title: Transcription factors T-bet and GATA-3 regulate development of airway remodeling.
abstract: BACKGROUND
  Airway remodeling is an important feature of chronic asthma that causes irreversible airflow obstruction. Although asthma is considered to be a Th2 disease, the role of T-bet and GATA-3, the key transcription factors for differentiation toward Th1 and Th2 cells, in the pathogenesis of airway remodeling is poorly understood.
  
  
  OBJECTIVE
  We therefore examined the effects of GATA-3 or T-bet induction of Th1/Th2 bias on the development of airway remodeling in mice.
  
  
  METHODS
  The development of airway remodeling after repeated allergen challenges was analyzed using transgenic mice overexpressing either GATA-3 or T-bet.
  
  
  RESULTS
  The degrees of subepithelial fibrosis and airway smooth muscle hyperplasia after repeated allergen exposure were significantly enhanced in mice overexpressing GATA-3, compared with wild-type mice. Allergen-induced goblet cell hyperplasia and mucus hypersecretion were significantly lower in mice overexpressing T-bet than in wild-type mice. Eosinophilic airway inflammation increased in mice overexpressing GATA-3, but decreased in mice overexpressing T-bet after repeated allergen exposure. Cytokine analysis revealed that the Th1/Th2 cytokine balance shifted to Th2 in lung homogenates and lung T cells of mice overexpressing GATA-3, whereas this balance shifted to Th1 in those of mice overexpressing T-bet after allergen exposure. Lung transforming growth factor-beta and eotaxin levels were associated with the degree of subepithelial fibrosis and eosinophilic airway inflammation, respectively.
  
  
  CONCLUSIONS
  Overall, the results indicate that development of airway remodeling is regulated by the lung Th1/Th2 bias induced by GATA-3 and T-bet.
authors.affiliation: Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Kiwamoto
authors.forename: Yukio
authors.initials: Y
authors.lastname: Ishii
authors.forename: Yuko
authors.initials: Y
authors.lastname: Morishima
authors.forename: Keigyou
authors.initials: K
authors.lastname: Yoh
authors.forename: Atsuko
authors.initials: A
authors.lastname: Maeda
authors.forename: Kazusa
authors.initials: K
authors.lastname: Ishizaki
authors.forename: Takashi
authors.initials: T
authors.lastname: Iizuka
authors.forename: Ahmed E
authors.initials: AE
authors.lastname: Hegab
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Matsuno
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Homma
authors.forename: Akihiro
authors.initials: A
authors.lastname: Nomura
authors.forename: Tohru
authors.initials: T
authors.lastname: Sakamoto
authors.forename: Satoru
authors.initials: S
authors.lastname: Takahashi
authors.forename: Kiyohisa
authors.initials: K
authors.lastname: Sekizawa
mesh_terms: D000818:Animals; D001249:Asthma / Q000235:genetics* / Q000473:pathology*; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000032:analysis; D004195:Disease Models, Animal; D004804:Eosinophils / Q000378:metabolism; D005355:Fibrosis; D050990:GATA3 Transcription Factor / Q000276:immunology*; D020397:Goblet Cells / Q000473:pathology; D006965:Hyperplasia; D006984:Hypertrophy; D007136:Immunoglobulins / Q000097:blood; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009077:Mucins / Q000378:metabolism; D009130:Muscle, Smooth / Q000473:pathology; D020825:T-Box Domain Proteins; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D014157:Transcription Factors / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000502:physiology; D000098815:T-bet Transcription Factor
chemical_list: C515457:Ccl11 protein, mouse; D054413:Chemokine CCL11; D019742:Chemokines, CC; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D007136:Immunoglobulins; D009077:Mucins; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D015847:Interleukin-4; D007371:Interferon-gamma