Histone deacetylase inhibitor impairs plasminogen activator inhibitor-1 expression via inhibiting TNF-α-activated MAPK/AP-1 signaling cascade.
Tumor necrosis factor-(TNF-)-α upregulates plasminogen activator inhibitor-(PAI-) 1 expression in pleural mesothelial cells (PMCs), contributing to fibrin deposition and pleural fibrosis. Histone deacetylases (HDACs) have been found implicated in fibrogenesis. However, the roles of TNF-α or HDAC in the regulation of PAI-1 expression have not been well investigated. We aimed to examine the effects and mechanisms of HDAC inhibition on TNF-α-induced PAI-1 expression in human PMCs. MeT-5A human PMCs were treated with TNF-α in the presence or absence of the m-carboxycinnamic acid bishydroxamide (CBHA), an HDAC class II inhibitor, and the HDAC activity, PAI-1 protein expression, mRNA, and activated signalings were analyzed. CBHA abrogated TNF-α-induced HDAC activity, PAI-1 protein and, mRNA expression in MeT-5A cells. Moreover, CBHA significantly enhanced mitogen-activated protein kinase phosphatase-(MKP-) 5/MKP-1 expression and inhibited p38/JNK activations, ATF2/c-Jun translocation, and PAI-1 promoter activity. Altogether, our data suggest that HDAC inhibition may abrogate TNF-α-activated MAPK/AP-1 signaling and PAI-1 expression in human PMCs. Given the antifibrotic effect through PAI-1 abrogation, CBHA may be utilized as a novel agent in the treatment of fibrotic diseases.
Graduate Institute of Medical Sciences and Department of Pharmacology, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110-31, Taiwan.
Wei-Lin
WL
Chen
Graduate Institute of Medical Sciences and Department of Pharmacology, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110-31, Taiwan.
Joen-Rong
JR
Sheu
School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei 110-31, Taiwan.
Che-Jen
CJ
Hsiao
Division of Pulmonary Medicine, Department of Internal Medicine, Taipei Medical University Hospital, Taipei 110-31, Taiwan.
Shih-Hsin
SH
Hsiao
School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei 110-31, Taiwan ; Division of Pulmonary Medicine, Department of Internal Medicine, Taipei Medical University Hospital, Taipei 110-31, Taiwan.
Chi-Li
CL
Chung
Graduate Institute of Medical Sciences and Department of Pharmacology, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110-31, Taiwan.
George
0000-0001-9079-3646
G
Hsiao
D051698:Activating Transcription Factor 2 / Q000235:genetics; D002478:Cells, Cultured; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics; D004848:Epithelium / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D056572:Histone Deacetylase Inhibitors; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; C051321:SERPINE1 protein, human; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D048670:MAP Kinase Kinase 4; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1