Elevated protein arginine methyltransferase 1 expression regulates fibroblast motility in pulmonary fibrosis

Dariusz Zakrzewicz; Anna Zakrzewicz; Miroslava Didiasova; Marek Korencak; Djuro Kosanovic; Ralph T Schermuly; Philipp Markart; Malgorzata Wygrecka

doi:10.1016/j.bbadis.2015.09.008

Elevated protein arginine methyltransferase 1 expression regulates fibroblast motility in pulmonary fibrosis

Biochim Biophys Acta. 2015 Dec;1852(12):2678-88. doi: 10.1016/j.bbadis.2015.09.008. Epub 2015 Sep 21.

Authors

Dariusz Zakrzewicz¹, Anna Zakrzewicz², Miroslava Didiasova³, Marek Korencak³, Djuro Kosanovic⁴, Ralph T Schermuly⁴, Philipp Markart⁵, Malgorzata Wygrecka³

Affiliations

¹ Department of Biochemistry, Faculty of Medicine, Universities of Giessen and Marburg Lung Center, Friedrichstrasse 24, 35392 Giessen, Germany. Electronic address: dariusz.zakrzewicz@innere.med.uni-giessen.de.
² Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, Justus Liebig University Giessen, Feulgenstrasse 10-12, 35385 Giessen, Germany.
³ Department of Biochemistry, Faculty of Medicine, Universities of Giessen and Marburg Lung Center, Friedrichstrasse 24, 35392 Giessen, Germany.
⁴ Universities of Giessen and Marburg Lung Center, Aulweg 130, 35392 Giessen, Germany.
⁵ Department of Internal Medicine, Universities of Giessen and Marburg Lung Center, Klinikstrasse 33, 35392 Giessen, Germany.

PMID: 26391253
DOI: 10.1016/j.bbadis.2015.09.008

Abstract

Objective: Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by epithelial cell injury, fibroblast activation and excessive extracellular matrix deposition. Although protein arginine methyltransferase 1 (PRMT1) was found to regulate cell proliferation, differentiation and migration, its role in the development/progression of IPF has not yet been described.

Results: Expression of PRMT1 was elevated in lung homogenates from IPF patients. Significant upregulation of PRMT1 expression was also observed in the lungs of bleomycin-treated mice. Immunohistochemical analysis revealed PRMT1-positive staining in fibroblasts/myofibroblasts and alveolar type II cells of IPF lungs and in fibrotic lesions of bleomycin-injured lungs. Fibroblasts isolated from IPF lungs demonstrated increased PRMT1 expression. Interleukin-4 (IL-4), a profibrotic cytokine, enhanced the expression of PRMT1 and the migration of donor and IPF fibroblasts. Interference with the expression or the activity of PRMT1 diminished the migration of the cells in response to IL-4. Strikingly, even though the incubation of donor and IPF fibroblasts with IL-4 did not affect their proliferation, depletion, but not blockage of PRMT1 activity suppressed cell growth.

Conclusions: PRMT1 can contribute to the development of pulmonary fibrosis by regulating fibroblast activities. Thus, interference with its expression and/or activity may provide a novel therapeutic option for patients with IPF.

Keywords: ADMA; Arginine methylation; Fibroblasts; Interleukin-4; Migration; PRMT; Proliferation.