title: Lung epithelial CCAAT/enhancer-binding protein-β is necessary for the integrity of inflammatory responses to cigarette smoke.
abstract: BACKGROUND
  Cigarette smoke is the major cause of chronic obstructive pulmonary disease and lung cancer. The mechanisms by which smoking induces pulmonary dysfunction are complex, involving stress from toxic components and inflammatory responses. Although CCCAAT/enhancer-binding protein (C/EBP)-β is known as a key intracellular regulator of inflammatory signaling, its role in pulmonary inflammation has not been established.
  
  
  OBJECTIVE
  To characterize the role of C/EBPβ in the airway epithelial response to cigarette smoke.
  
  
  METHODS
  mRNA expression in the airway epithelium of current, former, and never-smokers, and in in vitro cigarette smoke extract-treated primary human airway epithelial cells, was analyzed by microarray and quantitative real-time polymerase chain reaction, respectively. Mice with lung epithelial-specific inactivation of C/EBPβ were generated and exposed to cigarette smoke for 4 or 11 days. Lung histology, bronchoalveolar lavage cell differentials, and expression of inflammatory and innate immune mediators in the lungs were assessed.
  
  
  RESULTS
  C/EBPβ was significantly down-regulated in the airway epithelium of both current and former smokers compared with never-smokers, and in cigarette smoke-treated primary human airway epithelial cells in vitro. Cigarette smoke-exposed mice with a lung epithelial-specific inactivation of C/EBPβ displayed blunted respiratory neutrophil influx and compromised induction of neutrophil chemoattractants growth-regulated oncogene-α, macrophage inflammatory protein-1γ, granulocyte colony-stimulating factor, and serum amyloid A 3 and proinflammatory cytokines tumor necrosis factor-α and interleukin-1β, compared with smoke-exposed controls. Inhibition of C/EBPβ in human airway cells in vitro caused a similarly compromised response to smoke.
  
  
  CONCLUSIONS
  Our data suggest a previously unknown role for C/EBPβ and the airway epithelium in mediating inflammatory and innate immune responses to cigarette smoke.
authors.affiliation: Respiratory Medicine Unit, Department of Medicine, Karolinska Institute, Stockholm, Sweden. lud2002@med.cornell.edu
authors.forename: Lukas
authors.initials: L
authors.lastname: Didon
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Barton
authors.forename: Abraham B
authors.initials: AB
authors.lastname: Roos
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Gaschler
authors.forename: Carla M T
authors.initials: CM
authors.lastname: Bauer
authors.forename: Tove
authors.initials: T
authors.lastname: Berg
authors.forename: Martin R
authors.initials: MR
authors.lastname: Stämpfli
authors.forename: Magnus
authors.initials: M
authors.lastname: Nord
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000276:immunology*; D018929:Cell Culture Techniques; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D007249:Inflammation / Q000276:immunology*; D008168:Lung / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012907:Smoking / Q000276:immunology*
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta