Abstract

Hypoxia was identified as a mediator of lung fibrosis in patients with chronic obstructive asthma (COA). Overexpression of a disintegrin and metalloproteinase 17 (ADAM 17) and connective tissue growth factor (CTGF) leads to development of tissue fibrosis. However, the signaling pathway in hypoxia-induced ADAM 17 expression remains poorly defined. In this study, we investigated the roles that ribosomal S-6 kinase 1 (RSK1)/CCAAT/enhancer-binding protein β (C/EBPβ)-dependent ADAM 17 expression plays in hypoxia-induced CTGF expression in human lung fibroblasts. We observed that hypoxia caused increases in ADAM 17 expression and ADAM 17-luciferase activity in WI-38 cells. Hypoxia-induced CTGF-luciferase activity and CTGF expression were reduced in cells transfected with small interfering (si)RNA of ADAM 17 in WI-38 cells. Moreover, hypoxia-induced ADAM 17 expression was reduced by RSK1 siRNA and C/EBPβ siRNA. Hypoxia caused time-dependent increases in RSK1 phosphorylation at Thr359/Ser363. Exposure of cells to hypoxia resulted in increased C/EBPβ phosphorylation at Thr266 and C/EBPβ-luciferase activity in time-dependent manners, and these effects were suppressed by RSK1 siRNA. Hypoxia induced recruitment of C/EBPβ to the ADAM 17 promoter. Furthermore, CTGF-luciferase activity induced by hypoxia was attenuated by RSK1 siRNA and C/EBPβ siRNA. These results suggest that hypoxia instigates the RSK1-dependent C/EBPβ signaling pathway, which in turn initiates binding of C/EBPβ to the ADAM 17 promoter and ultimately induces ADAM 17 expression in human lung fibroblasts. Moreover, RSK1/C/EBPβ-dependent ADAM 17 expression is involved in hypoxia-induced CTGF expression. Our results suggest possible therapeutic approaches for treating hypoxia-mediated lung fibrosis in COA.

Original languageEnglish
Pages (from-to)155-163
Number of pages9
JournalMolecular Immunology
Volume88
DOIs
Publication statusPublished - Aug 1 2017

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CCAAT-Enhancer-Binding Proteins
Disintegrins
S 6
Metalloproteases
Phosphotransferases
Fibroblasts
Connective Tissue Growth Factor
Lung
Small Interfering RNA
Luciferases
Fibrosis
Hypoxia
Asthma
Phosphorylation
Cell Hypoxia

Keywords

  • ADAM 17
  • C/EBPβ
  • CTGF
  • Hypoxia
  • lung fibrosis
  • RSK1

ASJC Scopus subject areas

  • Immunology
  • Molecular Biology

Cite this

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title = "Hypoxia-induced ADAM 17 expression is mediated by RSK1-dependent C/EBPβ activation in human lung fibroblasts",
abstract = "Hypoxia was identified as a mediator of lung fibrosis in patients with chronic obstructive asthma (COA). Overexpression of a disintegrin and metalloproteinase 17 (ADAM 17) and connective tissue growth factor (CTGF) leads to development of tissue fibrosis. However, the signaling pathway in hypoxia-induced ADAM 17 expression remains poorly defined. In this study, we investigated the roles that ribosomal S-6 kinase 1 (RSK1)/CCAAT/enhancer-binding protein β (C/EBPβ)-dependent ADAM 17 expression plays in hypoxia-induced CTGF expression in human lung fibroblasts. We observed that hypoxia caused increases in ADAM 17 expression and ADAM 17-luciferase activity in WI-38 cells. Hypoxia-induced CTGF-luciferase activity and CTGF expression were reduced in cells transfected with small interfering (si)RNA of ADAM 17 in WI-38 cells. Moreover, hypoxia-induced ADAM 17 expression was reduced by RSK1 siRNA and C/EBPβ siRNA. Hypoxia caused time-dependent increases in RSK1 phosphorylation at Thr359/Ser363. Exposure of cells to hypoxia resulted in increased C/EBPβ phosphorylation at Thr266 and C/EBPβ-luciferase activity in time-dependent manners, and these effects were suppressed by RSK1 siRNA. Hypoxia induced recruitment of C/EBPβ to the ADAM 17 promoter. Furthermore, CTGF-luciferase activity induced by hypoxia was attenuated by RSK1 siRNA and C/EBPβ siRNA. These results suggest that hypoxia instigates the RSK1-dependent C/EBPβ signaling pathway, which in turn initiates binding of C/EBPβ to the ADAM 17 promoter and ultimately induces ADAM 17 expression in human lung fibroblasts. Moreover, RSK1/C/EBPβ-dependent ADAM 17 expression is involved in hypoxia-induced CTGF expression. Our results suggest possible therapeutic approaches for treating hypoxia-mediated lung fibrosis in COA.",
keywords = "ADAM 17, C/EBPβ, CTGF, Hypoxia, lung fibrosis, RSK1",
author = "Chen, {Jing Yun} and Lin, {Chien Huang} and Chen, {Bing Chang}",
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T1 - Hypoxia-induced ADAM 17 expression is mediated by RSK1-dependent C/EBPβ activation in human lung fibroblasts

AU - Chen, Jing Yun

AU - Lin, Chien Huang

AU - Chen, Bing Chang

PY - 2017/8/1

Y1 - 2017/8/1

N2 - Hypoxia was identified as a mediator of lung fibrosis in patients with chronic obstructive asthma (COA). Overexpression of a disintegrin and metalloproteinase 17 (ADAM 17) and connective tissue growth factor (CTGF) leads to development of tissue fibrosis. However, the signaling pathway in hypoxia-induced ADAM 17 expression remains poorly defined. In this study, we investigated the roles that ribosomal S-6 kinase 1 (RSK1)/CCAAT/enhancer-binding protein β (C/EBPβ)-dependent ADAM 17 expression plays in hypoxia-induced CTGF expression in human lung fibroblasts. We observed that hypoxia caused increases in ADAM 17 expression and ADAM 17-luciferase activity in WI-38 cells. Hypoxia-induced CTGF-luciferase activity and CTGF expression were reduced in cells transfected with small interfering (si)RNA of ADAM 17 in WI-38 cells. Moreover, hypoxia-induced ADAM 17 expression was reduced by RSK1 siRNA and C/EBPβ siRNA. Hypoxia caused time-dependent increases in RSK1 phosphorylation at Thr359/Ser363. Exposure of cells to hypoxia resulted in increased C/EBPβ phosphorylation at Thr266 and C/EBPβ-luciferase activity in time-dependent manners, and these effects were suppressed by RSK1 siRNA. Hypoxia induced recruitment of C/EBPβ to the ADAM 17 promoter. Furthermore, CTGF-luciferase activity induced by hypoxia was attenuated by RSK1 siRNA and C/EBPβ siRNA. These results suggest that hypoxia instigates the RSK1-dependent C/EBPβ signaling pathway, which in turn initiates binding of C/EBPβ to the ADAM 17 promoter and ultimately induces ADAM 17 expression in human lung fibroblasts. Moreover, RSK1/C/EBPβ-dependent ADAM 17 expression is involved in hypoxia-induced CTGF expression. Our results suggest possible therapeutic approaches for treating hypoxia-mediated lung fibrosis in COA.

AB - Hypoxia was identified as a mediator of lung fibrosis in patients with chronic obstructive asthma (COA). Overexpression of a disintegrin and metalloproteinase 17 (ADAM 17) and connective tissue growth factor (CTGF) leads to development of tissue fibrosis. However, the signaling pathway in hypoxia-induced ADAM 17 expression remains poorly defined. In this study, we investigated the roles that ribosomal S-6 kinase 1 (RSK1)/CCAAT/enhancer-binding protein β (C/EBPβ)-dependent ADAM 17 expression plays in hypoxia-induced CTGF expression in human lung fibroblasts. We observed that hypoxia caused increases in ADAM 17 expression and ADAM 17-luciferase activity in WI-38 cells. Hypoxia-induced CTGF-luciferase activity and CTGF expression were reduced in cells transfected with small interfering (si)RNA of ADAM 17 in WI-38 cells. Moreover, hypoxia-induced ADAM 17 expression was reduced by RSK1 siRNA and C/EBPβ siRNA. Hypoxia caused time-dependent increases in RSK1 phosphorylation at Thr359/Ser363. Exposure of cells to hypoxia resulted in increased C/EBPβ phosphorylation at Thr266 and C/EBPβ-luciferase activity in time-dependent manners, and these effects were suppressed by RSK1 siRNA. Hypoxia induced recruitment of C/EBPβ to the ADAM 17 promoter. Furthermore, CTGF-luciferase activity induced by hypoxia was attenuated by RSK1 siRNA and C/EBPβ siRNA. These results suggest that hypoxia instigates the RSK1-dependent C/EBPβ signaling pathway, which in turn initiates binding of C/EBPβ to the ADAM 17 promoter and ultimately induces ADAM 17 expression in human lung fibroblasts. Moreover, RSK1/C/EBPβ-dependent ADAM 17 expression is involved in hypoxia-induced CTGF expression. Our results suggest possible therapeutic approaches for treating hypoxia-mediated lung fibrosis in COA.

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