Jennifer T Cairns
Loss of ELK1 has differential effects on age-dependent organ fibrosis and integrin expression
Cairns, Jennifer T; Habgood, Anthony; Edwards-Pritchard, Rochelle C; Wilkinson, Chloe; Stewart, Iain D; Leslie, Jack; Blaxall, Burns C; Susztak, Katalin; Alberti, Siegfried; Nordheim, Alfred; Oakley, Fiona; Jenkins, R Gisli; Tatler, Amanda L
Authors
Anthony Habgood
Rochelle C Edwards-Pritchard
Chloe Wilkinson
Iain D Stewart
Jack Leslie
Burns C Blaxall
Katalin Susztak
Siegfried Alberti
Alfred Nordheim
Fiona Oakley
R Gisli Jenkins
AMANDA TATLER AMANDA.TATLER@NOTTINGHAM.AC.UK
Principal Research Fellow
Abstract
ETS domain-containing protein-1 (ELK1) is a transcription factor important in regulating ?v?6 integrin expression. ?v?6 integrins activate the profibrotic cytokine Transforming Growth Factor ?1 (TGF?1) and are increased in the alveolar epithelium in idiopathic pulmonary fibrosis (IPF). IPF is a disease associated with aging and therefore we hypothesised that aged animals lacking Elk1 globally would develop spontaneous fibrosis in organs where ?v?6 mediated TGF? activation has been implicated. Here we identify that Elk1-knockout (Elk1?/0) mice aged to one year developed spontaneous fibrosis in the absence of injury in both the lung and the liver but not in the heart or kidneys. The lungs of Elk1?/0 aged mice demonstrated increased collagen deposition, in particular collagen 3?1, located in small fibrotic foci and thickened alveolar walls. Despite the liver having relatively low global levels of ELK1 expression, Elk1?/0 animals developed hepatosteatosis and fibrosis. The loss of Elk1 also had differential effects on Itgb1, Itgb5 and Itgb6 expression in the four organs potentially explaining the phenotypic differences in these organs. To understand the potential causes of reduced ELK1 in human disease we exposed human lung epithelial cells and murine lung slices to cigarette smoke extract, which lead to reduced ELK1 expression andmay explain the loss of ELK1 in human disease. These data support a fundamental role for ELK1 in protecting against the development of progressive fibrosis via transcriptional regulation of beta integrin subunit genes, and demonstrate that loss of ELK1 can be caused by cigarette smoke.
Citation
Cairns, J. T., Habgood, A., Edwards-Pritchard, R. C., Wilkinson, C., Stewart, I. D., Leslie, J., …Tatler, A. L. (2020). Loss of ELK1 has differential effects on age-dependent organ fibrosis and integrin expression. International Journal of Biochemistry and Cell Biology, 120, Article 105668. https://doi.org/10.1016/j.biocel.2019.105668
Journal Article Type | Article |
---|---|
Acceptance Date | Dec 16, 2019 |
Online Publication Date | Dec 23, 2019 |
Publication Date | 2020-03 |
Deposit Date | Feb 25, 2020 |
Publicly Available Date | Mar 12, 2020 |
Journal | International Journal of Biochemistry and Cell Biology |
Print ISSN | 1357-2725 |
Publisher | Elsevier |
Volume | 120 |
Article Number | 105668 |
DOI | https://doi.org/10.1016/j.biocel.2019.105668 |
Public URL | https://nottingham-repository.worktribe.com/output/3032076 |
Publisher URL | https://www.sciencedirect.com/science/article/pii/S1357272519302456 |
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Publisher Licence URL
https://creativecommons.org/licenses/by-nc-nd/4.0/
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