Reduced Ets Domain-containing Protein Elk1 Promotes Pulmonary Fibrosis via Increased Integrin αvβ6 Expression*
- Amanda L. Tatler‡1,
- Anthony Habgood‡,
- Joanne Porte‡,
- Alison E. John‡,
- Anastasios Stavrou‡,
- Emily Hodge‡,
- Cheryl Kerama-Likoko‡,
- Shelia M. Violette§,
- Paul H. Weinreb§,
- Alan J. Knox‡,
- Geoffrey Laurent¶,‖,
- Helen Parfrey**,
- Paul John Wolters‡‡,
- William Wallace§§,
- Siegfried Alberti¶¶,
- Alfred Nordheim¶¶ and
- Gisli Jenkins‡
- From the ‡Division of Respiratory Medicine, University of Nottingham, Nottingham University Hospitals, City Campus, Nottingham NG5 1PB, United Kingdom,
- §Biogen Inc., Cambridge, Massachusetts 02142,
- the ¶Centre for Respiratory Research, University College London, London WC1E 6JF, United Kingdom,
- the ‖Centre for Cell Therapy and Regenerative Medicine, University of Western Australia, Crawley WA 6009, Australia,
- the **Department of Medicine, University of Cambridge and Papworth Hospital NHSFT, Cambridge CB2 0SP, United Kingdom,
- the ‡‡Department of Medicine, University of California, San Francisco, San Francisco, California 94143,
- the §§Division of Pathology, University of Edinburgh, Edinburgh EH4 2XR, United Kingdom, and
- the ¶¶Interfaculty Institute of Cell Biology, Tübingen University, Tübingen 72076, Germany
- ↵1 To whom correspondence should be addressed: Div. of Respiratory Medicine, City Campus, Nottingham University Hospitals, Hucknall Rd., Nottingham NG5 1PB, UK. Tel.: 44-1158231106; E-mail: amanda.tatler{at}nottingham.ac.uk.
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with high mortality. Active TGFβ1 is considered central to the pathogenesis of IPF. A major mechanism of TGFβ1 activation in the lung involves the epithelially restricted αvβ6 integrin. Expression of the αvβ6 integrin is dramatically increased in IPF. How αvβ6 integrin expression is regulated in the pulmonary epithelium is unknown. Here we identify a region in the β6 subunit gene (ITGB6) promoter acting to markedly repress basal gene transcription, which responds to both the Ets domain-containing protein Elk1 (Elk1) and the glucocorticoid receptor (GR). Both Elk1 and GR can regulate αvβ6 integrin expression in vitro. We demonstrate Elk1 binding to the ITGB6 promoter basally and that manipulation of Elk1 or Elk1 binding alters ITGB6 promoter activity, gene transcription, and αvβ6 integrin expression. Crucially, we find that loss of Elk1 causes enhanced Itgb6 expression and exaggerated lung fibrosis in an in vivo model of fibrosis, whereas the GR agonist dexamethasone inhibits Itgb6 expression. Moreover, Elk1 dysregulation is present in epithelium from patients with IPF. These data reveal a novel role for Elk1 regulating ITGB6 expression and highlight how dysregulation of Elk1 can contribute to human disease.
Footnotes
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↵* This work was supported by Wellcome Trust Grant 085350 (to G. J.), the National Centre for the Replacement, Refinement, and Reduction of Animals in Research Grant G110564 (to G. J.), German Cancer Aid Grant 109886 (to A. N.), and an NC3Rs David Sainsbury fellowship (to A. T.). S. M. V. and P. H. W. are shareholders of Biogen Idec. G. J. has received consultancy fees from GlaxoSmithKline, Intermune, Boehringer Ingelheim, Biogen, and PharmAkea and lecture fees from Intermune, Medimmune, Roche, and Boehringer Ingelheim and has sponsored research agreements with GlaxoSmithKline, Novartis, and Biogen.
- Received September 14, 2015.
- Revision received February 9, 2016.
- © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
Author's Choice—Final version free via Creative Commons CC-BY license.
