Gene expression profiling reveals novel TGF beta targets in adult lung fibroblasts

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Title: Gene expression profiling reveals novel TGF beta targets in adult lung fibroblasts
Authors: Renzoni, EA
Abraham, DJ
Howat, S
Xu, SW
Sestini, P
Bou-Gharios, G
Wells, AU
Veeraraghavan, S
Nicholson, AG
Denton, CP
Leask, A
Pearson, JD
Black, CM
Welsh, KI
Du Bois, RM
Item Type: Journal Article
Abstract: Background: Transforming growth factor beta (TGFβ), a multifunctional cytokine, plays a crucial role in the accumulation of extracellular matrix components in lung fibrosis, where lung fibroblasts are considered to play a major role. Even though the effects of TGFβ on the gene expression of several proteins have been investigated in several lung fibroblast cell lines, the global pattern of response to this cytokine in adult lung fibroblasts is still unknown. Methods: We used Affymetrix oligonucleotide microarrays U95v2, containing approximately 12,000 human genes, to study the transcriptional profile in response to a four hour treatment with TGFβ in control lung fibroblasts and in fibroblasts from patients with idiopathic and sclerodermaassociated pulmonary fibrosis. A combination of the Affymetrix change algorithm (Microarray Suite 5) and of analysis of variance models was used to identify TGFβ-regulated genes. Additional criteria were an average up- or down- regulation of at least two fold. Results: Exposure of fibroblasts to TGFβ had a profound impact on gene expression, resulting in regulation of 129 transcripts. We focused on genes not previously found to be regulated by TGFβ in lung fibroblasts or other cell types, including nuclear co-repressor 2, SMAD specific E3 ubiquitin protein ligase 2 (SMURF2), bone morphogenetic protein 4, and angiotensin II receptor type 1 (AGTR1), and confirmed the microarray results by real time-PCR. Western Blotting confirmed induction at the protein level of AGTR1, the most highly induced gene in both control and fibrotic lung fibroblasts among genes encoding for signal transduction molecules. Upregulation of AGTR1 occurred through the MKK1/MKK2 signalling pathway. Immunohistochemical staining showed AGTR1 expression by lung fibroblasts in fibroblastic foci within biopsies of idiopathic pulmonary fibrosis. Conclusions: This study identifies several novel TGFβ targets in lung fibroblasts, and confirms with independent methods the induction of angiotensin II receptor type 1, underlining a potential role for angiotensin II receptor 1 antagonism in the treatment of lung fibrosis.
Issue Date: 30-Nov-2004
Date of Acceptance: 30-Nov-2004
URI: http://hdl.handle.net/10044/1/49354
DOI: https://dx.doi.org/10.1186/1465-9921-5-24
ISSN: 1465-9921
Publisher: BioMed Central
Journal / Book Title: Respiratory Research
Volume: 5
Issue: 1
Copyright Statement: © 2004 Renzoni et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Science & Technology
Life Sciences & Biomedicine
Respiratory System
RESPIRATORY SYSTEM
GROWTH-FACTOR-BETA
IDIOPATHIC PULMONARY FIBROSIS
ANGIOTENSIN-II
CARDIAC FIBROBLASTS
SYSTEMIC-SCLEROSIS
TYPE-1 RECEPTOR
INHIBITOR
DISEASE
DEGRADATION
ACTIVATION
Cells, Cultured
Drug Delivery Systems
Fibroblasts
Gene Expression Profiling
Humans
Pulmonary Fibrosis
Receptor, Angiotensin, Type 1
Transforming Growth Factor beta
1102 Cardiovascular Medicine And Haematology
1103 Clinical Sciences
Publication Status: Published
Article Number: ARTN 24
Appears in Collections:Population Genetics and Gene Therapy
National Heart and Lung Institute
Faculty of Medicine



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