IPF-Fibroblast Erk1/2 Activity Is Independent from microRNA Cluster 17-92 but Can Be Inhibited by Treprostinil through DUSP1

Idiopathic pulmonary fibrosis (IPF) is a progressive terminal lung disease, and therapies aim to block fibrosis. Fibroblast proliferation is controlled by C/EBP-β, microRNA cluster 17-92 (miR17-92), and Erk1/2 mitogen-activated protein kinase. This study assessed the role of miR17-92 in IPF-fibrobla...

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Autores principales:	Sabrina Blumer, Lei Fang, Wei-Chih Chen, Petra Khan, Katrin Hostettler, Michael Tamm, Michael Roth, Christopher Lambers
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	idiopathic pulmonary fibrosis fibroblast transforming growth factor β1 platelet-derived growth factor-BB Erk1/2 mitogen-activated protein kinase dual specificity phosphatase 1 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/1c3b0218fdf9491ea0dc4bc75a99dac4
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spelling	oai:doaj.org-article:1c3b0218fdf9491ea0dc4bc75a99dac42021-11-25T17:07:44ZIPF-Fibroblast Erk1/2 Activity Is Independent from microRNA Cluster 17-92 but Can Be Inhibited by Treprostinil through DUSP110.3390/cells101128362073-4409https://doaj.org/article/1c3b0218fdf9491ea0dc4bc75a99dac42021-10-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/2836https://doaj.org/toc/2073-4409Idiopathic pulmonary fibrosis (IPF) is a progressive terminal lung disease, and therapies aim to block fibrosis. Fibroblast proliferation is controlled by C/EBP-β, microRNA cluster 17-92 (miR17-92), and Erk1/2 mitogen-activated protein kinase. This study assessed the role of miR17-92 in IPF-fibroblast proliferation and its modification by treprostinil. Fibroblasts were isolated from eight IPF patients, five interstitial lung fibrosis patients, and seven control lungs. Fibroblasts were stimulated with TGF-β1 over 24 h. The miR17-92 expression was analyzed by RT-qPCR, and protein expression by Western blotting. TGF-β1 upregulated C/EBP-β in all fibroblasts, which was reduced by treprostinil in control-fibroblasts, but not in IPF-fibroblasts. Compared to controls, the guide strands miR-19a-3p, miR-19b-3p, miR-20a-5p, and miR-92a-3p, as well as the passenger strands miR-17-3p, miR-18-3p, miR-19a-1-5p, and miR-92a-5p were significantly increased in IPF-fibroblasts. In controls, TGF-β1 and treprostinil significantly reduced specific miR17-92 members. IPF-fibroblast proliferation was inhibited by treprostinil through increased expression of the Erk1/2 inhibitor DUSP1. These data suggest that proliferation control via miR17-92 and C/EBP-β is disrupted in IPF-fibroblasts. Therefore, the inhibition of early stages of signaling cascades or specific mitogen receptors might be less effective. However, the increased proliferation is sensitive to Erk1/2 inhibition by treprostinil-induced DUSP1.Sabrina BlumerLei FangWei-Chih ChenPetra KhanKatrin HostettlerMichael TammMichael RothChristopher LambersMDPI AGarticleidiopathic pulmonary fibrosisfibroblasttransforming growth factor β1platelet-derived growth factor-BBErk1/2 mitogen-activated protein kinasedual specificity phosphatase 1Biology (General)QH301-705.5ENCells, Vol 10, Iss 2836, p 2836 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	idiopathic pulmonary fibrosis fibroblast transforming growth factor β1 platelet-derived growth factor-BB Erk1/2 mitogen-activated protein kinase dual specificity phosphatase 1 Biology (General) QH301-705.5
spellingShingle	idiopathic pulmonary fibrosis fibroblast transforming growth factor β1 platelet-derived growth factor-BB Erk1/2 mitogen-activated protein kinase dual specificity phosphatase 1 Biology (General) QH301-705.5 Sabrina Blumer Lei Fang Wei-Chih Chen Petra Khan Katrin Hostettler Michael Tamm Michael Roth Christopher Lambers IPF-Fibroblast Erk1/2 Activity Is Independent from microRNA Cluster 17-92 but Can Be Inhibited by Treprostinil through DUSP1
description	Idiopathic pulmonary fibrosis (IPF) is a progressive terminal lung disease, and therapies aim to block fibrosis. Fibroblast proliferation is controlled by C/EBP-β, microRNA cluster 17-92 (miR17-92), and Erk1/2 mitogen-activated protein kinase. This study assessed the role of miR17-92 in IPF-fibroblast proliferation and its modification by treprostinil. Fibroblasts were isolated from eight IPF patients, five interstitial lung fibrosis patients, and seven control lungs. Fibroblasts were stimulated with TGF-β1 over 24 h. The miR17-92 expression was analyzed by RT-qPCR, and protein expression by Western blotting. TGF-β1 upregulated C/EBP-β in all fibroblasts, which was reduced by treprostinil in control-fibroblasts, but not in IPF-fibroblasts. Compared to controls, the guide strands miR-19a-3p, miR-19b-3p, miR-20a-5p, and miR-92a-3p, as well as the passenger strands miR-17-3p, miR-18-3p, miR-19a-1-5p, and miR-92a-5p were significantly increased in IPF-fibroblasts. In controls, TGF-β1 and treprostinil significantly reduced specific miR17-92 members. IPF-fibroblast proliferation was inhibited by treprostinil through increased expression of the Erk1/2 inhibitor DUSP1. These data suggest that proliferation control via miR17-92 and C/EBP-β is disrupted in IPF-fibroblasts. Therefore, the inhibition of early stages of signaling cascades or specific mitogen receptors might be less effective. However, the increased proliferation is sensitive to Erk1/2 inhibition by treprostinil-induced DUSP1.
format	article
author	Sabrina Blumer Lei Fang Wei-Chih Chen Petra Khan Katrin Hostettler Michael Tamm Michael Roth Christopher Lambers
author_facet	Sabrina Blumer Lei Fang Wei-Chih Chen Petra Khan Katrin Hostettler Michael Tamm Michael Roth Christopher Lambers
author_sort	Sabrina Blumer
title	IPF-Fibroblast Erk1/2 Activity Is Independent from microRNA Cluster 17-92 but Can Be Inhibited by Treprostinil through DUSP1
title_short	IPF-Fibroblast Erk1/2 Activity Is Independent from microRNA Cluster 17-92 but Can Be Inhibited by Treprostinil through DUSP1
title_full	IPF-Fibroblast Erk1/2 Activity Is Independent from microRNA Cluster 17-92 but Can Be Inhibited by Treprostinil through DUSP1
title_fullStr	IPF-Fibroblast Erk1/2 Activity Is Independent from microRNA Cluster 17-92 but Can Be Inhibited by Treprostinil through DUSP1
title_full_unstemmed	IPF-Fibroblast Erk1/2 Activity Is Independent from microRNA Cluster 17-92 but Can Be Inhibited by Treprostinil through DUSP1
title_sort	ipf-fibroblast erk1/2 activity is independent from microrna cluster 17-92 but can be inhibited by treprostinil through dusp1
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/1c3b0218fdf9491ea0dc4bc75a99dac4
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IPF-Fibroblast Erk1/2 Activity Is Independent from microRNA Cluster 17-92 but Can Be Inhibited by Treprostinil through DUSP1

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