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      Mechanisms underlying effects of 1,25-dihydroxyvitamin D 3 on the Th17 cells

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          Abstract

          Th17 cells, a class of CD4 + T cells, have been identified as novel effector cells, which play a pivotal role in several inflammatory and autoimmune diseases. 1,25-Dihydroxyvitamin D 3 (1,25(OH) 2D 3), the active form of vitamin D, has emerged as a direct regulator of immune system function in humans. Accumulating reports demonstrated that 1,25(OH) 2D 3 possessed anti-inflammatory activity on Th17 cells to maintain immunologic homeostasis. This report will review the novel immune regulatory role of 1,25(OH) 2D 3 in its potential use for Th17 cell-related inflammatory and autoimmune conditions.

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          Most cited references17

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          1alpha,25-Dihydroxyvitamin d3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells.

          1alpha,25-Dihydroxyvitamin D3 (vitD3) is an immunoregulatory hormone with beneficial effects on Th1 mediated autoimmune diseases. Although the inhibitory effects of vitD3 on macrophages and dendritic cells are well documented, any direct effects of vitD3 on Th cell development are not clearly defined. Using CD4(+)Mel14(+) T cells derived from mice on a BALB/c and a C57BL/6 genetic background we examined the effect of vitD3 on Th cell development. We demonstrated that vitD3 affects Th cell polarization by inhibiting Th1 (IFN-gamma production) and augmenting Th2 cell development (IL-4, IL-5, and IL-10 production). These effects were observed in cultures driven with splenic APC and Ag, as well as with anti-CD3 and anti-CD28 alone, indicating that CD4(+) cells can also be direct targets for vitD3. The enhanced Th2 development by vitD3 was found in both BALB/c and C57BL/6 mice. An increased expression of the Th2-specific transcription factors GATA-3 and c-maf correlated with the increased production of Th2 cytokines after vitD3 treatment. The vitD3-induced effects were largely mediated via IL-4, because neutralization of IL-4 almost completely abrogated the augmented Th2 cell development after vitD3 treatment. These findings suggest that vitD3 acts directly on Th cells and can, in the absence of APC, enhance the development of a Th2 phenotype and augment the expression of the transcription factors c-maf and GATA-3. Our findings suggest that the beneficial effects of vitD3 in autoimmune diseases and transplantation operate through prevention of strong Th1 responses via the action on the APC, while simultaneously directly acting on the T cell to enhance Th2 cell development.
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            1,25-dihydroxyvitamin D(3) ameliorates Th17 autoimmunity via transcriptional modulation of interleukin-17A.

            A new class of inflammatory CD4(+) T cells that produce interleukin-17 (IL-17) (termed Th17) has been identified, which plays a critical role in numerous inflammatory conditions and autoimmune diseases. The active form of vitamin D, 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], has a direct repressive effect on the expression of IL-17A in both human and mouse T cells. In vivo treatment of mice with ongoing experimental autoimmune encephalomyelitis (EAE; a mouse model of multiple sclerosis) diminishes paralysis and progression of the disease and reduces IL-17A-secreting CD4(+) T cells in the periphery and central nervous system (CNS). The mechanism of 1,25(OH)(2)D(3) repression of IL-17A expression was found to be transcriptional repression, mediated by the vitamin D receptor (VDR). Transcription assays, gel shifting, and chromatin immunoprecipitation (ChIP) assays indicate that the negative effect of 1,25(OH)(2)D(3) on IL-17A involves blocking of nuclear factor for activated T cells (NFAT), recruitment of histone deacetylase (HDAC), sequestration of Runt-related transcription factor 1 (Runx1) by 1,25(OH)(2)D(3)/VDR, and a direct effect of 1,25(OH)(2)D(3) on induction of Foxp3. Our results describe novel mechanisms and new concepts with regard to vitamin D and the immune system and suggest therapeutic targets for the control of autoimmune diseases.
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              Calcitriol suppresses antiretinal autoimmunity through inhibitory effects on the Th17 effector response.

              Experimental autoimmune uveitis (EAU) serves as a model for human autoimmune uveitis and for cell-mediated autoimmunity in general. EAU induced in mice by immunization with the retinal Ag interphotoreceptor retinoid-binding protein in CFA is driven by the Th17 response. Oral calcitriol (1,25-dihydroxyvitamin D(3)) prevented as well as partly reversed disease and suppressed immunological responses. In vitro, calcitriol directly suppressed IL-17 induction in purified naive CD4(+) T cells without inhibiting Th17 lineage commitment, as reflected by unaltered RORgammat, STAT3, and FoxP3 expression. In contrast, in vivo treatment with calcitriol of mice challenged for EAU impaired commitment to the Th17 lineage, as judged by reduction of both RORgammat and IL-17 in CD4(+) T cells. Innate immune response parameters in draining lymph nodes of treated mice were suppressed, as was production of IL-1, IL-6, TNF-alpha, and IL-12/IL-23p40, but not IL-10, by explanted splenic dendritic cells (DC). Finally, supernatants of calcitriol-conditioned bone marrow-derived DC had reduced ability to support Th17 polarization of naive CD4(+) T cells in vitro and in vivo. Thus, calcitriol appears to suppress autoimmunity by inhibiting the Th17 response at several levels, including the ability of DC to support priming of Th17 cells, the ability of CD4(+) T cells to commit to the Th17 lineage, and the ability of committed Th17 T cells to produce IL-17.
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                Author and article information

                Journal
                1886
                122234
                European Journal of Microbiology and Immunology
                EuJMI
                Akadémiai Kiadó, co-published with Springer Science+Business Media B.V., Formerly Kluwer Academic Publishers B.V.
                2062-509X
                2062-8633
                1 December 2013
                : 3
                : 4
                : 237-240
                Affiliations
                [ 1 ] Department of Gastroenterology, The Second Hospital of Hebei Medical University, Hebei Key Laboratory of Gastroenterology Hebei Institute of Gastroenterology, No. 215 Heping West Road, 050000, Shijiazhuang, China
                [ 2 ] F. Widjaja Foundations, Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
                Author notes
                [* ] +86-311-66002955, +86-13703313189, xiaolanzh@ 123456126.com
                Article
                1
                10.1556/eujmi.3.2013.4.1
                3838538
                24294492
                3ad83548-e974-442a-93da-5e6be4793c2c
                Categories
                Review Article

                Medicine,Immunology,Health & Social care,Microbiology & Virology,Infectious disease & Microbiology
                VDR,immune response,Th17,1,25(OH)2D3

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