title: Localized expression of tenascin in systemic sclerosis-associated pulmonary fibrosis and its regulation by insulin-like growth factor binding protein 3.
abstract: OBJECTIVE
  To determine the role of insulin-like growth factor binding protein 3 (IGFBP-3) in mediating the effects of transforming growth factor β (TGFβ) on tenascin-C (TN-C) production and to assess the levels of TN-C in vivo in patients with systemic sclerosis (SSc)-associated pulmonary fibrosis.
  
  
  METHODS
  Human primary lung fibroblasts were stimulated with TGFβ or IGFBP-3 in the presence or absence of specific small interfering RNAs and chemical inhibitors of the signaling cascade. TN-C levels in lung tissue specimens obtained from patients with SSc-associated pulmonary fibrosis were assessed using immunohistochemical analysis and were compared with the levels in specimens obtained from normal donors. TN-C levels were quantified in sera from normal donors and patients with SSc with or without pulmonary fibrosis, using an enzyme-linked immunosorbent assay.
  
  
  RESULTS
  IGFBP-3 mediated the induction of TN-C by TGFβ. Direct induction of TN-C by IGFBP-3 occurred in a p38 MAP kinase-dependent manner. TN-C levels were abundant in lung tissues from patients with SSc and were localized to subepithelial layers of the distal airways. No TN-C was detectable around the proximal airways. Patients with SSc-associated pulmonary fibrosis had significantly higher levels of circulating TN-C compared with SSc patients without pulmonary fibrosis. Longitudinal samples obtained from patients with SSc before and after the onset of pulmonary fibrosis showed increased levels of TN-C after the onset of pulmonary fibrosis.
  
  
  CONCLUSIONS
  IGFBP-3, which is overexpressed in fibrotic lungs, induces production of TN-C by subepithelial fibroblasts. The increased lung tissue levels of TN-C parallel the levels detected in the sera of SSc patients with pulmonary fibrosis, suggesting that TN-C may be a useful biomarker for SSc-related pulmonary fibrosis.
authors: University of Pittsburgh, Department of Medicine, Pittsburgh, Pennsylvania 15231, USA.
authors: Monique
authors: M
authors: Brissett
authors: Kristen L
authors: KL
authors: Veraldi
authors: Joseph M
authors: JM
authors: Pilewski
authors: Thomas A
authors: TA
authors: Medsger
authors: Carol A
authors: CA
authors: Feghali-Bostwick
mesh_terms: D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage; D011994:Recombinant Proteins / Q000494:pharmacology; D012595:Scleroderma, Systemic / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D019063:Tenascin / Q000032:analysis / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D018972:Insulin-Like Growth Factor Binding Protein 3; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D019063:Tenascin; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases