Abstract

Plasminogen activator inhibitor-1 (PAI-1) is a primary regulator of plasminogen activation that plays an essential role in regulating the physiological thrombotic/fibrinogenic balance. The elevation of PAI-1 expression by human pleural mesothelial cells has been reported to contribute to pleural fibrosis and pleurodesis. In this study, we examined the effects on PAI-1 expression of dynasore, a cell-permeable inhibitor of dynamin, and its mechanisms in a human pleural mesothelial cell line (MeT-5A). The results indicated that dynasore enhanced transforming growth factor (TGF)- β1- and TNFα-induced PAI-1 protein expression in a concentration-dependent manner. Furthermore, dynasore significantly up-regulated PAI-1 protein and its messenger RNA expressions. Interestingly, Smad2/3 activation was induced by TGF-β1 but not by dynasore. Among signaling inhibitors, a c-Jun NH2-terminal kinase (JNK) inhibitor (SP600125) markedly attenuated dynasore-stimulated PAI-1 protein production. Consistently, dynasore strongly increased JNK phosphorylation. Onthe other hand, therewasnoenhancement effectby dynasore on TGF-β1-induced matrix metalloproteinase-2 activation. These findings suggest that dynasore may stimulate PAI-1 protein expression and enhance TGF-β1 activity through activation of JNK-mediated signaling in human pleural mesothelial cells. Given the profibrotic effect of dynasore, further in vivo studies may be conducted to evaluate its potential as a pleurodesing agent.

Original languageEnglish
Pages (from-to)692-700
Number of pages9
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume40
Issue number6
DOIs
Publication statusPublished - Jun 1 2009

Fingerprint

Dynamins
Plasminogen Activator Inhibitor 1
Replication Protein C
Transforming Growth Factors
JNK Mitogen-Activated Protein Kinases
Chemical activation
Proteins
Pleurodesis
N'-(3,4-dihydroxybenzylidene)-3-hydroxy-2-naphthahydrazide
Phosphorylation
Plasminogen
Matrix Metalloproteinase 2
Fibrosis
Hand
Cells
Cell Line
Messenger RNA

Keywords

  • Dynasore
  • JNK
  • MMP-2
  • PAI-1
  • TGF-β1

ASJC Scopus subject areas

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this

Dynasore, a dynamin inhibitor, induces PAI-1 expression in MeT-5A human pleural mesothelial cells. / Chung, Chi Li; Sheu, Joen Rong; Liu, Hsiang Erh; Chang, Shi Chuan; Chou, Yung Chen; Chen, Wei Lin; Chou, Duen Suey; Hsiao, George.

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 40, No. 6, 01.06.2009, p. 692-700.

Research output: Contribution to journalArticle

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AU - Chung, Chi Li

AU - Sheu, Joen Rong

AU - Liu, Hsiang Erh

AU - Chang, Shi Chuan

AU - Chou, Yung Chen

AU - Chen, Wei Lin

AU - Chou, Duen Suey

AU - Hsiao, George

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N2 - Plasminogen activator inhibitor-1 (PAI-1) is a primary regulator of plasminogen activation that plays an essential role in regulating the physiological thrombotic/fibrinogenic balance. The elevation of PAI-1 expression by human pleural mesothelial cells has been reported to contribute to pleural fibrosis and pleurodesis. In this study, we examined the effects on PAI-1 expression of dynasore, a cell-permeable inhibitor of dynamin, and its mechanisms in a human pleural mesothelial cell line (MeT-5A). The results indicated that dynasore enhanced transforming growth factor (TGF)- β1- and TNFα-induced PAI-1 protein expression in a concentration-dependent manner. Furthermore, dynasore significantly up-regulated PAI-1 protein and its messenger RNA expressions. Interestingly, Smad2/3 activation was induced by TGF-β1 but not by dynasore. Among signaling inhibitors, a c-Jun NH2-terminal kinase (JNK) inhibitor (SP600125) markedly attenuated dynasore-stimulated PAI-1 protein production. Consistently, dynasore strongly increased JNK phosphorylation. Onthe other hand, therewasnoenhancement effectby dynasore on TGF-β1-induced matrix metalloproteinase-2 activation. These findings suggest that dynasore may stimulate PAI-1 protein expression and enhance TGF-β1 activity through activation of JNK-mediated signaling in human pleural mesothelial cells. Given the profibrotic effect of dynasore, further in vivo studies may be conducted to evaluate its potential as a pleurodesing agent.

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