title: Airway epithelial transcription factor NK2 homeobox 1 inhibits mucous cell metaplasia and Th2 inflammation.
abstract: BACKGROUND
  Airway mucous cell metaplasia and chronic inflammation are pathophysiological features that influence morbidity and mortality associated with asthma and other chronic pulmonary disorders. Elucidation of the molecular mechanisms regulating mucous metaplasia and hypersecretion provides the scientific basis for diagnostic and therapeutic opportunities to improve the care of chronic pulmonary diseases.
  
  
  OBJECTIVE
  To determine the role of the airway epithelial–specific transcription factor NK2 homeobox 1 (NKX2-1, also known as thyroid transcription factor-1 [TTF-1]) in mucous cell metaplasia and lung inflammation.
  
  
  METHODS
  Expression of NKX2-1 in airway epithelial cells from patients with asthma was analyzed. NKX2-1 +/-gene targeted or transgenic mice expressing NKX2-1 in conducting airway epithelial cells were sensitized to the aeroallergen ovalbumin. In vitro studies were used to identify mechanisms by which NKX2-1 regulates mucous cell metaplasia and inflammation.
  
  
  RESULTS
  NKX2-1 was suppressed in airway epithelial cells from patients with asthma. Reduced expression of NKX2-1 in heterozygous NKX2-1 +/- gene targeted mice increased mucous metaplasia in the small airways after pulmonary sensitization to ovalbumin. Conversely, mucous cell metaplasia induced by aeroallergen was inhibited by expression of NKX2-1 in the respiratory epithelium in vivo. Genome-wide mRNA analysis of lung tissue from ovalbumin-treated mice demonstrated that NKX2-1 inhibited mRNAs associated with mucous metaplasia and Th2-regulated inflammation,including Spdef, Ccl17, and Il13. In vitro, NKX2-1 inhibited SPDEF, a critical regulator of airway mucous cell metaplasia,and the Th2 chemokine CCL26.
  
  
  CONCLUSIONS
  The present data demonstrate a novel function for NKX2-1 in a gene network regulating mucous cell metaplasia and allergic inflammation in the respiratory epithelium.
authors.affiliation: Perinatal Institute, Divisions of Neonatology, Perinatal, and Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Maeda
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.forename: Hans Michael
authors.initials: HM
authors.lastname: Haitchi
authors.forename: Lingling
authors.initials: L
authors.lastname: Du
authors.forename: Angela R
authors.initials: AR
authors.lastname: Keiser
authors.forename: Peter H
authors.initials: PH
authors.lastname: Howarth
authors.forename: Donna E
authors.initials: DE
authors.lastname: Davies
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Holgate
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Whitsett
mesh_terms: D000293:Adolescent; D000328:Adult; D000485:Allergens / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000378:metabolism; D054414:Chemokine CCL17 / Q000235:genetics; D015536:Down-Regulation; D005260:Female; D053263:Gene Regulatory Networks; D051542:Hepatocyte Nuclear Factor 3-beta / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D007114:Immunization; D066298:In Vitro Techniques; D008168:Lung / Q000378:metabolism; D008297:Male; D008679:Metaplasia / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010047:Ovalbumin / Q000276:immunology; D011014:Pneumonia / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D050783:Proto-Oncogene Proteins c-ets / Q000037:antagonists & inhibitors / Q000235:genetics; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D020545:Respiratory Mucosa / Q000378:metabolism* / Q000473:pathology*; D018418:Th2 Cells / Q000473:pathology*; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000485:Allergens; C499538:Ccl17 protein, mouse; D054414:Chemokine CCL17; C496503:Foxa2 protein, mouse; C000614412:NKX2-1 protein, human; C000614414:Nkx2-1 protein, mouse; D009687:Nuclear Proteins; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger; C519908:Spdef protein, mouse; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; D051542:Hepatocyte Nuclear Factor 3-beta; D010047:Ovalbumin