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Pirfenidone anti-fibrotic effects are partially mediated by the inhibition of MUC1 bioactivation
Pirfenidone is a pleiotropic molecule approved to treat idiopathic pulmonary fibrosis (IPF). Pirfenidone has demonstrated to downregulate transforming growth factor-β1 (TGF-β1) cellular effects. However, its anti-fibrotic mechanism remains unclear. Here, we aim to analyze the effects of pirfenidone...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170494/ https://www.ncbi.nlm.nih.gov/pubmed/32341751 http://dx.doi.org/10.18632/oncotarget.27526 |
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author | Ballester, Beatriz Milara, Javier Cortijo, Julio |
author_facet | Ballester, Beatriz Milara, Javier Cortijo, Julio |
author_sort | Ballester, Beatriz |
collection | PubMed |
description | Pirfenidone is a pleiotropic molecule approved to treat idiopathic pulmonary fibrosis (IPF). Pirfenidone has demonstrated to downregulate transforming growth factor-β1 (TGF-β1) cellular effects. However, its anti-fibrotic mechanism remains unclear. Here, we aim to analyze the effects of pirfenidone on the TGF-β1 canonical and non-canonical pathways, as well as, on the most characteristic IPF cellular processes. Results observed in this work showed that TGF-β1-induced canonical SMAD3 and non-canonical ERK1/2 phosphorylations were not inhibited by pirfenidone in alveolar A549 and lung fibroblasts MRC5 cells. In contrast, pirfenidone inhibited TGF-β1-induced MUC1-CT Thr(41) (1224) and Tyr(46) (1229) phosphorylations, thus reducing the β-catenin activation. Additionally, immunoprecipitation and immunofluorescence studies in ATII cells and lung fibroblasts showed that pirfenidone inhibited the formation and nuclear translocation of the transcriptional fibrotic TGF-β1-induced phospho-SMAD3/MUC1-CT/active-β-catenin complex, and consequently the SMAD-binding element activation (SBE). This study provided also evidence of the inhibitory effect of pirfenidone on the TGF-β1-induced ATII to mesenchymal and fibroblast to myofibroblast transitions, fibroblast proliferation and ATII and fibroblast senescence. Therefore, it indicates that pirfenidone’s inhibitory effect on TGF-β1-induced fibrotic cellular processes is mediated by the inhibition of MUC1-CT phosphorylation, β-catenin activation, nuclear complex formation of phospho-SMAD3/MUC1-CT/active β-catenin and SBE activation, which may be of value to further develop anti-fibrotic IPF therapies. |
format | Online Article Text |
id | pubmed-7170494 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-71704942020-04-27 Pirfenidone anti-fibrotic effects are partially mediated by the inhibition of MUC1 bioactivation Ballester, Beatriz Milara, Javier Cortijo, Julio Oncotarget Research Paper Pirfenidone is a pleiotropic molecule approved to treat idiopathic pulmonary fibrosis (IPF). Pirfenidone has demonstrated to downregulate transforming growth factor-β1 (TGF-β1) cellular effects. However, its anti-fibrotic mechanism remains unclear. Here, we aim to analyze the effects of pirfenidone on the TGF-β1 canonical and non-canonical pathways, as well as, on the most characteristic IPF cellular processes. Results observed in this work showed that TGF-β1-induced canonical SMAD3 and non-canonical ERK1/2 phosphorylations were not inhibited by pirfenidone in alveolar A549 and lung fibroblasts MRC5 cells. In contrast, pirfenidone inhibited TGF-β1-induced MUC1-CT Thr(41) (1224) and Tyr(46) (1229) phosphorylations, thus reducing the β-catenin activation. Additionally, immunoprecipitation and immunofluorescence studies in ATII cells and lung fibroblasts showed that pirfenidone inhibited the formation and nuclear translocation of the transcriptional fibrotic TGF-β1-induced phospho-SMAD3/MUC1-CT/active-β-catenin complex, and consequently the SMAD-binding element activation (SBE). This study provided also evidence of the inhibitory effect of pirfenidone on the TGF-β1-induced ATII to mesenchymal and fibroblast to myofibroblast transitions, fibroblast proliferation and ATII and fibroblast senescence. Therefore, it indicates that pirfenidone’s inhibitory effect on TGF-β1-induced fibrotic cellular processes is mediated by the inhibition of MUC1-CT phosphorylation, β-catenin activation, nuclear complex formation of phospho-SMAD3/MUC1-CT/active β-catenin and SBE activation, which may be of value to further develop anti-fibrotic IPF therapies. Impact Journals LLC 2020-04-14 /pmc/articles/PMC7170494/ /pubmed/32341751 http://dx.doi.org/10.18632/oncotarget.27526 Text en http://creativecommons.org/licenses/by/3.0/ Copyright: Ballester et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Ballester, Beatriz Milara, Javier Cortijo, Julio Pirfenidone anti-fibrotic effects are partially mediated by the inhibition of MUC1 bioactivation |
title | Pirfenidone anti-fibrotic effects are partially mediated by the inhibition of MUC1 bioactivation |
title_full | Pirfenidone anti-fibrotic effects are partially mediated by the inhibition of MUC1 bioactivation |
title_fullStr | Pirfenidone anti-fibrotic effects are partially mediated by the inhibition of MUC1 bioactivation |
title_full_unstemmed | Pirfenidone anti-fibrotic effects are partially mediated by the inhibition of MUC1 bioactivation |
title_short | Pirfenidone anti-fibrotic effects are partially mediated by the inhibition of MUC1 bioactivation |
title_sort | pirfenidone anti-fibrotic effects are partially mediated by the inhibition of muc1 bioactivation |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170494/ https://www.ncbi.nlm.nih.gov/pubmed/32341751 http://dx.doi.org/10.18632/oncotarget.27526 |
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