title: Microarray profiling reveals suppressed interferon stimulated gene program in fibroblasts from scleroderma-associated interstitial lung disease.
abstract: BACKGROUND
  Interstitial lung disease is a major cause of morbidity and mortality in systemic sclerosis (SSc), with insufficiently effective treatment options. Progression of pulmonary fibrosis involves expanding populations of fibroblasts, and the accumulation of extracellular matrix proteins. Characterisation of SSc lung fibroblast gene expression profiles underlying the fibrotic cell phenotype could enable a better understanding of the processes leading to the progressive build-up of scar tissue in the lungs. In this study we evaluate the transcriptomes of fibroblasts isolated from SSc lung biopsies at the time of diagnosis, compared with those from control lungs.
  
  
  METHODS
  We used Affymetrix oligonucleotide microarrays to compare the gene expression profile of pulmonary fibroblasts cultured from 8 patients with pulmonary fibrosis associated with SSc (SSc-ILD), with those from control lung tissue peripheral to resected cancer (n=10). Fibroblast cultures from 3 patients with idiopathic pulmonary fibrosis (IPF) were included as a further comparison. Genes differentially expressed were identified using two separate analysis programs following a set of pre-determined criteria: only genes significant in both analyses were considered. Microarray expression data was verified by qRT-PCR and/or western blot analysis.
  
  
  RESULTS
  A total of 843 genes were identified as differentially expressed in pulmonary fibroblasts from SSc-ILD and/or IPF compared to control lung, with a large overlap in the expression profiles of both diseases. We observed increased expression of a TGF-β response signature including fibrosis associated genes and myofibroblast markers, with marked heterogeneity across samples. Strongly suppressed expression of interferon stimulated genes, including antiviral, chemokine, and MHC class 1 genes, was uniformly observed in fibrotic fibroblasts. This expression profile includes key regulators and mediators of the interferon response, such as STAT1, and CXCL10, and was also independent of disease group.
  
  
  CONCLUSIONS
  This study identified a strongly suppressed interferon-stimulated gene program in fibroblasts from fibrotic lung. The data suggests that the repressed expression of interferon-stimulated genes may underpin critical aspects of the profibrotic fibroblast phenotype, identifying an area in pulmonary fibrosis that requires further investigation.
authors.affiliation: Interstitial Lung Disease Unit, Royal Brompton Hospital and National Heart and Lung Institute, Imperial College London, Emmanuel Kaye Building, 1B Manresa Road, London SW3 6LR, UK. g.lindahl@imperial.ac.uk
authors.forename: Gisela E
authors.initials: GE
authors.lastname: Lindahl
authors.forename: Carmel Jw
authors.initials: CJ
authors.lastname: Stock
authors.forename: Xu
authors.initials: X
authors.lastname: Shi-Wen
authors.forename: Patricia
authors.initials: P
authors.lastname: Leoni
authors.forename: Piersante
authors.initials: P
authors.lastname: Sestini
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Howat
authors.forename: George
authors.initials: G
authors.lastname: Bou-Gharios
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Nicholson
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Denton
authors.forename: Jan C
authors.initials: JC
authors.lastname: Grutters
authors.forename: Toby M
authors.initials: TM
authors.lastname: Maher
authors.forename: Athol U
authors.initials: AU
authors.lastname: Wells
authors.forename: David J
authors.initials: DJ
authors.lastname: Abraham
authors.forename: Elisabetta A
authors.initials: EA
authors.lastname: Renzoni
mesh_terms: D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D015536:Down-Regulation; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D007372:Interferons / Q000378:metabolism*; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D017563:Lung Diseases, Interstitial / Q000150:complications* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D040081:Protein Array Analysis; D012595:Scleroderma, Systemic / Q000150:complications* / Q000378:metabolism* / Q000473:pathology
chemical_list: D007372:Interferons
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