title: IL-4 blocks TH1-polarizing/inflammatory cytokine gene expression during monocyte-derived dendritic cell differentiation through histone hypoacetylation.
abstract: BACKGROUND
  Whereas recent research has characterized the mechanism by which dendritic cells (DCs) induce T(H)1/T(H)17 responses, the functional specialization enabling DCs to polarize T(H)2 responses remains undefined. Because IL-4 is essential during T(H)2 responses not only by acting on CD4(+) T cells through the activation of GATA-3 but also by regulating IgE class-switching, epithelial cell permeability, and muscle contractility, we hypothesized that IL-4 could also have a role in the conditioning of DCs during T(H)2 responses.
  
  
  OBJECTIVE
  We sought to analyze whether IL-4 exerts an immunomodulatory function on DCs during their differentiation, leading to their functional specialization for the induction of T(H)2 responses.
  
  
  METHODS
  Monocyte-derived DCs (moDCs) conditioned by IL-4 during their differentiation (IL-4-conditioned moDCs [IL-4-moDCs]) were analyzed for T(H)1-polarizing/inflammatory cytokine production in response to Toll-like receptor stimulation. The acetylation level of the promoters of the genes encoding these cytokines was analyzed by using chromatin immunoprecipitation. Gene expression profiling of IL-4-moDCs was defined by using mouse genome microarrays. IL-4-moDCs were tested for their capacity to induce house dust mite-mediated allergic reactions.
  
  
  RESULTS
  Our data suggest that IL-4 inhibits T(H)1-polarizing/inflammatory cytokine gene expression on IL-4-moDCs through the deacetylation of the promoters of these genes, leading to their transcriptional repression. Microarray analyses confirmed that IL-4 upregulated T(H)2-related genes as eosinophil-associated ribonucleases, eosinophil/basophil chemokines, and M2 genes. IL-4 licensed moDCs for the induction of T(H)2 responses, causing house dust mite-mediated allergic airway inflammation.
  
  
  CONCLUSIONS
  This study describes a new role for IL-4 by demonstrating that moDCs are conditioned by IL-4 for the induction of T(H)2 responses by blocking T(H)1-polarizing/inflammatory cytokine production through histone hypoacetylation and upregulating T(H)2-related genes.
authors.affiliation: Departamento de Inmunología y Oncología, Centro Nacional de Biotecnología (CNB/CSIC), Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: López-Bravo
authors.forename: María
authors.initials: M
authors.lastname: Minguito de la Escalera
authors.forename: Pilar M
authors.initials: PM
authors.lastname: Domínguez
authors.forename: Leticia
authors.initials: L
authors.lastname: González-Cintado
authors.forename: Carlos
authors.initials: C
authors.lastname: del Fresno
authors.forename: Pilar
authors.initials: P
authors.lastname: Martín
authors.forename: Gloria
authors.initials: G
authors.lastname: Martínez del Hoyo
authors.forename: Carlos
authors.initials: C
authors.lastname: Ardavín
mesh_terms: D000107:Acetylation; D000818:Animals; D039741:Antigens, Dermatophagoides / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006967:Hypersensitivity / Q000276:immunology*; D018836:Inflammation Mediators / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology; D011401:Promoter Regions, Genetic / Q000235:genetics; D039981:Pyroglyphidae; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*
chemical_list: D039741:Antigens, Dermatophagoides; D016207:Cytokines; D006657:Histones; D018836:Inflammation Mediators; D015847:Interleukin-4
keywords: AAMΦ; Alternatively activated macrophage; BMDC; BMMΦ; Bone marrow macrophage; Bone marrow–derived dendritic cell; C-moDC; C-moMΦ; CTL; Caudal mediastinal lymph node; ChIP; Chromatin immunoprecipitation; Control moDC; Control moMΦ; Conventional dendritic cell; Cytotoxic T lymphocyte; DC; Dendritic cell; Ear; Eosinophil-associated ribonuclease; HDAC; HDM; Histone deacetylase; House dust mite; IL-4; IL-4–DC; IL-4–conditioned DC; IL-4–conditioned moDC; IL-4–conditioned moMΦ; IL-4–moDC; IL-4–moMΦ; Inducible nitric oxide synthase; Monocyte-derived DC; Monocyte-derived macrophage; NO; Nitric oxide; PPARγ; Peroxisome proliferator-activated receptor γ; Quantitative PCR; Signal transducer and activator of transcription; Stat; T(H)2 responses; T(H)2-DC; T(H)2-polarizing DC; TLR; TSA; Toll-like receptor; Trichostatin A; cDC; cM-LN; dendritic cells; house dust mite–induced allergic reactions; iNOS; moDC; moMΦ; monocyte-derived dendritic cells; qPCR