This Article Full Text Full Text (PDF) All Versions of this Article: 25/5/1078    most recent 01.ATV.0000159701.24372.49v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dong, J. Articles by Kitabatake, A. Search for Related Content PubMed PubMed Citation Articles by Dong, J. Articles by Kitabatake, A.

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1078.)
© 2005 American Heart Association, Inc.

Thrombosis

Interleukin-6 and Mevastatin Regulate Plasminogen Activator Inhibitor-1 Through CCAAT/Enhancer-Binding Protein-

Jie Dong; Satoshi Fujii; Hongmei Li; Hidekazu Nakabayashi; Masaharu Sakai; Shinzo Nishi; Daisuke Goto; Tomoo Furumoto; Shogo Imagawa; Tarikuz A.K.M. Zaman; Akira Kitabatake

From the Departments of Cardiovascular Medicine and Molecular Biology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

Correspondence to Satoshi Fujii, MD, PhD, The Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Kita 15, Nishi 7, Kitaku, Sapporo, Japan 060-8638. 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/EBPß, 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.

IL-6 increases hepatic PAI-1 expression mediated by the –232- to –210-bp region of the promoter containing a C/EBP binding site. Mevastatin attenuated IL-6–mediated increase of C/EBP protein in the nuclear extracts. C/EBP may be responsible for hepatic PAI-1 expression induced by IL-6 and its attenuation by statins.

Key Words: IL-6 • statins • PAI-1 • C/EBP • thrombosis

This article has been cited by other articles:

				D. Ozel Demiralp, H. Aktas, and N. Akar The Effect of Plasminogen Activator Inhibitor-1 -675 4G/5G Polymorphism on PAI-1 Gene Expression and Adipocyte Differentiation Clinical and Applied Thrombosis/Hemostasis, October 1, 2008; 14(4): 438 - 446. [Abstract] [PDF]

				J. Dong, S. Fujii, S. Imagawa, S. Matsumoto, M. Matsushita, S. Todo, H. Tsutsui, and B. E. Sobel IL-1 and IL-6 induce hepatocyte plasminogen activator inhibitor-1 expression through independent signaling pathways converging on C/EBP{delta} Am J Physiol Cell Physiol, January 1, 2007; 292(1): C209 - C215. [Abstract] [Full Text] [PDF]

				M. D. Sternlicht, A. M. Dunning, D. H. Moore, P. D.P. Pharoah, D. G. Ginzinger, K. Chin, J. W. Gray, F. M. Waldman, B. A.J. Ponder, and Z. Werb Prognostic Value of PAI1 in Invasive Breast Cancer: Evidence That Tumor-Specific Factors Are More Important Than Genetic Variation in Regulating PAI1 Expression. Cancer Epidemiol. Biomarkers Prev., November 1, 2006; 15(11): 2107 - 2114. [Abstract] [Full Text] [PDF]

				S. Imagawa, S. Fujii, J. Dong, T. Furumoto, T. Kaneko, T. Zaman, Y. Satoh, H. Tsutsui, and B. E Sobel Hepatocyte Growth Factor Regulates E Box-Dependent Plasminogen Activator Inhibitor Type 1 Gene Expression in HepG2 Liver Cells Arterioscler. Thromb. Vasc. Biol., October 1, 2006; 26(10): 2407 - 2413. [Abstract] [Full Text] [PDF]

				A. Okamoto, Y. Iwamoto, and Y. Maru Oxidative Stress-Responsive Transcription Factor ATF3 Potentially Mediates Diabetic Angiopathy Mol. Cell. Biol., February 1, 2006; 26(3): 1087 - 1097. [Abstract] [Full Text] [PDF]