Chang JH, Cha HR, Lee DS et al.1,25-Dihydroxyvitamin D3 inhibits the differentiation and migration of T(H)17 cells to protect against experimental autoimmune encephalomyelitis. PloS ONE 5:e12925

Mucosal Immunology Section, Laboratory Science Division, International Vaccine Institute, Seoul, Korea.
PLoS ONE (Impact Factor: 3.23). 12/2010; 5(9):e12925. DOI: 10.1371/journal.pone.0012925
Source: PubMed


Vitamin D(3), the most physiologically relevant form of vitamin D, is an essential organic compound that has been shown to have a crucial effect on the immune responses. Vitamin D(3) ameliorates the onset of the experimental autoimmune encephalomyelitis (EAE); however, the direct effect of vitamin D(3) on T cells is largely unknown.
In an in vitro system using cells from mice, the active form of vitamin D(3) (1,25-dihydroxyvitamin D(3)) suppresses both interleukin (IL)-17-producing T cells (T(H)17) and regulatory T cells (Treg) differentiation via a vitamin D receptor signal. The ability of 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) to reduce the amount of IL-2 regulates the generation of Treg cells, but not T(H)17 cells. Under T(H)17-polarizing conditions, 1,25(OH)(2)D(3) helps to increase the numbers of IL-10-producing T cells, but 1,25(OH)(2)D(3)'s negative regulation of T(H)17 development is still defined in the IL-10(-/-) T cells. Although the STAT1 signal reciprocally affects the secretion of IL-10 and IL-17, 1,25(OH)(2)D(3) inhibits IL-17 production in STAT1(-/-) T cells. Most interestingly, 1,25(OH)(2)D(3) negatively regulates CCR6 expression which might be essential for T(H)17 cells to enter the central nervous system and initiate EAE.
Our present results in an experimental murine model suggest that 1,25(OH)(2)D(3) can directly regulate T cell differentiation and could be applied in preventive and therapeutic strategies for T(H)17-mediated autoimmune diseases.

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    • "Finally, we examined the role of vitamin A and D in regulating the generation of Th17 cells. Both ATRA and 1,25D3 have been shown to suppress Th17 generation via downregulation of RARa and the transcriptional factor RORc, which orchestrates Th17 differentiation (Mucida et al., 2007; Chang et al., 2010; Ikeda et al., 2010). We found that ATRA and 1,25D3 inhibited IL-17 mRNA and protein expression in response to stimulation with P. acnes. "
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    ABSTRACT: Acne vulgaris is the most common skin disorder affecting millions of people worldwide and inflammation resulting from the immune response targeting Propionibacterium acnes plays a significant role in its pathogenesis. In this study, we have demonstrated that P. acnes is a potent inducer of Th17 and Th1, but not Th2 responses in human PBMCs. P. acnes stimulated expression of key Th17-related genes, including IL-17A, RORα, RORc, IL-17RA and IL-17RC, and triggered IL-17 secretion from CD4(+), but not CD8(+) T cells. Supernatants from P. acnes-stimulated PBMCs were sufficient to promote the differentiation of naïve CD4(+)CD45RA T cells into Th17 cells. Furthermore, we found that the combination of IL-1β, IL-6 and TGF-β neutralizing antibodies completely inhibited P. acnes-induced IL-17 production. Importantly, we showed that IL-17-expressing cells were present in skin biopsies from acne patients but not from normal donors. Finally, vitamin A (all-trans retinoic acid) and vitamin D (1,25-dihydroxyvitamin D3) inhibited P. acnes-induced Th17 differentiation. Together, our data demonstrate that IL-17 is induced by P. acnes and expressed in acne lesions and that both vitamin A and vitamin D could be effective tools to modulate Th17-mediated diseases such as acne.Journal of Investigative Dermatology accepted article preview online, 7 August 2013. doi:10.1038/jid.2013.334.
    Journal of Investigative Dermatology 08/2013; 134(2). DOI:10.1038/jid.2013.334 · 7.22 Impact Factor
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    • "Preclinical studies have shown that 1,25(OH)2D3 treatment effectively ameliorated EAE in mice [6], [7], [8], [9], [10], [11]. However, the mechanism by which this hormone provides the therapeutic effects has not been fully understood. "
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    ABSTRACT: 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) suppresses autoimmunity and inflammation; however, the mechanism of its action has not been fully understood. We sought in this study to determine whether the anti-immune/anti-inflammatory action of 1,25(OH)2D3 is in part mediated through an interplay between 1,25(OH)2D3 and toll-like receptor (TLR)7/8 signaling. 1,25(OH)2D3 treatment prior to and/or following experimental autoimmune encephalomyelitis (EAE) induction effectively reduced inflammatory cytokine expression in the spinal cord and ameliorated EAE. These effects were accompanied with a reduction in expression of several TLRs with the most profound effect observed for TLR8. The expression of TLR8 adaptor protein MyD88 was also significantly reduced by 1,25(OH)2D3. To determine the molecular mechanism by which 1,25(OH)2D3 suppresses EAE induction of TLR8 and inflammatory cytokine expression, we evaluated whether 1,25(OH)2D3 can directly inhibit TLR8 signaling and the resulting inflammatory responses in human THP-1 monocytes. 1,25(OH)2D3 treatment not only significantly reduced TLR8 expression but also the expression or activity of MyD88, IRF-4, IRF-7 and NF-kB in monocytes challenged with TLR8 ligands. TLR8 promoter-luciferase reporter assays indicated that 1,25(OH)2D3 decreases TLR8 mRNA level in part via inhibiting TLR8 gene transcription activity. As a result of inhibition on TLR8 signaling cascade at various stages, 1,25(OH)2D3 significantly diminished the TLR8 target gene expression (TNF-α and IL-1β). In summary, our novel findings suggest that TLR8 is a new target of 1,25(OH)2D3 and may mediate the anti-inflammatory action of 1,25(OH)2D3. Our findings also point to a destructive role of TLR8 in EAE and shed lights on pathogenesis of multiple sclerosis.
    PLoS ONE 03/2013; 8(3):e58808. DOI:10.1371/journal.pone.0058808 · 3.23 Impact Factor
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    • "In fact, several groups have established that 1,25-(OH) 2 D 3 inhibits both T H 1 and T H 17 cell differentiation in vitro (Mattner et al., 2000; Chang et al., 2010a). Using the EAE model, in vivo use of 1,25-(OH) 2 D 3 (3 mg/kg) inhibited both T H 1 and T H 17 mediated disease induction, as evidenced by decreased inflammatory infiltration and reduced demyelination of the brain and spinal cord (Mattner et al., 2000; Chang et al., 2010a). In addition, 1,25-(OH) 2 D 3 has been shown to inhibit macrophage accumulation in the CNS during EAE development; thus, 1,25-(OH) 2 D 3 is acting on various cell types, leading to the protective effects seen after administration of vitamin D 3 (Nashold et al., 2000). "
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    ABSTRACT: Nuclear receptors are ligand-activated transcription factors and include the receptors for steroid hormones, lipophilic vitamins, sterols, and bile acids. These receptors serve as targets for development of myriad drugs that target a range of disorders. Classically defined ligands that bind to the ligand-binding domain of nuclear receptors, whether they are endogenous or synthetic, either activate receptor activity (agonists) or block activation (antagonists) and due to the ability to alter activity of the receptors are often termed receptor "modulators." The complex pharmacology of nuclear receptors has provided a class of ligands distinct from these simple modulators where ligands display agonist/partial agonist/antagonist function in a tissue or gene selective manner. This class of ligands is defined as selective modulators. Here, we review the development and pharmacology of a range of selective nuclear receptor modulators.
    Pharmacological reviews 02/2013; 65(2):710-78. DOI:10.1124/pr.112.006833 · 17.10 Impact Factor
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