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Glycogen synthase kinase-3 (GSK-3) regulates TGF-β₁-induced differentiation of pulmonary fibroblasts.
Br J Pharmacol. 2013 Jun; 169(3):590-603.BJ

Abstract

BACKGROUND

Chronic lung diseases such as asthma, COPD and pulmonary fibrosis are characterized by abnormal extracellular matrix (ECM) turnover. 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 signalling pathways; its role in TGF-β₁-induced myofibroblast differentiation is currently largely unknown.

PURPOSE

To determine the contribution of GSK-3 signalling in TGF-β₁-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-β₁ 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-β₁-induced expression of these myofibroblasts markers. Moreover, silencing of GSK-3 by siRNA or pharmacological inhibition by CT/CHIR99021 fully inhibited the TGF-β₁-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 a functional antagonist of TGF-β/smad signalling.

CONCLUSION AND IMPLICATION

We demonstrate that GSK-3 signalling regulates TGF-β₁-induced myofibroblast differentiation by regulating CREB phosphorylation. GSK-3 may constitute a useful target for treatment of chronic lung diseases.

Authors+Show Affiliations

Department of Molecular Pharmacology, GRIAC Research Institute, University of Groningen, Groningen, The Netherlands. h.a.baarsma@rug.nlNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23297769

Citation

Baarsma, Hoeke A., et al. "Glycogen Synthase Kinase-3 (GSK-3) Regulates TGF-β₁-induced Differentiation of Pulmonary Fibroblasts." British Journal of Pharmacology, vol. 169, no. 3, 2013, pp. 590-603.
Baarsma HA, Engelbertink LH, van Hees LJ, et al. Glycogen synthase kinase-3 (GSK-3) regulates TGF-β₁-induced differentiation of pulmonary fibroblasts. Br J Pharmacol. 2013;169(3):590-603.
Baarsma, H. A., Engelbertink, L. H., van Hees, L. J., Menzen, M. H., Meurs, H., Timens, W., Postma, D. S., Kerstjens, H. A., & Gosens, R. (2013). Glycogen synthase kinase-3 (GSK-3) regulates TGF-β₁-induced differentiation of pulmonary fibroblasts. British Journal of Pharmacology, 169(3), 590-603. https://doi.org/10.1111/bph.12098
Baarsma HA, et al. Glycogen Synthase Kinase-3 (GSK-3) Regulates TGF-β₁-induced Differentiation of Pulmonary Fibroblasts. Br J Pharmacol. 2013;169(3):590-603. PubMed PMID: 23297769.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Glycogen synthase kinase-3 (GSK-3) regulates TGF-β₁-induced differentiation of pulmonary fibroblasts. AU - Baarsma,Hoeke A, AU - Engelbertink,Lilian H J M, AU - van Hees,Lonneke J, AU - Menzen,Mark H, AU - Meurs,Herman, AU - Timens,Wim, AU - Postma,Dirkje S, AU - Kerstjens,Huib A M, AU - Gosens,Reinoud, PY - 2012/10/24/received PY - 2012/12/12/accepted PY - 2013/1/10/entrez PY - 2013/1/10/pubmed PY - 2014/9/16/medline SP - 590 EP - 603 JF - British journal of pharmacology JO - Br J Pharmacol VL - 169 IS - 3 N2 - BACKGROUND: Chronic lung diseases such as asthma, COPD and pulmonary fibrosis are characterized by abnormal extracellular matrix (ECM) turnover. 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 signalling pathways; its role in TGF-β₁-induced myofibroblast differentiation is currently largely unknown. PURPOSE: To determine the contribution of GSK-3 signalling in TGF-β₁-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-β₁ 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-β₁-induced expression of these myofibroblasts markers. Moreover, silencing of GSK-3 by siRNA or pharmacological inhibition by CT/CHIR99021 fully inhibited the TGF-β₁-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 a functional antagonist of TGF-β/smad signalling. CONCLUSION AND IMPLICATION: We demonstrate that GSK-3 signalling regulates TGF-β₁-induced myofibroblast differentiation by regulating CREB phosphorylation. GSK-3 may constitute a useful target for treatment of chronic lung diseases. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/23297769/Glycogen_synthase_kinase_3__GSK_3__regulates_TGF_β₁_induced_differentiation_of_pulmonary_fibroblasts_ L2 - https://doi.org/10.1111/bph.12098 DB - PRIME DP - Unbound Medicine ER -