Dynasore, a dynamin inhibitor, induces PAI-1 expression in MeT-5A human pleural mesothelial cells.
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.
Chung
Chi-Li
CL
Department of Chest Medicine, Taipei Medical University Hospital and School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Sheu
Joen-Rong
JR
Liu
Hsiang-Erh
HE
Chang
Shi-Chuan
SC
Chou
Yung-Chen
YC
Chen
Wei-Lin
WL
Chou
Duen-Suey
DS
Hsiao
George
G
D002460:Cell Line; D034281:Dynamins / Q000037:antagonists & inhibitors*; D004705:Endocytosis; D004848:Epithelium / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D006835:Hydrazones / Q000737:chemistry / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D008954:Models, Biological; D018384:Oxidative Stress; D017395:Plasminogen Activator Inhibitor 1 / Q000737:chemistry / Q000378:metabolism*; D010994:Pleura / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
D006835:Hydrazones; C511794:N'-(3,4-dihydroxybenzylidene)-3-hydroxy-2-naphthahydrazide; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; C051321:SERPINE1 protein, human; D013778:Tetrazolium Salts; D013844:Thiazoles; D053773:Transforming Growth Factor beta1; D048670:MAP Kinase Kinase 4; D020778:Matrix Metalloproteinase 2; D034281:Dynamins; C022616:thiazolyl blue