title: The DNA methylation inhibitor 5-azacytidine increases regulatory T cells and alleviates airway inflammation in ovalbumin-sensitized mice.
abstract: BACKGROUND
  Asthma is characterized as a chronic inflammatory disorder of the airways associated with an enhanced TH2 response to inhaled allergens. CD4+ T regulatory (Treg) cells are controlled by the master transcription factor FoxP3 and strictly maintain peripheral immunotolerance. Epigenetic regulation of FoxP3 by DNA methyltransferase inhibitors, such as 5-azacytidine (Aza), can generate a steady supply of functional Treg cells. Therefore, we propose that Aza can augment Treg cells in vivo to prevent the pathogenesis of asthma.
  
  
  METHODS
  BALB/c mice were sensitized with chicken ovalbumin (OVA) and treated with different doses of Aza. Airway hyperresponsiveness to methacholine, eosinophilia in bronchoalveolar lavage fluid, circulating titers of OVA-specific IgG1 and IgE, and stimulating levels of TH2 cytokines from splenocytes were then determined. Cellular populations were examined by flow cytometry. PC61 antibody, which depletes CD25+ cells, was used to verify the role of CD25+ cells in Aza-induced tolerance.
  
  
  RESULTS
  Administration of Aza to OVA-sensitized mice diminished airway hyperreactivity, pulmonary eosinophilia, levels of OVA-specific IgG1 and IgE in serum, and secretion of TH2 cytokines from OVA-stimulated splenocytes in a dose-dependent manner. Percentages of CD25+ and FoxP3+ cells in the CD4+ cell population were notably increased in Aza-treated mice compared to sensitized control mice. Furthermore, the major symptoms of asthma were exacerbated by depleting CD25+ cells in Aza-treated mice.
  
  
  CONCLUSIONS
  Aza may have applications as a novel clinical strategy to increase the production of Treg cells in order to modulate the airway inflammation associated with asthma.
authors.affiliation: Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan, ROC.
authors.forename: Cheng-Jang
authors.initials: CJ
authors.lastname: Wu
authors.forename: Chin-Yu
authors.initials: CY
authors.lastname: Yang
authors.forename: Yi-Hsin
authors.initials: YH
authors.lastname: Chen
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Chen
authors.forename: Li-Chen
authors.initials: LC
authors.lastname: Chen
authors.forename: Ming-Ling
authors.initials: ML
authors.lastname: Kuo
mesh_terms: D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology; D001374:Azacitidine / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D016535:Bronchial Hyperreactivity / Q000188:drug therapy* / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D015704:CD4 Antigens / Q000096:biosynthesis; D019175:DNA Methylation / Q000187:drug effects; D004802:Eosinophilia / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D007073:Immunoglobulin E / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D018793:Interleukin-13 / Q000032:analysis; D053645:Interleukin-2 Receptor alpha Subunit / Q000037:antagonists & inhibitors / Q000276:immunology; D015847:Interleukin-4 / Q000032:analysis; D015848:Interleukin-5 / Q000032:analysis; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology; D012137:Respiratory System / Q000276:immunology / Q000378:metabolism; D013154:Spleen / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007074:Immunoglobulin G; D018793:Interleukin-13; D053645:Interleukin-2 Receptor alpha Subunit; D015848:Interleukin-5; D016210:Methacholine Chloride; D015847:Interleukin-4; D007073:Immunoglobulin E; D010047:Ovalbumin; D001374:Azacitidine