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Casein Kinase 1δ/ε Inhibitor, PF670462 Attenuates the Fibrogenic Effects of Transforming Growth Factor-β in Pulmonary Fibrosis

Transforming growth factor-beta (TGF-β) is a major mediator of fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). However, therapeutic global inhibition of TGF-β is limited by unwanted immunosuppression and mitral valve defects. We performed an extensive literature search to uncover a...

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Autores principales: Keenan, Christine R., Langenbach, Shenna Y., Jativa, Fernando, Harris, Trudi, Li, Meina, Chen, Qianyu, Xia, Yuxiu, Gao, Bryan, Schuliga, Michael J., Jaffar, Jade, Prodanovic, Danica, Tu, Yan, Berhan, Asres, Lee, Peter V. S., Westall, Glen P., Stewart, Alastair G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048361/
https://www.ncbi.nlm.nih.gov/pubmed/30042678
http://dx.doi.org/10.3389/fphar.2018.00738
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author Keenan, Christine R.
Langenbach, Shenna Y.
Jativa, Fernando
Harris, Trudi
Li, Meina
Chen, Qianyu
Xia, Yuxiu
Gao, Bryan
Schuliga, Michael J.
Jaffar, Jade
Prodanovic, Danica
Tu, Yan
Berhan, Asres
Lee, Peter V. S.
Westall, Glen P.
Stewart, Alastair G.
author_facet Keenan, Christine R.
Langenbach, Shenna Y.
Jativa, Fernando
Harris, Trudi
Li, Meina
Chen, Qianyu
Xia, Yuxiu
Gao, Bryan
Schuliga, Michael J.
Jaffar, Jade
Prodanovic, Danica
Tu, Yan
Berhan, Asres
Lee, Peter V. S.
Westall, Glen P.
Stewart, Alastair G.
author_sort Keenan, Christine R.
collection PubMed
description Transforming growth factor-beta (TGF-β) is a major mediator of fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). However, therapeutic global inhibition of TGF-β is limited by unwanted immunosuppression and mitral valve defects. We performed an extensive literature search to uncover a little-known connection between TGF-β signaling and casein kinase (CK) activity. We have examined the abundance of CK1 delta and epsilon (CK1δ/ε) in lung tissue from IPF patients and non-diseased controls, and investigated whether inhibition of CK1δ/ε with PF670462 inhibits pulmonary fibrosis. CK1δ/ε levels in lung tissue from IPF patients and non-diseased controls were assessed by immunohistochemistry. Anti-fibrotic effects of the CK1δ/ε inhibitor PF670462 were assessed in pre-clinical models, including acute and chronic bleomycin mouse models and in vitro experiments on spheroids made from primary human lung fibroblast cells from IPF and control donors, and human A549 alveolar-like adenocarcinoma-derived epithelial cells. Increased expression of CK1δ and ε in IPF lungs compared to non-diseased controls was accompanied by increased levels of the product, phospho-period 2. In vitro, PF670462 prevented TGF-β-induced epithelial-mesenchymal transition. The stiffness of IPF-derived spheroids was reduced by PF670462 and TGF-β-induced fibrogenic gene expression was inhibited. The CK1δ/ε inhibitor PF670462 administered systemically or locally by inhalation prevented both acute and chronic bleomycin-induced pulmonary fibrosis in mice. PF670462 administered in a ‘therapeutic’ regimen (day 7 onward) prevented bleomycin-induced lung collagen accumulation. Elevated expression and activity of CK1 δ and ε in IPF and anti-fibrogenic effects of the dual CK1δ/ε inhibitor, PF670462, support CK1δ/ε as novel therapeutic targets for IPF.
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spelling pubmed-60483612018-07-24 Casein Kinase 1δ/ε Inhibitor, PF670462 Attenuates the Fibrogenic Effects of Transforming Growth Factor-β in Pulmonary Fibrosis Keenan, Christine R. Langenbach, Shenna Y. Jativa, Fernando Harris, Trudi Li, Meina Chen, Qianyu Xia, Yuxiu Gao, Bryan Schuliga, Michael J. Jaffar, Jade Prodanovic, Danica Tu, Yan Berhan, Asres Lee, Peter V. S. Westall, Glen P. Stewart, Alastair G. Front Pharmacol Pharmacology Transforming growth factor-beta (TGF-β) is a major mediator of fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). However, therapeutic global inhibition of TGF-β is limited by unwanted immunosuppression and mitral valve defects. We performed an extensive literature search to uncover a little-known connection between TGF-β signaling and casein kinase (CK) activity. We have examined the abundance of CK1 delta and epsilon (CK1δ/ε) in lung tissue from IPF patients and non-diseased controls, and investigated whether inhibition of CK1δ/ε with PF670462 inhibits pulmonary fibrosis. CK1δ/ε levels in lung tissue from IPF patients and non-diseased controls were assessed by immunohistochemistry. Anti-fibrotic effects of the CK1δ/ε inhibitor PF670462 were assessed in pre-clinical models, including acute and chronic bleomycin mouse models and in vitro experiments on spheroids made from primary human lung fibroblast cells from IPF and control donors, and human A549 alveolar-like adenocarcinoma-derived epithelial cells. Increased expression of CK1δ and ε in IPF lungs compared to non-diseased controls was accompanied by increased levels of the product, phospho-period 2. In vitro, PF670462 prevented TGF-β-induced epithelial-mesenchymal transition. The stiffness of IPF-derived spheroids was reduced by PF670462 and TGF-β-induced fibrogenic gene expression was inhibited. The CK1δ/ε inhibitor PF670462 administered systemically or locally by inhalation prevented both acute and chronic bleomycin-induced pulmonary fibrosis in mice. PF670462 administered in a ‘therapeutic’ regimen (day 7 onward) prevented bleomycin-induced lung collagen accumulation. Elevated expression and activity of CK1 δ and ε in IPF and anti-fibrogenic effects of the dual CK1δ/ε inhibitor, PF670462, support CK1δ/ε as novel therapeutic targets for IPF. Frontiers Media S.A. 2018-07-10 /pmc/articles/PMC6048361/ /pubmed/30042678 http://dx.doi.org/10.3389/fphar.2018.00738 Text en Copyright © 2018 Keenan, Langenbach, Jativa, Harris, Li, Chen, Xia, Gao, Schuliga, Jaffar, Prodanovic, Tu, Berhan, Lee, Westall and Stewart. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Keenan, Christine R.
Langenbach, Shenna Y.
Jativa, Fernando
Harris, Trudi
Li, Meina
Chen, Qianyu
Xia, Yuxiu
Gao, Bryan
Schuliga, Michael J.
Jaffar, Jade
Prodanovic, Danica
Tu, Yan
Berhan, Asres
Lee, Peter V. S.
Westall, Glen P.
Stewart, Alastair G.
Casein Kinase 1δ/ε Inhibitor, PF670462 Attenuates the Fibrogenic Effects of Transforming Growth Factor-β in Pulmonary Fibrosis
title Casein Kinase 1δ/ε Inhibitor, PF670462 Attenuates the Fibrogenic Effects of Transforming Growth Factor-β in Pulmonary Fibrosis
title_full Casein Kinase 1δ/ε Inhibitor, PF670462 Attenuates the Fibrogenic Effects of Transforming Growth Factor-β in Pulmonary Fibrosis
title_fullStr Casein Kinase 1δ/ε Inhibitor, PF670462 Attenuates the Fibrogenic Effects of Transforming Growth Factor-β in Pulmonary Fibrosis
title_full_unstemmed Casein Kinase 1δ/ε Inhibitor, PF670462 Attenuates the Fibrogenic Effects of Transforming Growth Factor-β in Pulmonary Fibrosis
title_short Casein Kinase 1δ/ε Inhibitor, PF670462 Attenuates the Fibrogenic Effects of Transforming Growth Factor-β in Pulmonary Fibrosis
title_sort casein kinase 1δ/ε inhibitor, pf670462 attenuates the fibrogenic effects of transforming growth factor-β in pulmonary fibrosis
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048361/
https://www.ncbi.nlm.nih.gov/pubmed/30042678
http://dx.doi.org/10.3389/fphar.2018.00738
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