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Microarray profiling reveals suppressed interferon stimulated gene program in fibroblasts from scleroderma-associated interstitial lung disease.

ABSTRACT: 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.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.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-? 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.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.

SUBMITTER: Lindahl GE

PROVIDER: S-EPMC3750263 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Microarray profiling reveals suppressed interferon stimulated gene program in fibroblasts from scleroderma-associated interstitial lung disease.

Lindahl Gisela E GE Stock Carmel Jw CJ Shi-Wen Xu X Leoni Patricia P Sestini Piersante P Howat Sarah L SL Bou-Gharios George G Nicholson Andrew G AG Denton Christopher P CP Grutters Jan C JC Maher Toby M TM Wells Athol U AU Abraham David J DJ Renzoni Elisabetta A EA

Respiratory research 20130802

<h4>Background</h4>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 s ...[more]

PMID: 23915349

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Project description:Although several genetic associations with scleroderma (SSc) are defined, very little is known on genetic susceptibility to SSc-associated interstitial lung disease (SSc-ILD). A number of common polymorphisms have been associated with SSc-ILD, but most have not been replicated in separate populations. Four SNPs in IRF5, and one in each of STAT4, CD226 and IRAK1, selected as having been previously the most consistently associated with SSc-ILD, were genotyped in 612 SSc patients, of European descent, of whom 394 had ILD. The control population (n?=?503) comprised individuals of European descent from the 1000 Genomes Project. After Bonferroni correction, two of the IRF5 SNPs, rs2004640 (OR (95% CI)1.30 (1.10-1.54), pcorr?=?0.015) and rs10488631 (OR 1.48 (1.14-1.92), pcorr?=?0.022), and the STAT4 SNP rs7574865 (OR 1.43 (1.18-1.73), pcorr?=?0.0015) were significantly associated with SSc compared with controls. However, none of the SNPs were significantly different between patients with SSc-ILD and controls. Two SNPs in IRF5, rs10488631 (OR 1.72 (1.24-2.39), pcorr?=?0.0098), and rs2004640 (OR 1.39 (1.11-1.75), pcorr?=?0.03), showed a significant difference in allele frequency between controls and patients without ILD, as did STAT4 rs7574865 (OR 1.86 (1.45-2.38), pcorr?=?6.6?×?10-6). A significant difference between SSc with and without ILD was only observed for STAT4 rs7574865, being less frequent in patients with ILD (OR 0.66 (0.51-0.85), pcorr?=?0.0084). In conclusion, IRF5 rs2004640 and rs10488631, and STAT4 rs7574865 were significantly associated with SSc as a whole. Only STAT4 rs7574865 showed a significant difference in allele frequency in SSc-ILD, with the T allele being protective against ILD.Key points• We confirm the associations of the IRF5 SNPs rs2004640 and rs10488631, and the STAT4 SNP rs7574865, with SSc as a whole.• None of the tested SNPs were risk factors for SSc-ILD specifically.• The STAT4 rs7574865 T allele was protective against the development of lung fibrosis in SSc patients.• Further work is required to understand the genetic basis of lung fibrosis in association with scleroderma.

Project description:Patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) are thought to have the greatest decline in lung function (forced vital capacity [FVC]% predicted) in the early years after disease onset. The aim of this study was to assess the natural history of the decline in FVC% predicted in patients receiving placebo in the Scleroderma Lung Study and to evaluate possible factors for cohort enrichment in future therapeutic trials.Patients randomized to receive placebo (n=79) were divided into 3 groups based on the duration of SSc (0-2 years, 2-4 years, and >4 years). Descriptive statistics and a mixed-effects model were used to analyze the rate of decline in the FVC% predicted over a 1-year period. Additional analyses stratified according to the severity of fibrosis on high-resolution computed tomography (HRCT) were performed, and interactions between disease severity and disease duration were explored.The mean±SD decline in the unadjusted FVC% predicted during the 1-year period was 4.2±12.8%. At baseline, 28.5%, 43.0%, and 28.5% of patients were in the groups with disease durations of 0-2 years, 2-4 years, and >4 years, respectively. The rate of decline in the FVC% predicted was not significantly different across the 3 disease groups (P=0.85). When stratified by baseline fibrosis on HRCT, the rate of decline in the FVC% predicted was statistically significantly greater in the group with severe fibrosis (mean annualized decline in the FVC% predicted 7.2% versus 2.7% in the groups with no or moderate fibrosis; P=0.008). The decline observed in the group with severe fibrosis was most pronounced in those with a relatively short disease duration (0-2 years; annualized decline 7.0%).Among patients with SSc-ILD in the Scleroderma Lung Study, the rates of progression of lung disease were similar irrespective of disease duration. The baseline HRCT fibrosis score is a predictor of a future decline in the FVC% predicted in the absence of effective treatment.

Dataset Information

Microarray profiling reveals suppressed interferon stimulated gene program in fibroblasts from scleroderma-associated interstitial lung disease.

Publications

Microarray profiling reveals suppressed interferon stimulated gene program in fibroblasts from scleroderma-associated interstitial lung disease.

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