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Dynasore, a dynamin inhibitor, induces PAI-1 expression in MeT-5A human pleural mesothelial cells
Chi-Li Chung1, Joen-Rong Sheu, Hsiang-Erh Liu
1Department of Chest Medicine, Taipei Medical University Hospital and School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan.
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)-beta(1)- and TNF-alpha-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-beta(1) but not by dynasore. Among signaling inhibitors, a c-Jun NH(2)-terminal kinase (JNK) inhibitor (SP600125) markedly attenuated dynasore-stimulated PAI-1 protein production. Consistently, dynasore strongly increased JNK phosphorylation. On the other hand, there was no enhancement effect by dynasore on TGF-beta(1)-induced matrix metalloproteinase-2 activation. These findings suggest that dynasore may stimulate PAI-1 protein expression and enhance TGF-beta(1) 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.
Insights
Dynasore, a dynamin inhibitor, boosts plasminogen activator inhibitor-1 (PAI-1) expression in human pleural cells via JNK signaling. This suggests potential for PAI-1-related conditions and pleurodesis applications.
Area of Science:
- Cell Biology
- Biochemistry
- Molecular Medicine
Background:
- Plasminogen activator inhibitor-1 (PAI-1) is crucial for thrombotic/fibrinogenic balance.
- Elevated PAI-1 in pleural mesothelial cells is linked to pleural fibrosis and pleurodesis.
- Understanding PAI-1 regulation is key for treating related conditions.
Purpose of the Study:
- To investigate the effects of dynasore, a dynamin inhibitor, on PAI-1 expression in human pleural mesothelial cells.
- To elucidate the underlying molecular mechanisms of dynasore's action on PAI-1.
- To assess dynasore's potential role in modulating TGF-beta(1) activity and its implications for pleurodesis.
Main Methods:
- Utilized human pleural mesothelial cell line (MeT-5A).
- Administered dynasore and measured PAI-1 protein and mRNA expression.
- Investigated signaling pathways including Smad2/3 and c-Jun NH(2)-terminal kinase (JNK) using specific inhibitors and phosphorylation assays.
- Assessed TGF-beta(1)-induced matrix metalloproteinase-2 activation.
Main Results:
- Dynasore enhanced TGF-beta(1)- and TNF-alpha-induced PAI-1 protein expression concentration-dependently.
- Dynasore significantly upregulated both PAI-1 protein and mRNA.
- Dynasore activated JNK signaling, and JNK inhibition markedly reduced dynasore-stimulated PAI-1 production.
- Dynasore did not induce Smad2/3 activation or affect TGF-beta(1)-induced MMP-2 activation.
Conclusions:
- Dynasore stimulates PAI-1 protein expression in human pleural mesothelial cells.
- The mechanism involves the activation of JNK-mediated signaling pathways.
- Dynasore may enhance TGF-beta(1) activity, suggesting potential therapeutic applications in pleurodesis.
