title: Attenuated expression of tenascin-C in ovalbumin-challenged STAT4-/- mice.
abstract: BACKGROUND
  Asthma leads to structural changes in the airways, including the modification of extracellular matrix proteins such as tenascin-C. The role of tenascin-C is unclear, but it might act as an early initiator of airway wall remodelling, as its expression is increased in the mouse and human airways during allergic inflammation. In this study, we examined whether Th1 or Th2 cells are important regulators of tenascin-C in experimental allergic asthma utilizing mice with impaired Th1 (STAT4-/-) or Th2 (STAT6-/-) immunity.
  
  
  METHODS
  Balb/c wildtype (WT), STAT4-/- and STAT6-/- mice were sensitized with intraperitoneally injected ovalbumin (OVA) followed by OVA or PBS airway challenge. Airway hyperreactivity (AHR) was measured and samples were collected. Real time PCR and immunohistochemistry were used to study cytokines and differences in the expression of tenascin-C. Tenascin-C expression was measured in human fibroblasts after treatment with TNF-α and IFN-γ in vitro.
  
  
  RESULTS
  OVA-challenged WT mice showed allergic inflammation and AHR in the airways along with increased expression of TNF-α, IFN-γ, IL-4 and tenascin-C in the lungs. OVA-challenged STAT4-/- mice exhibited elevated AHR and pulmonary eosinophilia. The mRNA expression of TNF-α and IFN-γ was low, but the expression of IL-4 was significantly elevated in these mice. OVA-challenged STAT6-/- mice had neither AHR nor pulmonary eosinophilia, but had increased expression of mRNA for TNF-α, IFN-γ and IL-4. The expression of tenascin-C in the lungs of OVA-challenged STAT4-/- mice was weaker than in those of OVA-challenged WT and STAT6-/- mice suggesting that TNF-α and IFN-γ may regulate tenascin-C expression in vivo. The stimulation of human fibroblasts with TNF-α and IFN-γ induced the expression of tenascin-C confirming our in vivo findings.
  
  
  CONCLUSIONS
  Expression of tenascin-C is significantly attenuated in the airways of STAT4-/- mice, which may be due to the impaired secretion of TNF-α and IFN-γ in these mice.
authors.affiliation: Institute of Biomedicine/Anatomy, University of Helsinki, Biomedicum, Helsinki, Finland. anna.meuronen@helsinki.fi
authors.forename: Anna
authors.initials: A
authors.lastname: Meuronen
authors.forename: Piia
authors.initials: P
authors.lastname: Karisola
authors.forename: Marina
authors.initials: M
authors.lastname: Leino
authors.forename: Terhi
authors.initials: T
authors.lastname: Savinko
authors.forename: Kristiina
authors.initials: K
authors.lastname: Sirola
authors.forename: Marja-Leena
authors.initials: ML
authors.lastname: Majuri
authors.forename: Päivi
authors.initials: P
authors.lastname: Piirilä
authors.forename: Ismo
authors.initials: I
authors.lastname: Virtanen
authors.forename: Mika
authors.initials: M
authors.lastname: Mäkelä
authors.forename: Annika
authors.initials: A
authors.lastname: Laitinen
authors.forename: Lauri A
authors.initials: LA
authors.lastname: Laitinen
authors.forename: Harri
authors.initials: H
authors.lastname: Alenius
mesh_terms: D056151:Airway Remodeling; D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D016535:Bronchial Hyperreactivity; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010047:Ovalbumin; D012333:RNA, Messenger / Q000378:metabolism; D050797:STAT4 Transcription Factor / Q000172:deficiency* / Q000235:genetics; D050800:STAT6 Transcription Factor / Q000172:deficiency / Q000235:genetics; D019063:Tenascin / Q000235:genetics / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D012333:RNA, Messenger; D050797:STAT4 Transcription Factor; D050800:STAT6 Transcription Factor; C494091:Stat4 protein, mouse; C494100:Stat6 protein, mouse; D019063:Tenascin; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D010047:Ovalbumin