1,25‐dihydroxyvitamin D<sub>3</sub> reverses experimental autoimmune encephalomyelitis by inhibiting chemokine synthesis and monocyte trafficking

Pedersen, Laura B.; Nashold, Faye E.; Spach, Karen; Hayes, Colleen E.

doi:10.1002/jnr.21382

Cited by 144 publications

(118 citation statements)

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“…However, in males and females, administering 1,25-(OH) 2 D 3 inhibited EAE induction and progression, and after disease establishment, induced EAE remission (30)(31)(32). In EAE, we found that 1,25-(OH) 2 D 3 did not inhibit pathogenic CD4 + T cell development or trafficking (32,33), but instead increased the sensitivity of pathogenic T cells to apoptotic signals within the CNS (33,34). These mechanisms required VDR expression in the pathogenic CD4 + T cells (11).…”

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confidence: 73%

“…We previously found that 64% of CD4 + T cells in the inflamed spinal cord of mice with EAE underwent apoptosis within 18 h after 1,25-(OH) 2 D 3 was administered, but immune cell trafficking into the spinal cord was unchanged (33). Accordingly, we suggest that fewer CD4 + T cells were detected in the CNS of mice receiving vitamin D 3 or 1,25-(OH) 2 D 3 compared with placebo controls because of diminished T cell longevity.…”

Section: Discussionmentioning

confidence: 99%

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TheIfngGene Is Essential forVdrGene Expression and Vitamin D3-Mediated Reduction of the Pathogenic T Cell Burden in the Central Nervous System in Experimental Autoimmune Encephalomyelitis, a Multiple Sclerosis Model

Spanier

Nashold

Olson

et al. 2012

The Journal of Immunology

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Compelling evidence suggests that vitamin D3 insufficiency may contribute causally to multiple sclerosis (MS) risk. Experimental autoimmune encephalomyelitis (EAE) research firmly supports this hypothesis. Vitamin D3 supports 1,25-dihydroxyvitamin D3 (1,25-[OH]2D3) synthesis in the CNS, initiating biological processes that reduce pathogenic CD4+ T cell longevity. MS is prevalent in Sardinia despite high ambient UV irradiation, challenging the vitamin D–MS hypothesis. Sardinian MS patients frequently carry a low Ifng expresser allele, suggesting that inadequate IFN-γ may undermine vitamin D3-mediated inhibition of demyelinating disease. Testing this hypothesis, we found vitamin D3 failed to inhibit EAE in female Ifng knockout (GKO) mice, unlike wild-type mice. The two strains did not differ in Cyp27b1 and Cyp24a1 gene expression, implying equivalent vitamin D3 metabolism in the CNS. The 1,25-(OH)2D3 inhibited EAE in both strains, but 2-fold more 1,25-(OH)2D3 was needed in GKO mice, causing hypercalcemic toxicity. Unexpectedly, GKO mice had very low Vdr gene expression in the CNS. Injecting IFN-γ intracranially into adult mice did not increase Vdr gene expression. Correlating with low Vdr expression, GKO mice had more numerous pathogenic Th1 and Th17 cells in the CNS, and 1,25-(OH)2D3 reduced these cells in GKO and wild-type mice without altering Foxp3+ regulatory T cells. Thus, the Ifng gene was needed for CNS Vdr gene expression and vitamin D3-dependent mechanisms that inhibit EAE. Individuals with inadequate Ifng expression may have increased MS risk despite high ambient UV irradiation because of low Vdr gene expression and a high encephalitogenic T cell burden in the CNS.

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confidence: 73%

Section: Discussionmentioning

confidence: 99%

TheIfngGene Is Essential forVdrGene Expression and Vitamin D3-Mediated Reduction of the Pathogenic T Cell Burden in the Central Nervous System in Experimental Autoimmune Encephalomyelitis, a Multiple Sclerosis Model

Spanier

Nashold

Olson

et al. 2012

The Journal of Immunology

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“…If vitamin D3 is used, the beneficial effect predominates in females, likely via a potentiation by oestrogens [Spach and Hayes, 2005;Nashold et al 2009;Subramanian et al 2012]. Various immunological mechanisms have been reported to explain the vitamin D and calcitriol effects: an anti-inflammatory effect [Spach et al, 2004], actions on macrophages [Nashold et al 2000], on different types of cytokines [Cantorna et al 1998;Spach et al 2006;Pedersen et al 2007], on regulatory T lymphocyte cells (Tregs), lymphocyte T helper 1 (Th1), Th17 and Th2 [Mattner et al 2000;Muthian et al 2006;Chang et al 2010;Mayne et al 2011] and invariant natural killer T-cells (iNKTs) [Cantorna et al 2012]. Interestingly, with low VDR gene expression, EAE is facilitated, with an increase in Th1 and Th17, suggesting that, in a similar genetic situation in humans, the MS risk may be increased despite high ambient UV radiation (e.g.…”

Section: Multiplicity Of Vitamin D Actionsmentioning

confidence: 99%

Contribution of vitamin D insufficiency to the pathogenesis of multiple sclerosis

Pierrot‐Deseilligny

Souberbielle

2013

Ther Adv Neurol Disord

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Abstract:The contribution of vitamin D insufficiency to the pathogenesis of multiple sclerosis (MS) is reviewed. Among the multiple recently discovered actions of vitamin D, an immunomodulatory role has been documented in experimental autoimmune encephalomyelitis and in humans. This action in the peripheral immune system is currently the main known mechanism through which vitamin D might influence MS, but other types of actions could be involved within the central nervous system. Furthermore, vitamin D insufficiency is widespread in temperate countries and in patients with MS at the earliest stages of the disease, suggesting that the deleterious effects related to vitamin D insufficiency may be exerted in these patients. In fact, many genetic and environmental risk factors appear to interact and contribute to MS. In genetics, several human leukocyte antigen (HLA) alleles (more particularly HLA-DRB1*1501) could favour the disease whereas some others could be protective. Some of the genes involved in vitamin D metabolism (e.g. CYP27B1) also play a significant role. Furthermore, three environmental risk factors have been identified: past Epstein-Barr virus infection, vitamin D insufficiency and cigarette smoking. Interactions between genetic and environmental risk or protective factors may occur during the mother's pregnancy and could continue during childhood and adolescence and until the disease is triggered in adulthood, therefore possibly modulating the MS risk throughout the first decades of life. Furthermore, some clinical findings already strongly suggest that vitamin D status influences the relapse rate and radiological lesions in patients with MS, although the results of adequately powered randomized clinical trials using vitamin D supplementation have not yet been reported. While awaiting these incontrovertible results, which might be long in coming, patients with MS who are currently in vitamin D insufficiency should be supplemented, at least for their general health status, using moderate doses of the vitamin.

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“…However, the concentrations of 1,25D3 employed in many studies are often above the physiological range, bringing into question the physiological relevance of the effect of 1,25D3 on T cells. Nonetheless, modulation of CD4ϩ T cells by 1,25D3 is intriguing because several studies have demonstrated that 1,25D3 is capable of suppressing inflammation in vivo (7)(8)(9)(10).…”

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confidence: 99%

Vitamin D Suppresses Th17 Cytokine Production by Inducing C/EBP Homologous Protein (CHOP) Expression

Chang

Chung²,

Dong

2010

Journal of Biological Chemistry

168

130

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Vitamin D is an essential nutrient that regulates calcium and phosphate transport and bone mineralization (1). In recent years, however, vitamin D has been found to have a much broader range of actions, including regulation of cell differentiation, proliferation, and apoptosis (2). The role of vitamin D in immune system is complex and diverse. The systemic or locally produced active form of vitamin D, 1,25-dihydroxyvitamin D 3 (1,25D3), 3 can exercise its effects on several immune cells, including macrophages, dendritic cells, and T and B cells. Several reports indicated that 1,25D3 can act directly on T cells or indirectly on dendritic cells to modulate T cell function (3-6). However, the concentrations of 1,25D3 employed in many studies are often above the physiological range, bringing into question the physiological relevance of the effect of 1,25D3 on T cells. Nonetheless, modulation of CD4ϩ T cells by 1,25D3 is intriguing because several studies have demonstrated that 1,25D3 is capable of suppressing inflammation in vivo (7-10).Recently, a new subset of CD4ϩ T cells, Th17 cells, was reported to have an essential role in dampening local inflammation (11-13). Th17 cells produce proinflammatory molecules, IL-17, IL-17F, and IL-22, which act on tissue resident cells to promote inflammation. TGF␤ and IL-6 are critical in generation of Th17 cells by activating STAT3 and inducing the transcription factors, retinoic acid-related orphan receptor (ROR␥t) (14) and ROR␣ (15). IL-1 and IL-23 are also important cytokines to stabilize and maintain Th17 cells (16,17). Therefore, pathways to regulate Th17 cell development and its cytokines are relevant. Of interest, a previous report indicated that 1,25D3 is able to prevent experimental autoimmune uveitis, partially because of its suppressive effect directly on Th17 cells (10). However, it is not known whether the effect is mediated through vitamin D receptor (VDR) and how 1,25D3 suppresses IL-17 and other Th17 cytokine production in T cells.In this study, we have examined the mechanism whereby 1,25D3 regulates CD4ϩ T cell function at physiological concentrations. We found that in response to 1,25D3, Th17 cells produced reduced levels of cytokines at the protein level, whereas their transcriptions were not affected. Moreover, 1,25D3 treatment in Th17 cells induced the expression of C/EBP homologous protein (CHOP). Overexpression of CHOP in Th17 cells suppressed their cytokine production. Our data thus suggest a post-transcriptional inhibition of Th17 cell function by VDR. EXPERIMENTAL PROCEDURESMice-C57Bl/6-and VDR-deficient mice were purchased from The Jackson Laboratory, and 6 -8-week-old mice were used in experiments. Mice were housed in the specific pathogen-free animal facility at MD Anderson Cancer Center, and the animal experiments were performed using protocols approved by the Institutional Animal Care and Use Committee.Th Cell Differentiation-Naive CD4lo T cells from C57Bl/6 mice were FACS-sorted and stimulated with plate-bound anti-CD3 (0.5 g/ml) plus soluble anti...

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1,25‐dihydroxyvitamin D₃ reverses experimental autoimmune encephalomyelitis by inhibiting chemokine synthesis and monocyte trafficking

Cited by 144 publications

References 44 publications

TheIfngGene Is Essential forVdrGene Expression and Vitamin D3-Mediated Reduction of the Pathogenic T Cell Burden in the Central Nervous System in Experimental Autoimmune Encephalomyelitis, a Multiple Sclerosis Model

TheIfngGene Is Essential forVdrGene Expression and Vitamin D3-Mediated Reduction of the Pathogenic T Cell Burden in the Central Nervous System in Experimental Autoimmune Encephalomyelitis, a Multiple Sclerosis Model

Contribution of vitamin D insufficiency to the pathogenesis of multiple sclerosis

Vitamin D Suppresses Th17 Cytokine Production by Inducing C/EBP Homologous Protein (CHOP) Expression

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1,25‐dihydroxyvitamin D3 reverses experimental autoimmune encephalomyelitis by inhibiting chemokine synthesis and monocyte trafficking

Cited by 144 publications

References 44 publications

TheIfngGene Is Essential forVdrGene Expression and Vitamin D3-Mediated Reduction of the Pathogenic T Cell Burden in the Central Nervous System in Experimental Autoimmune Encephalomyelitis, a Multiple Sclerosis Model

TheIfngGene Is Essential forVdrGene Expression and Vitamin D3-Mediated Reduction of the Pathogenic T Cell Burden in the Central Nervous System in Experimental Autoimmune Encephalomyelitis, a Multiple Sclerosis Model

Contribution of vitamin D insufficiency to the pathogenesis of multiple sclerosis

Vitamin D Suppresses Th17 Cytokine Production by Inducing C/EBP Homologous Protein (CHOP) Expression

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1,25‐dihydroxyvitamin D₃ reverses experimental autoimmune encephalomyelitis by inhibiting chemokine synthesis and monocyte trafficking