| Glycogen synthase kinase-3 (GSK-3) regulates TGF-β(1) -induced differentiation of pulmonary fibroblasts. | |
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MedLine Citation:
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PMID: 23297769 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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BACKGROUND: Chronic lung diseases such as asthma, COPD and pulmonary fibrosis are characterized by abnormal extracellular matrix (ECM) turnover. Transforming growth factor-β (TGF-β) is a key mediator stimulating ECM production by recruiting and activating lung fibroblasts and initiating their differentiation process into more active myofibroblasts. Glycogen synthase kinase-3 (GSK-3) regulates various intracellular signaling pathways; its role in TGF-β(1) -induced myofibroblast differentiation is currently largely unknown. PURPOSE: To determine the contribution of GSK-3 signaling in TGF-β(1) -induced myofibroblast differentiation. EXPERIMENTAL APPROACH: We used MRC5 human lung fibroblasts and primary pulmonary fibroblasts of individuals with and without COPD. Protein and mRNA expression were determined by immunoblotting and RT-PCR analysis, respectively. RESULTS: Stimulation of MRC5 and primary human lung fibroblasts with TGF-β(1) resulted in time- and dose-dependent increases of α-sm-actin and fibronectin expression, indicative of myofibroblast differentiation. Pharmacological inhibition of GSK-3 by SB216763 dose-dependently attenuated TGF-β(1) -induced expression of these myofibroblasts markers. Moreover, silencing of GSK-3 by siRNA or pharmacological inhibition by CT/CHIR99021 fully inhibited the TGF-β(1) -induced expression of α-sm-actin and fibronectin. The effect of GSK-3 inhibition on α-sm-actin expression was similar in fibroblasts from individuals with and without COPD. Neither smad, NF-κB, nor ERK1/2 were involved in the inhibitory actions of GSK-3 inhibition by SB126763 on myofibroblast differentiation. Rather, SB216763 increased the phosphorylation of CREB, which in its phosphorylated form acts as functional antagonist of TGF-β/smad signaling. CONCLUSION AND IMPLICATION: We demonstrate that GSK-3 signaling regulates TGF-β(1) -induced myofibroblast differentiation by regulating CREB phosphorylation. GSK-3 may constitute a useful target for treatment of chronic lung diseases. |
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Authors:
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Hoeke A Baarsma; Lilian H J M Engelbertink; Lonneke J van Hees; Mark H Menzen; Herman Meurs; Wim Timens; Dirkje S Postma; Huib A M Kerstjens; Reinoud Gosens |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2013-1-9 |
Journal Detail:
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Title: British journal of pharmacology Volume: - ISSN: 1476-5381 ISO Abbreviation: Br. J. Pharmacol. Publication Date: 2013 Jan |
Date Detail:
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Created Date: 2013-1-9 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7502536 Medline TA: Br J Pharmacol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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© 2013 The Authors. British Journal of Pharmacology © 2013 The British Pharmacological Society. |
Affiliation:
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Department of Molecular Pharmacology, GRIAC research institute, University of Groningen, Groningen, The Netherlands. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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