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Molecular and Cellular Biology, July 2006, p. 5518-5527, Vol. 26, No. 14
0270-7306/06/$08.00+0     doi:10.1128/MCB.00625-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Constitutive ALK5-Independent c-Jun N-Terminal Kinase Activation Contributes to Endothelin-1 Overexpression in Pulmonary Fibrosis: Evidence of an Autocrine Endothelin Loop Operating through the Endothelin A and B Receptors

Xu Shi-Wen,1 Fernando Rodríguez-Pascual,2 Santiago Lamas,2 Alan Holmes,1 Sarah Howat,3 Jeremy D. Pearson,3 Michael R. Dashwood,4 Roland M. du Bois,5 Christopher P. Denton,1 Carol M. Black,1 David J. Abraham,1* and Andrew Leask6*

Centre for Rheumatology, Department of Medicine, Royal Free and University College Medical School, Rowland Hill Street, London NW3 2PF, United Kingdom,1 Departamento de Estructura y Función de Proteínas, Centro de Investigaciones Biológicas, C.S.I.C., Ramiro de Maeztu 9, E-28040 Madrid, Spain,2 Centre for Cardiovascular Biology & Medicine, GKT School of Biomedical Sciences, King's College London, Guy's Campus, London SE1 1UL, United Kingdom,3 Department of Molecular Pathology, Royal Free and University College Medical School, Rowland Hill Street, London NW3 2PF, United Kingdom,4 Interstitial Lung Disease Unit, Royal Brompton Hospital, Imperial College of Science, Technology and Medicine, Emmanuel Kaye Building, 1B Manresa Road, London SW3 6LR, United Kingdom,5 CIHR Group in Skeletal Development and Remodeling, Division of Oral Biology, Schulich School of Medicine and Dentistry, Dental Sciences Bldg., University of Western Ontario, London, Ontario N6A 5C1, Canada6

Received 11 April 2006/ Returned for modification 27 April 2006/ Accepted 8 May 2006

The signal transduction mechanisms generating pathological fibrosis are almost wholly unknown. Endothelin-1 (ET-1), which is up-regulated during tissue repair and fibrosis, induces lung fibroblasts to produce and contract extracellular matrix. Lung fibroblasts isolated from scleroderma patients with chronic pulmonary fibrosis produce elevated levels of ET-1, which contribute to the persistent fibrotic phenotype of these cells. Transforming growth factor ß (TGF-ß) induces fibroblasts to produce and contract matrix. In this report, we show that TGF-ß induces ET-1 in normal and fibrotic lung fibroblasts in a Smad-independent ALK5/c-Jun N-terminal kinase (JNK)/Ap-1-dependent fashion. ET-1 induces JNK through TAK1. Fibrotic lung fibroblasts display constitutive JNK activation, which was reduced by the dual ETA/ETB receptor inhibitor, bosentan, providing evidence of an autocrine endothelin loop. Thus, ET-1 and TGF-ß are likely to cooperate in the pathogenesis of pulmonary fibrosis. As elevated JNK activation in fibrotic lung fibroblasts contributes to the persistence of the myofibroblast phenotype in pulmonary fibrosis by promoting an autocrine ET-1 loop, targeting the ETA and ETB receptors or constitutive JNK activation by fibrotic lung fibroblasts is likely to be of benefit in combating chronic pulmonary fibrosis.

* Corresponding author. Mailing address for David J. Abraham: Centre for Rheumatology, Department of Medicine, Royal Free and University College Medical School, Rowland Hill Street, London NW3 2PF, United Kingdom. Phone: 44-(0)207-794-0500, ext. 34062. Fax: 44-(0)207-794-0432. E-mail: d.abraham{at}medsch.ucl.ac.uk. Mailing address for Andrew Leask: CIHR Group in Skeletal Development and Remodeling, Division of Oral Biology, Schulich School of Medicine and Dentistry, Dental Sciences Building, University of Western Ontario, London, Ontario N6A 5C1, Canada. Phone: (519) 661-2111, ext. 81102. Fax: (519) 850-2459. E-mail: Andrew.Leask{at}schulich.uwo.ca.

Molecular and Cellular Biology, July 2006, p. 5518-5527, Vol. 26, No. 14
0270-7306/06/$08.00+0     doi:10.1128/MCB.00625-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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