Inhibition of activator protein 1 signaling abrogates transforming growth factor β-mediated activation of fibroblasts and prevents experimental fibrosis

Avouac J, Palumbo K, Tomcik M, Zerr P, Dees C, Horn A, Maurer B, Akhmetshina A, Beyer C, Sadowski A, Schneider H, Shiozawa S, Distler O, Schett G, Allanore Y, Distler J (2012)

Publication Type: Journal article

Publication year: 2012

Journal

Book Volume: 64

Pages Range: 1642-1652

Journal Issue: 5

DOI: 10.1002/art.33501

Abstract

Objective To investigate whether c-Jun and c-Fos contribute to the pathologic activation of fibroblasts in systemic sclerosis (SSc) and to evaluate the antifibrotic potential of selective activator protein 1 (AP-1) inhibition. Methods Expression of c-Jun and c-Fos was determined by real-time polymerase chain reaction (PCR) and immunohistochemical analysis. Fibroblasts were stimulated with transforming growth factor β (TGFβ) and incubated with T-5224, a small-molecule inhibitor of AP-1, or were transfected with small interfering RNA (siRNA) duplexes against c-Jun and c-Fos. Collagen synthesis was quantified by real-time PCR and hydroxyproline assay. Differentiation of resting fibroblasts into myofibroblasts was assessed by staining for α-smooth muscle actin and stress fibers. The antifibrotic potential of T-5224 was evaluated in mouse models of dermal fibrosis induced by bleomycin or by adenoviral overexpression of a constitutively active TGFβ receptor type I. Results Up-regulation of c-Jun and c-Fos was detected in mouse models of SSc and in the skin and dermal fibroblasts of patients with SSc. Stimulation of healthy fibroblasts with TGFβ induced the expression of c-Jun and c-Fos. Treatment with T-5224 or nucleofection with siRNA directed against c-Jun and c-Fos abrogated the profibrotic effects of TGFβ. T-5224 decreased the release of collagen selectively in SSc fibroblasts. T-5224 was well tolerated and prevented dermal fibrosis induced by bleomycin or by adenoviral activation of TGFβ signaling. Conclusion AP-1 is up-regulated in a TGFβ-dependent manner in SSc. The selective AP-1 inhibitor T-5224 reduced collagen synthesis selectively in SSc fibroblasts and efficiently prevented the development of experimental dermal fibrosis. Thus, AP-1 might be a promising new molecular target for the treatment of SSc. Copyright © 2012 by the American College of Rheumatology.

Authors with CRIS profile

Involved external institutions

Univerzita Karlova v Praze / Charles University in Prague Czech Republic (CZ) University of Paris 5 - René Descartes / Université Paris V René Descartes France (FR) Kobe University / 神戸大学 Japan (JP) Universitätsspital Zürich (USZ) Switzerland (CH)

How to cite

APA:

Avouac, J., Palumbo, K., Tomcik, M., Zerr, P., Dees, C., Horn, A.,... Distler, J. (2012). Inhibition of activator protein 1 signaling abrogates transforming growth factor β-mediated activation of fibroblasts and prevents experimental fibrosis. Arthritis and Rheumatism, 64(5), 1642-1652. https://doi.org/10.1002/art.33501

MLA:

Avouac, Jerome, et al. "Inhibition of activator protein 1 signaling abrogates transforming growth factor β-mediated activation of fibroblasts and prevents experimental fibrosis." Arthritis and Rheumatism 64.5 (2012): 1642-1652.

BibTeX: Download