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Glycogen synthase kinase-3 (GSK-3) regulates TGF-β(1) -induced differentiation of pulmonary fibroblasts.
MedLine Citation:
PMID:  23297769     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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.
Authors:
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:
Type:  JOURNAL ARTICLE     Date:  2013-1-9
Journal Detail:
Title:  British journal of pharmacology     Volume:  -     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-9     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
© 2013 The Authors. British Journal of Pharmacology © 2013 The British Pharmacological Society.
Affiliation:
Department of Molecular Pharmacology, GRIAC research institute, University of Groningen, Groningen, The Netherlands.
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