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Molecular Medicine

, Volume 20, Issue 1, pp 248–256 | Cite as

Low-Dose 5-Aza-2′-deoxycytidine Pretreatment Inhibits Experimental Autoimmune Encephalomyelitis by Induction of Regulatory T Cells

  • Michael W. Y. Chan
  • Chia-Bin Chang
  • Chien-Hsueh Tung
  • Justin Sun
  • Jau-Ling Suen
  • Shu-Fen Wu
Research Article

Abstract

Forkhead box P3 (Foxp3) is the major transcription factor controlling the development and function of regulatory T (Treg) cells. Previous studies have indicated epigenetic regulation of Foxp3 expression. Here, we investigated whether the deoxyribonucleic acid (DNA) methyltransferase inhibitor 5-aza-2′-deoxycytidine (5-Aza) applied peripherally could modulate central nervous system (CNS) inflammation, by using a mouse experimental autoimmune encephalomyelitis (EAE) model. We found that disease activity was inhibited in a myelin oligodendrocyte glycoprotein (MOG) peptide-induced EAE mouse briefly pretreated with low-dose (0.15 mg/kg) 5-Aza, ameliorating significant CNS inflammatory responses, as indicated by greatly decreased proinflammatory cytokines. On the contrary, control EAE mice expressed high levels of IFN-γ and interleukin (IL)-17. In addition, 5-Aza treatment in vitro increased GFP expression in CD4+GFP T cells isolated from GFP knock-in Foxp3 transgenic mice. Importantly, 5-Aza treatment increased Treg cell numbers, in EAE mice, at both disease onset and peak. However, Treg inhibition assays showed 5-Aza treatment did not enhance per-cell Treg inhibitory function, but did maintain a lower activation threshold for effector cells in EAE mice. In conclusion, 5-Aza treatment prevented EAE development and suppressed CNS inflammation, by increasing the number of Treg cells and inhibiting effector cells in the periphery.

Notes

Acknowledgments

This work was supported by the National Science Council (Taiwan, Republic of China; NSC-98-01740-01, NSC-99-2320-B-194-001-MY3 and NSC-102-2320-B-194-001) and in part by the Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation (Chia-Yi, Taiwan). The authors would like to thank Jia-Chiun Pan for assistance in statistical calculation.

Supplementary material

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Supplementary material, approximately 451 KB.

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Authors and Affiliations

  • Michael W. Y. Chan
    • 1
  • Chia-Bin Chang
    • 1
  • Chien-Hsueh Tung
    • 1
    • 2
  • Justin Sun
    • 1
  • Jau-Ling Suen
    • 3
  • Shu-Fen Wu
    • 1
  1. 1.Department of Life Science and Institute of Molecular BiologyNational Chung-Cheng UniversityChia-YiTaiwan, Republic of China
  2. 2.Division of Allergy, Immunology and RheumatologyDalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, DalinChia-YiTaiwan, Republic of China
  3. 3.Graduate Institute of MedicineKaohsiung Medical UniversityKaohsiungTaiwan, Republic of China

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