Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Zeitelhofer, M; Adzemovic, MZ; Gomez-Cabrero, D; Bergman, P; Hochmeister, S; N'diaye, M; Paulson, A; Ruhrmann, S; Almgren, M; Tegnér, JN; Ekström, TJ; Guerreiro-Cacais, AO; Jagodic, M.
Functional genomics analysis of vitamin D effects on CD4+ T cells in vivo in experimental autoimmune encephalomyelitis .
Proc Natl Acad Sci U S A. 2017; 114(9):E1678-E1687
Doi: 10.1073/pnas.1615783114
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- Co-Autor*innen der Med Uni Graz
- Hochmeister Sonja
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- Abstract:
- Vitamin D exerts multiple immunomodulatory functions and has been implicated in the etiology and treatment of several autoimmune diseases, including multiple sclerosis (MS). We have previously reported that in juvenile/adolescent rats, vitamin D supplementation protects from experimental autoimmune encephalomyelitis (EAE), a model of MS. Here we demonstrate that this protective effect associates with decreased proliferation of CD4+ T cells and lower frequency of pathogenic T helper (Th) 17 cells. Using transcriptome, methylome, and pathway analyses in CD4+ T cells, we show that vitamin D affects multiple signaling and metabolic pathways critical for T-cell activation and differentiation into Th1 and Th17 subsets in vivo. Namely, Jak/Stat, Erk/Mapk, and Pi3K/Akt/mTor signaling pathway genes were down-regulated upon vitamin D supplementation. The protective effect associated with epigenetic mechanisms, such as (i) changed levels of enzymes involved in establishment and maintenance of epigenetic marks, i.e., DNA methylation and histone modifications; (ii) genome-wide reduction of DNA methylation, and (iii) up-regulation of noncoding RNAs, including microRNAs, with concomitant down-regulation of their protein-coding target RNAs involved in T-cell activation and differentiation. We further demonstrate that treatment of myelin-specific T cells with vitamin D reduces frequency of Th1 and Th17 cells, down-regulates genes in key signaling pathways and epigenetic machinery, and impairs their ability to transfer EAE. Finally, orthologs of nearly 50% of candidate MS risk genes and 40% of signature genes of myelin-reactive T cells in MS changed their expression in vivo in EAE upon supplementation, supporting the hypothesis that vitamin D may modulate risk for developing MS.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- CD4-Positive T-Lymphocytes - drug effects
- Cell Differentiation - drug effects
- Cell Proliferation - drug effects
- Down-Regulation - drug effects
- Encephalomyelitis, Autoimmune, Experimental - drug therapy
- Epigenesis, Genetic - drug effects
- Genomics - methods
- Lymphocyte Activation - drug effects
- Multiple Sclerosis - drug therapy
- Rats -
- Signal Transduction - genetics
- Signal Transduction - immunology
- Th1 Cells - drug effects
- Th17 Cells - drug effects
- Up-Regulation - drug effects
- Vitamin D - pharmacology
- Find related publications in this database (Keywords)
- vitamin D
- experimental autoimmune encephalomyelitis
- multiple sclerosis
- epigenetics
- DNA methylation