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/EBPalpha, C/EBPbeta, and C/EBPdelta 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/EBPdelta binding activity was increased by IL-6 and attenuated by mevastatin. Mevastatin attenuated IL-6-mediated increase of C/EBPdelta protein in the nuclear extracts. IL-6 also increased PAI-1 and C/EBPdelta 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/EBPdelta binding site. Vascular protection by statins may be partly mediated through regulation of CEBPdelta and consequent modulation of PAI-1 expression.
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 humanhepatoma-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/EBPalpha, C/EBPbeta, and C/EBPdelta 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/EBPdelta binding activity was increased by IL-6 and attenuated by mevastatin. Mevastatin attenuated IL-6-mediated increase of C/EBPdelta protein in the nuclear extracts. IL-6 also increased PAI-1 and C/EBPdelta 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/EBPdelta binding site. Vascular protection by statins may be partly mediated through regulation of CEBPdelta and consequent modulation of PAI-1 expression.
Authors: Mark D Sternlicht; Alison M Dunning; Dan H Moore; Paul D P Pharoah; David G Ginzinger; Koei Chin; Joe W Gray; Frederic M Waldman; Bruce A J Ponder; Zena Werb Journal: Cancer Epidemiol Biomarkers Prev Date: 2006-11 Impact factor: 4.254
Authors: K A Patterson; X Zhang; S K Wrobleski; A E Hawley; D A Lawrence; T W Wakefield; D D Myers; J A Diaz Journal: Thromb Res Date: 2012-12-29 Impact factor: 3.944
Authors: Simeng Chen; Teng Feng; Maja Vujić Spasić; Sandro Altamura; Katja Breitkopf-Heinlein; Jutta Altenöder; Thomas S Weiss; Steven Dooley; Martina U Muckenthaler Journal: J Biol Chem Date: 2016-04-27 Impact factor: 5.157
Authors: Tieying Hou; Brian C Tieu; Sutapa Ray; Adrian Recinos Iii; Ruwen Cui; Ronald G Tilton; Allan R Brasier Journal: Curr Cardiol Rev Date: 2008-08