title: Prostaglandin E2 inhibits α-smooth muscle actin transcription during myofibroblast differentiation via distinct mechanisms of modulation of serum response factor and myocardin-related transcription factor-A.
abstract: Differentiation of lung fibroblasts into contractile protein-expressing myofibroblasts by transforming growth factor-β1 (TGF-β1) is a critical event in the pathogenesis of pulmonary fibrosis. Transcription of the contractile protein α-smooth muscle actin (α-SMA) is mediated by the transcription factor serum-response factor (SRF) along with its co-activator, myocardin-related transcription factor-A (MRTF-A). The endogenous lipid mediator prostaglandin E2 (PGE2) exerts anti-fibrotic effects, including the inhibition of myofibroblast differentiation. However, the mechanism by which PGE2 inhibits α-SMA expression is incompletely understood. Here, we show in normal lung fibroblasts that PGE2 reduced the nuclear accumulation of MRTF-A·SRF complexes and consequently inhibited α-SMA promoter activation. It did so both by independently inhibiting SRF gene expression and nuclear import of MRTF-A. We identified that p38 MAPK is critical for TGF-β1-induced SRF gene expression and that PGE2 inhibition of SRF expression is associated with its ability to inhibit p38 activation. Its inhibition of MRTF-A import occurs via activation of cofilin 1 and inactivation of vasodilator-stimulated phosphoprotein. Similar effects of PGE2 on SRF gene expression were observed in fibroblasts from the lungs of patients with idiopathic pulmonary fibrosis. Thus, PGE2 is the first substance described to prevent myofibroblast differentiation by disrupting, via distinct mechanisms, the actions of both SRF and MRTF-A.
authors.affiliation: From the Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109.
authors.forename: Loka R K
authors.initials: LR
authors.lastname: Penke
authors.affiliation: From the Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109.
authors.forename: Steven K
authors.initials: SK
authors.lastname: Huang
authors.affiliation: From the Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109.
authors.forename: Eric S
authors.initials: ES
authors.lastname: White
authors.affiliation: From the Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109 petersm@umich.edu.
authors.forename: Marc
authors.initials: M
authors.lastname: Peters-Golden
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D051338:Cofilin 1 / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015232:Dinoprostone / Q000494:pharmacology*; D006801:Humans; D008168:Lung / Q000166:cytology; D008840:Microfilament Proteins / Q000378:metabolism; D058628:Myofibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D026362:Serum Response Factor / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D015815:Cell Adhesion Molecules; D051338:Cofilin 1; D004268:DNA-Binding Proteins; C431575:MRTFA protein, human; D008840:Microfilament Proteins; D015514:Oncogene Proteins, Fusion; D010750:Phosphoproteins; D026362:Serum Response Factor; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D000098662:Vasodilator-Stimulated Phosphoprotein; D048051:p38 Mitogen-Activated Protein Kinases; D015232:Dinoprostone
keywords: Differentiation; Myofibroblast; Prostaglandin; Transcription Regulation; Transforming Growth Factor-{beta} (TGF-{beta})