TGF-β1 targets the GSK-3β/β-catenin pathway via ERK activation in the transition of human lung fibroblasts into myofibroblasts

Filippo Caraci, Elisa Gili, Marco Calafiore, Marco Failla, Cristina La Rosa, Nunzio Crimi, Maria Angela Sortino, Ferdinando Nicoletti, Agata Copani, Carlo Vancheri

Research output: Contribution to journalArticle

Abstract

Transforming growth factor-β1 (TGF-β1) is known to induce the transition of human lung fibroblasts to myofibroblasts, a primary event in the pathogenesis of idiopathic pulmonary fibrosis. The molecular pathways involved in myofibroblast transformation are only partially identified. We found that a 24-h treatment with TGF-β1 (10 ng/ml) induced α-smooth actin (SMA) expression and collagen production in human lung fibroblasts. These effects were abrogated by PD98059, a specific inhibitor of the mitogen-activated protein kinase (MAPK) pathway. TGF-β1 treatment activated the MAPK pathway, as shown by an increased phosphorylation of extracellular-regulated kinases (ERK)1/2 after 30 min of exposure. TGF-β1 also increased the expression of the Ser-9-phosphorylated inactive form of glycogen synthase kinase-3β (GSK-3β), an effect that was largely attenuated by PD98059. A nuclear translocation of β-catenin in human lung fibroblasts was observed 2 h after TGF-β1 addition both by confocal microscopy and nuclear protein analysis. At this time, TGF-β1 also increased the total levels of β-catenin, an effect that was prevented by PD98059. Similarly to TGF-β1, the GSK-3β inhibitor lithium chloride (10 mM), increased the total levels of β-catenin and promoted α-SMA expression and collagen production. This study demonstrates that TGF-β1 induces α-SMA expression and collagen production in human lung fibroblasts via ERK1/2 activation, GSK-3β inhibition and nuclear β-catenin translocation. The evidence that the silencing of β-catenin by siRNAs was able to prevent the induction of α-SMA expression in TGF-β1-treated fibroblasts further supports the hypothesis of a contribution of the GSK-3β/β-catenin pathway in the pathogenesis of idiopathic pulmonary fibrosis.

Original languageEnglish
Pages (from-to)274-282
Number of pages9
JournalPharmacological Research
Volume57
Issue number4
DOIs
Publication statusPublished - Apr 2008

Fingerprint

Glycogen Synthase Kinase 3
Catenins
Myofibroblasts
Transforming Growth Factors
Phosphotransferases
Fibroblasts
Lung
Actins
Idiopathic Pulmonary Fibrosis
Collagen
Mitogen-Activated Protein Kinases
Lithium Chloride
Nuclear Proteins
Confocal Microscopy
Phosphorylation

Keywords

  • α-SMA
  • β-Catenin
  • ERK1/2
  • Fibroblast
  • GSK-3β
  • TGF-β1

ASJC Scopus subject areas

  • Pharmacology

Cite this

TGF-β1 targets the GSK-3β/β-catenin pathway via ERK activation in the transition of human lung fibroblasts into myofibroblasts. / Caraci, Filippo; Gili, Elisa; Calafiore, Marco; Failla, Marco; La Rosa, Cristina; Crimi, Nunzio; Sortino, Maria Angela; Nicoletti, Ferdinando; Copani, Agata; Vancheri, Carlo.

In: Pharmacological Research, Vol. 57, No. 4, 04.2008, p. 274-282.

Research output: Contribution to journalArticle

Caraci, Filippo ; Gili, Elisa ; Calafiore, Marco ; Failla, Marco ; La Rosa, Cristina ; Crimi, Nunzio ; Sortino, Maria Angela ; Nicoletti, Ferdinando ; Copani, Agata ; Vancheri, Carlo. / TGF-β1 targets the GSK-3β/β-catenin pathway via ERK activation in the transition of human lung fibroblasts into myofibroblasts. In: Pharmacological Research. 2008 ; Vol. 57, No. 4. pp. 274-282.
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AU - La Rosa, Cristina

AU - Crimi, Nunzio

AU - Sortino, Maria Angela

AU - Nicoletti, Ferdinando

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AB - Transforming growth factor-β1 (TGF-β1) is known to induce the transition of human lung fibroblasts to myofibroblasts, a primary event in the pathogenesis of idiopathic pulmonary fibrosis. The molecular pathways involved in myofibroblast transformation are only partially identified. We found that a 24-h treatment with TGF-β1 (10 ng/ml) induced α-smooth actin (SMA) expression and collagen production in human lung fibroblasts. These effects were abrogated by PD98059, a specific inhibitor of the mitogen-activated protein kinase (MAPK) pathway. TGF-β1 treatment activated the MAPK pathway, as shown by an increased phosphorylation of extracellular-regulated kinases (ERK)1/2 after 30 min of exposure. TGF-β1 also increased the expression of the Ser-9-phosphorylated inactive form of glycogen synthase kinase-3β (GSK-3β), an effect that was largely attenuated by PD98059. A nuclear translocation of β-catenin in human lung fibroblasts was observed 2 h after TGF-β1 addition both by confocal microscopy and nuclear protein analysis. At this time, TGF-β1 also increased the total levels of β-catenin, an effect that was prevented by PD98059. Similarly to TGF-β1, the GSK-3β inhibitor lithium chloride (10 mM), increased the total levels of β-catenin and promoted α-SMA expression and collagen production. This study demonstrates that TGF-β1 induces α-SMA expression and collagen production in human lung fibroblasts via ERK1/2 activation, GSK-3β inhibition and nuclear β-catenin translocation. The evidence that the silencing of β-catenin by siRNAs was able to prevent the induction of α-SMA expression in TGF-β1-treated fibroblasts further supports the hypothesis of a contribution of the GSK-3β/β-catenin pathway in the pathogenesis of idiopathic pulmonary fibrosis.

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