on February 17, 2005
Published online before print February 17, 2005, doi: 10.1161/01.ATV.0000159701.24372.49
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Submitted on July 26, 2004
Accepted on January 28, 2005
Interleukin-6 and Mevastatin Regulate Plasminogen Activator Inhibitor-1 Through CCAAT/Enhancer-Binding Protein-
Jie Dong ;
From the Departments of Cardiovascular Medicine and Molecular Biology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
* To whom correspondence should be addressed. E-mail: sfujii{at}med.hokudai.ac.jp.
Objective--We sought to determine the etiologic mechanism of proinflammatory cytokine, interleukin-6 (IL-6), and statin as regulators of synthesis of plasminogen activator inhibitor-1 (PAI-1), the physiological fibrinolysis inhibitor and an acute-phase reactant.
Methods and Results--Transient transfection and luciferase assay in HepG2 human hepatoma-derived cells demonstrated that IL-6 increased PAI-1 promoter activity and mevastatin decreased IL-6-inducible response. Systematic deletion assay of the promoter demonstrated that the region (-239 to -210 bp) containing a putative CCAAT/enhancer-binding protein (C/EBP) binding site was necessary. Point mutation in this site abolished the IL-6-inducible response. Electrophoretic mobility shift assay and chromatin immunoprecipitation assay demonstrated that C/EBP
, C/EBP
, and C/EBP
were involved in protein-DNA complex formation in intact cells. Deoxyribonuclease (DNase) I footprinting analysis revealed that 5' flanking region (-232 to -210 bp) is acute-phase response protein-binding site. C/EBP binding activity was increased by IL-6 and attenuated by mevastatin. Mevastatin attenuated IL-6-mediated increase of C/EBP protein in the nuclear extracts. IL-6 also increased PAI-1 and C/EBP mRNA in mouse primary hepatocytes.
Conclusions--IL-6 increases hepatic PAI-1 expression mediated by the -232- to -210-bp region of the promoter containing a C/EBP binding site. Vascular protection by statins may be partly mediated through regulation of CEBP and consequent modulation of PAI-1 expression.
Key words: IL-6 • statins • PAI-1 • C/EBP • thrombosis
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