title: Altered expression of membrane-bound and soluble CD95/Fas contributes to the resistance of fibrotic lung fibroblasts to FasL induced apoptosis.
abstract: BACKGROUND
  An altered susceptibility of lung fibroblasts to Fas-induced apoptosis has been implicated in the pathogenesis of pulmonary fibrosis; however, the underlying mechanism is not completely understood. Here, we studied the susceptibility of lung fibroblasts, obtained from patients with (f-fibs) and without pulmonary fibrosis (n-fibs), to FasL- (CD95L/APO-1) induced apoptosis in relation to the expression and the amounts of membrane-bound and soluble Fas. We also analysed the effects of tumor necrosis factor-beta on FasL-induced cell death.
  
  
  METHODS
  Apoptosis was induced with recombinant human FasL, with and without prior stimulation of the fibroblasts with tumor necrosis factor-alpha and measured by a histone fragmentation assay and flow cytometry. The expression of Fas mRNA was determined by quantitative PCR. The expression of cell surface Fas was determined by flow cytometry, and that of soluble Fas (sFas) was determined by enzyme-linked immunosorbent assay.
  
  
  RESULTS
  When compared to n-fibs, f-fibs were resistant to FasL-induced apoptosis, despite significantly higher levels of Fas mRNA. F-fibs showed lower expression of surface-bound Fas but higher levels of sFas. While TNF-alpha increased the susceptibility to FasL-induced apoptosis in n-fibs, it had no pro-apoptotic effect in f-fibs.
  
  
  CONCLUSIONS
  The data suggest that lower expression of surface Fas, but higher levels of apoptosis-inhibiting sFas, contribute to the resistance of fibroblasts in lung fibrosis against apoptosis, to increased cellularity and also to increased formation and deposition of extracellular matrix.
authors.affiliation: Institute of Immunology, Otto-von-Guericke-University, Magdeburg, Germany. frank@buehling.net
authors.forename: Frank
authors.initials: F
authors.lastname: Bühling
authors.forename: Aline
authors.initials: A
authors.lastname: Wille
authors.forename: Christoph
authors.initials: C
authors.lastname: Röcken
authors.forename: Olaf
authors.initials: O
authors.lastname: Wiesner
authors.forename: Anja
authors.initials: A
authors.lastname: Baier
authors.forename: Ingmar
authors.initials: I
authors.lastname: Meinecke
authors.forename: Tobias
authors.initials: T
authors.lastname: Welte
authors.forename: Thomas
authors.initials: T
authors.lastname: Pap
mesh_terms: D017209:Apoptosis / Q000276:immunology*; D002462:Cell Membrane / Q000737:chemistry / Q000276:immunology*; D002478:Cells, Cultured; D053222:Fas Ligand Protein; D005347:Fibroblasts / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D008168:Lung / Q000276:immunology* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000276:immunology*; D011658:Pulmonary Fibrosis / Q000276:immunology* / Q000473:pathology; D012995:Solubility; D048069:Tumor Necrosis Factors / Q000276:immunology*; D019014:fas Receptor / Q000737:chemistry / Q000276:immunology*
chemical_list: C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D048069:Tumor Necrosis Factors; D019014:fas Receptor