Transforming growth factor-β1 stimulates heme oxygenase-1 expression via the PI3K/Akt and NF-κB pathways in human lung epithelial cells

Background: Lung epithelial cells play critical roles in idiopathic pulmonary fibrosis. Methods: In the present study, we investigated whether transforming growth factor-β (TGF-β)-induced expression of connective tissue growth factor (CTGF) was regulated by the extracellular signal-regulated kinase (ERK)/a disintegrin and metalloproteinase 17 (ADAM17)/ribosomal S6 kinases 1 (RSK1)/CCAAT/enhancer-binding protein β (C/EBPβ) signaling pathway in human lung epithelial cells (A549). Results: Our results revealed that TGF-β-induced CTGF expression was weakened by ADAM17 small interfering RNA (ADAM17 siRNA), TNF-α processing inhibitor-0 (TAPI-0, an ADAM17 inhibitor), U0126 (an ERK inhibitor), RSK1 siRNA, and C/EBPβ siRNA. TGF-β-induced ERK phosphorylation as well as ADAM17 phosphorylation was attenuated by U0126. The TGF-β-induced increase in RSK1 phosphorylation was inhibited by TAPI-0 and U0126. TGF-β-induced C/EBPβ phosphorylation was weakened by U0126, ADAM17 siRNA, and RSK1 siRNA. In addition, TGF-β increased the recruitment of C/EBPβ to the CTGF promoter. Furthermore, TGF-β enhanced fibronectin (FN), an epithelial–mesenchymal transition (EMT) marker, and CTGF mRNA levels and reduced E-cadherin mRNA levels. Moreover, TGF-β-stimulated FN protein expression was reduced by ADAM17 siRNA and CTGF siRNA. Conclusion: The results suggested that TGF-β induces CTGF expression through the ERK/ADAM17/RSK1/C/EBPβ signaling pathway. Moreover, ADAM17 and CTGF participate in TGF-β-induced FN expression in human lung epithelial cells.

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Normal Human Lung Epithelial Cells Inhibit Transforming Growth Factor-β Induced Myofibroblast Differentiation via Prostaglandin E2

PLoS ONE ◽

10.1371/journal.pone.0135266 ◽

2015 ◽

Vol 10 (8) ◽

pp. e0135266 ◽

Cited By ~ 27

Author(s):

Amali P. Epa ◽

Thomas H. Thatcher ◽

Stephen J. Pollock ◽

Lindsay A. Wahl ◽

Elizabeth Lyda ◽

...

Keyword(s):

Growth Factor ◽

Prostaglandin E2 ◽

Transforming Growth Factor ◽

Human Lung ◽

Transforming Growth Factor Β ◽

Lung Epithelial Cells ◽

Myofibroblast Differentiation ◽

Lung Epithelial ◽

Normal Human ◽

Human Lung Epithelial Cells

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Fibroblast Growth Factor 2 Augments Transforming Growth Factor Beta 1 in Inducing Epithelial-Mesenchymal Transition in Human Lung Epithelial Cells

10.21203/rs.2.10955/v1 ◽

2019 ◽

Author(s):

Lamis M.F. El-Baz ◽

Nahla M. Shoukry ◽

Mohamed L. Salem ◽

Hani S. Hafez ◽

Robert D. Guzy

Keyword(s):

Wound Healing ◽

Growth Factor ◽

Epithelial Cells ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Human Lung ◽

A549 Cells ◽

Lung Epithelial Cells ◽

Mesenchymal Transition ◽

Lung Epithelial

Abstract Background: Epithelial-mesenchymal transition (EMT) is a critical event in wound healing and tissue repair following injury. Transforming growth factor beta-1 (TGFβ1) plays an important role in inducing EMT in lung epithelial cells in vitro and in vivo. As fibroblast growth factor-2 (FGF2) reverses TGFβ1-induced collagen I (COL1A1) and α-smooth muscle actin (Actin alpha 2; ACTA2) expression in primary mouse and human lung fibroblasts, we set out this study to determine the effect of FGF2 on TGFβ1-induced EMT in human lung epithelial cells. Methods: BEAS-2B and A549 cells were treated with recombinant FGF2 (2 nM) with or without TGFβ1 (2 ng/ml) for up to 4 days. The phenotypic alterations associated with EMT were assessed by quantitative real-time PCR and E-cadherin protein expression levels was assayed by western blot and immunofluorescence staining. Cell migration was confirmed using wound-healing assay. Results: TGFβ1 treatment led to significantly reduced expression of E-cadherin (CDH1) and markedly induced expression of mesenchymal proteins such as N-cadherin (CDH2), tenascin C (TNC), fibronectin (FN), ACTA2 and COL1A1. TGFβ1 also induced a morphological change and a significant increase in cell migration. FGF2 did not significantly alter EMT gene expression markers on its own, however enhanced TGFβ1-induced suppression of CDH1 and upregulation of ACTA2, but did not alter TNC, FN and CDH2 gene expression levels induced by TGFβ1. FGF2 maintained TGFβ1-induced morphologic changes as well as increased the migration of TGFβ1-treated cells. Furthermore, FGF2 treatment significantly inhibited TGFβ1-induced COL1A1 expression in both BEAS-2B and A549 cells. FGFR-specific tyrosine kinase inhibitor PD173074 blocked the synergism between these two growth factors. Conclusions: This study suggests a synergistic effect between TGFβ1 and FGF2 in inducing EMT, which may play an important role in wound healing and tissue repair after injury. Our findings provide insight into the effects of FGF2 following lung injury and in pulmonary fibrosis.

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