title: DNA methylation of TH1/TH2 cytokine genes affects sensitization and progress of experimental asthma.
abstract: BACKGROUND
  Epigenetic changes in DNA methylation have recently been demonstrated to be involved in effector T-cell polarization, resulting in differential secretion of T(H)1 and T(H)2 cytokines. However, the contribution to the development of a chronic inflammatory phenotype remains still unclear.
  
  
  OBJECTIVE
  We sought to investigate changes in DNA methylation in marker genes of T-cell subsets during allergen sensitization/challenge and their influence on the development of an allergic airway inflammatory response.
  
  
  METHODS
  The relationship between changes in DNA methylation and phenotype development were examined in a well-established model of experimental asthma. DNA methylation was investigated at genomic loci associated with T(H)1 (IFNG promoter) or T(H)2 (conserved noncoding sequence 1 [CNS1]) cytokine production by using bisulfite pyrosequencing.
  
  
  RESULTS
  Analysis of CD4(+) T cells revealed a significant increase in DNA methylation at the IFNG promoter after allergen sensitization/challenge, which correlated with decreased IFN-γ cytokine expression, whereas only minor changes were observed at the CNS1 locus. Furthermore, the increase in DNA methylation at the IFNG promoter could be reversed with a DNA methyltransferase (DNMT) inhibitor in vitro and in vivo with beneficial effects on sensitization status and allergic phenotype. The specific importance of the DNA methylation status in CD4(+) T cells could be confirmed by using adoptive transfer experiments.
  
  
  CONCLUSIONS
  We here report the novel finding that epigenetic regulation in T cells contributes to the development of experimental asthma and can be targeted pharmacologically.
authors.affiliation: Institute for Laboratory Medicine and Pathobiochemistry, Philipps University of Marburg, Marburg, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Brand
authors.forename: Dörthe Andrea
authors.initials: DA
authors.lastname: Kesper
authors.forename: René
authors.initials: R
authors.lastname: Teich
authors.forename: Esma
authors.initials: E
authors.lastname: Kilic-Niebergall
authors.forename: Olaf
authors.initials: O
authors.lastname: Pinkenburg
authors.forename: Evita
authors.initials: E
authors.lastname: Bothur
authors.forename: Michael
authors.initials: M
authors.lastname: Lohoff
authors.forename: Holger
authors.initials: H
authors.lastname: Garn
authors.forename: Petra Ina
authors.initials: PI
authors.lastname: Pfefferle
authors.forename: Harald
authors.initials: H
authors.lastname: Renz
mesh_terms: D000818:Animals; D001249:Asthma / Q000235:genetics* / Q000276:immunology; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000235:genetics*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D044127:Epigenesis, Genetic; D005260:Female; D007371:Interferon-gamma / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D011401:Promoter Regions, Genetic; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
chemical_list: D016207:Cytokines; D000077209:Decitabine; D007371:Interferon-gamma; D004248:DNA (Cytosine-5-)-Methyltransferases; D001374:Azacitidine