLoS ONE
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    • "Real-time RNA polymerase chain reaction was performed as described (D'Agostino et al., 2012) using 2 mg of total RNA. The primers used were farnesoid X receptor (FXR) forward, 59-ccaacctgggtttctaccc-39, and reverse, 59-cacacagct- catccccttt-39 (Cariou et al., 2006); pregnane X receptor (PXR) forward, 59-caaggccaatggctacca-39, and reverse, 59-cgggtgatctcgcaggtt-39 (Trousson et al., 2009); constitutive androstane receptor (CAR) forward, 59- ggagcggctgtggaaatattgcat-39, and reverse, 59-tccatcttgtagcaaagaggccca-39 (Patel et al., 2007); vitamin D receptor (VDR) forward, 59-ttcatcatgc- caatgccaatgtccac-39, and reverse, 59-gttcacctgccccttcaat-39 (Froicu et al., 2006); FGF15 forward, 59-gaggaccaaaacgaacgaaatt-39, and reverse, 59-acgtccttgatggcaatcg-39; small heterodimer partner (SHP) forward, 59-cgatcctcttcaacccagatg-39, and reverse, 59-agggctccaagactt- cacaca-39; CYP7A1 forward, 59-agcaactaaacaacctgccagtacta-39, and reverse, 59-gtccggatattcaaggatgca-39 (Inagaki et al., 2005); ileal bile acid-binding protein forward, 59-ggtcttccaggagacgtgat-39, and reverse, 59-acattctttgccaatggtga-39 (Kim et al., 2007); ileal apical sodium bile transporter (ASBT) forward, 59-tgggtttcttcctggctagact-39, and reverse, 59-tgttctgcattccagtttccaa-39 (Miyata et al., 2011), and CYP3A11 forward, 59-gacaaacaagcagggatgg-39, and reverse, 59-aatgtgggggacag- caaag-39 (Zhang et al., 2003). The levels of target gene mRNAs in various total RNA preparations were normalized by the level of GAPDH mRNA in a given sample. "
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    ABSTRACT: Tissue-specific deletion of the gene for NADPH-cytochrome P450 reductase (CPR), the essential electron donor to all microsomal cytochrome P450 (P450/CYP) enzymes, in either liver or intestine leads to up-regulation of many P450 genes in the tissue with the Cpr deletion. Here, by studying the liver-specific Cpr-null (LCN) mouse, we examined whether an inter-organ regulatory pathway exists, such that a loss of hepatic CPR would cause compensatory changes in intestinal P450 expression and capacity for first-pass metabolism of oral drugs. We show for the first time that intestinal expression of CYP2B, 2C and 3A proteins was increased in LCN mice, by 2- to 3-fold, compared with wild-type (WT) mice, accompanied by significant increases in small intestinal (SI) microsomal lovastatin-hydroxylase activity and systemic clearance of oral lovastatin (at 5 mg/kg). Additional studies showed that the hepatic Cpr deletion, which caused large decreases in bile acid (BA) levels in liver, intestine, plasma and intestinal content, led to drastic decreases in the mRNA levels of intestinal fibroblast growth factor 15 (FGF15), a target gene of the BA receptor farnesoid X receptor (FXR). Furthermore, treatment of mice with FGF19 (the human counterpart of mouse FGF15) abolished the difference between WT and LCN mice in SI CYP3A levels, at 6 h after the treatment. Our findings reveal a previously unrecognized, direct role of intestinal FGF15/19 in the regulation of SI P450 expression, and may have profound implications for the prediction of drug exposure in patients with compromised hepatic P450 function.
    Preview · Article · Nov 2013 · Molecular pharmacology
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