title: PDGF-BB induces PRMT1 expression through ERK1/2 dependent STAT1 activation and regulates remodeling in primary human lung fibroblasts.
abstract: Tissue remodeling of sub-epithelial mesenchymal cells is a major pathology occurring in chronic obstructive pulmonary disease (COPD) and asthma. Fibroblasts, as a major source of interstitial connective tissue extracellular matrix, contribute to the fibrotic and inflammatory changes in these airways diseases. Previously, we described that protein arginine methyltransferase-1 (PRMT1) participates in airway remodeling in a rat model of pulmonary inflammation. In this study we investigated the mechanism by which PDGF-BB regulates PRMT1 in primary lung fibroblasts, isolated from human lung biopsies. Fibroblasts were stimulated with PDGF-BB for up-to 48h and the regulatory and activation of signaling pathways controlling PRMT1 expression were determined. PRMT1 was localized by immuno-histochemistry in human lung tissue sections and by immunofluorescence in isolated fibroblasts. PRMT1 activity was suppressed by the pan-PRMT inhibitor AMI1. ERK1/2 mitogen activated protein kinase (MAPK) was blocked by PD98059, p38 MAPK by SB203580, and STAT1 by small interference (si) RNA treatment. The results showed that PDGF-BB significantly increased PRMT1 expression after 1h lasting over 48h, through ERK1/2 MAPK and STAT1 signaling. The inhibition of ERK1/2 MAPK or of PRMT1 activity decreased PDGF-BB induced fibroblast proliferation, COX2 production, collagen-1A1 secretion, and fibronectin production. These findings suggest that PRMT1 is a central regulator of tissue remodeling and that the signaling sequence controlling its expression in primary human lung fibroblast is PDGF-ERK-STAT1. Therefore, PRMT1 presents a novel therapeutic and diagnostic target for the control of airway wall remodeling in chronic lung diseases.
authors.affiliation: Department of Biochemistry and Molecular Biology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, PR China; Pneumology and Pulmonary Cell Research, Department of Biomedicine, University and University Hospital Basel, Basel 4031, Switzerland.
authors.forename: Qingzhu
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Department of Biochemistry and Molecular Biology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Pneumology and Pulmonary Cell Research, Department of Biomedicine, University and University Hospital Basel, Basel 4031, Switzerland.
authors.forename: Jyotshna
authors.initials: J
authors.lastname: Mandal
authors.affiliation: Dept of Respiratory Diseases, University of Naples, Federico II, Naples, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Molino
authors.affiliation: Pneumology and Pulmonary Cell Research, Department of Biomedicine, University and University Hospital Basel, Basel 4031, Switzerland.
authors.forename: Daiana
authors.initials: D
authors.lastname: Stolz
authors.affiliation: Pneumology and Pulmonary Cell Research, Department of Biomedicine, University and University Hospital Basel, Basel 4031, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Tamm
authors.affiliation: Department of Biochemistry and Molecular Biology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, PR China.
authors.forename: Shemin
authors.initials: S
authors.lastname: Lu
authors.affiliation: Pneumology and Pulmonary Cell Research, Department of Biomedicine, University and University Hospital Basel, Basel 4031, Switzerland. Electronic address: Michael.Roth@usb.ch.
authors.forename: Michael
authors.initials: M
authors.lastname: Roth
mesh_terms: D000818:Animals; D000077214:Becaplermin; D002460:Cell Line; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011484:Protein-Arginine N-Methyltransferases / Q000096:biosynthesis* / Q000235:genetics; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D012097:Repressor Proteins / Q000096:biosynthesis* / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D005419:Flavonoids; D007093:Imidazoles; D020574:Proto-Oncogene Proteins c-sis; D011725:Pyridines; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D000077214:Becaplermin; C099988:PRMT1 protein, human; D011484:Protein-Arginine N-Methyltransferases; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: Airway remodeling; ERK; PRMT1; Primary lung fibroblast; STAT1