title: Bcl6 in pulmonary epithelium coordinately controls the expression of the CC-type chemokine genes and attenuates allergic airway inflammation.
abstract: BACKGROUND
  There is synteny in the CC-type chemokine gene clusters between humans (CCL2/MCP-1, CCL7MCP-3, CCL11/eotaxin, CCL8/MCP-2, CCL13/MCP-4, and CCL1/I-309) and mice (CCL2, CCL7, CCL11, CCL12/MCP-5, CCL8, and CCL1).
  
  
  OBJECTIVE
  As many putative Bcl6/STAT-binding sequences are observed in the clusters, we examined the roles of a transcriptional repressor Bcl6 and the regional histone modification in the expression of these chemokine genes in pulmonary epithelium.
  
  
  METHODS
  We generated transgenic (Tg) mice carrying the Bcl6 or the dominant-negative (DN)-Bcl6 gene under the control of the surfactant protein C (SPC) promoter that induces the exogenous gene expression in the distal lung epithelium. For in vitro studies, A549, alveolar type II-like epithelial cell line transfected with the SPC-DN-Bcl6 gene were stimulated with IL-4+TNF-α, and Bcl6 or STAT6 binding to and histone modification of the cluster in the transfectants were analysed by chromatin immunoprecipitation assays. Tg mice sensitized with ovalbumin (OVA) were challenged with OVA inhalation. The amounts of mRNAs in each sample were analysed by quantitative RT-PCR.
  
  
  RESULTS
  The amount of Bcl6 bound to the cluster decreased in A549 cells stimulated with IL-4 and TNF-α, whereas STAT6 binding increased in association with regional histone H3-K9/14 acetylation and H3-K4 methylation. The expression of all chemokine genes in the gene cluster was augmented in activated A549 cells transfected with the DN-Bcl6 gene. We also induced allergic airway inflammation in Tg mice. Expression of the chemokine genes and infiltrated cell numbers in the lungs of these Tg mice with allergic airway inflammation were inversely correlated with the amount of Bcl6 in the lungs.
  
  
  CONCLUSIONS
  Expression of the pulmonary epithelium-derived CC-type chemokine genes in the cluster is orchestrated by the conserved machinery related to Bcl6. Thus, Bcl6 in pulmonary epithelium may be a critical regulator for pathogenesis of various pulmonary inflammatory diseases.
authors.affiliation: Department of Developmental Genetics (H2), Graduate School of Medicine, Chiba University, Chiba, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Seto
authors.forename: M
authors.initials: M
authors.lastname: Yoshitake
authors.forename: T
authors.initials: T
authors.lastname: Ogasawara
authors.forename: J
authors.initials: J
authors.lastname: Ikari
authors.forename: A
authors.initials: A
authors.lastname: Sakamoto
authors.forename: M
authors.initials: M
authors.lastname: Hatano
authors.forename: H
authors.initials: H
authors.lastname: Hirata
authors.forename: T
authors.initials: T
authors.lastname: Fukuda
authors.forename: T
authors.initials: T
authors.lastname: Kuriyama
authors.forename: K
authors.initials: K
authors.lastname: Tatsumi
authors.forename: T
authors.initials: T
authors.lastname: Tokuhisa
authors.forename: M
authors.initials: M
authors.lastname: Arima
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D001665:Binding Sites; D002460:Cell Line; D019742:Chemokines, CC / Q000235:genetics* / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism*; D015870:Gene Expression; D005786:Gene Expression Regulation; D023061:Gene Order; D006657:Histones / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology; D051560:Proto-Oncogene Proteins c-bcl-6; D012130:Respiratory Hypersensitivity / Q000235:genetics* / Q000276:immunology*
chemical_list: D000941:Antigens; C490010:Bcl6 protein, mouse; D019742:Chemokines, CC; D004268:DNA-Binding Proteins; D006657:Histones; D051560:Proto-Oncogene Proteins c-bcl-6; D010047:Ovalbumin