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 language | English |
|---|---|
| Pages (from-to) | 692-700 |
| Number of pages | 9 |
| Journal | American Journal of Respiratory Cell and Molecular Biology |
| Volume | 40 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - Jun 1 2009 |
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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 journal › Article
}
TY - JOUR
T1 - Dynasore, a dynamin inhibitor, induces PAI-1 expression in MeT-5A human pleural mesothelial cells
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
PY - 2009/6/1
Y1 - 2009/6/1
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.
AB - 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.
KW - Dynasore
KW - JNK
KW - MMP-2
KW - PAI-1
KW - TGF-β1
UR - http://www.scopus.com/inward/record.url?scp=66349085317&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=66349085317&partnerID=8YFLogxK
U2 - 10.1165/rcmb.2008-0087OC
DO - 10.1165/rcmb.2008-0087OC
M3 - Article
C2 - 18978303
AN - SCOPUS:66349085317
VL - 40
SP - 692
EP - 700
JO - American Journal of Respiratory Cell and Molecular Biology
JF - American Journal of Respiratory Cell and Molecular Biology
SN - 1044-1549
IS - 6
ER -