title: Low-dose 5-aza-2'-deoxycytidine pretreatment inhibits experimental autoimmune encephalomyelitis by induction of regulatory T cells.
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.
authors.affiliation: Department of Life Science and Institute of Molecular Biology, National Chung-Cheng University, Min-Hsiung, Chia-Yi, Taiwan, Republic of China.
authors.forename: Michael W Y
authors.initials: MW
authors.lastname: Chan
authors.affiliation: Department of Life Science and Institute of Molecular Biology, National Chung-Cheng University, Min-Hsiung, Chia-Yi, Taiwan, Republic of China.
authors.forename: Chia-Bin
authors.initials: CB
authors.lastname: Chang
authors.affiliation: Department of Life Science and Institute of Molecular Biology, National Chung-Cheng University, Min-Hsiung, Chia-Yi, Taiwan, Republic of China Division of Allergy, Immunology and Rheumatology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Dalin, Chia-Yi, Taiwan, Republic of China.
authors.forename: Chien-Hsueh
authors.initials: CH
authors.lastname: Tung
authors.affiliation: Department of Life Science and Institute of Molecular Biology, National Chung-Cheng University, Min-Hsiung, Chia-Yi, Taiwan, Republic of China.
authors.forename: Justin
authors.initials: J
authors.lastname: Sun
authors.affiliation: Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, Republic of China.
authors.forename: Jau-Ling
authors.initials: JL
authors.lastname: Suen
authors.affiliation: Department of Life Science and Institute of Molecular Biology, National Chung-Cheng University, Min-Hsiung, Chia-Yi, Taiwan, Republic of China.
authors.forename: Shu-Fen
authors.initials: SF
authors.lastname: Wu
mesh_terms: D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D000077209:Decitabine; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009169:Mycobacterium tuberculosis; D063308:Myelin-Oligodendrocyte Glycoprotein; D013116:Spinal Cord / Q000473:pathology; D013154:Spleen / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C571327:Mog protein, mouse; D063308:Myelin-Oligodendrocyte Glycoprotein; D000077209:Decitabine; D015254:DNA Modification Methylases; D001374:Azacitidine