Donate Help Contact The AHA Sign In Home
American Heart Association
Arteriosclerosis, Thrombosis, and Vascular Biology
Search: search_blue_button Advanced Search
« Previous Article | Table of Contents | Next Article »
Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1078-1084
Published online before print February 17, 2005, doi: 10.1161/01.ATV.0000159701.24372.49
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
25/5/1078    most recent
01.ATV.0000159701.24372.49v1
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Dong, J.
Right arrow Articles by Kitabatake, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Dong, J.
Right arrow 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-{delta}

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{alpha}, C/EBPß, and C/EBP{delta} 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{delta} binding activity was increased by IL-6 and attenuated by mevastatin. Mevastatin attenuated IL-6–mediated increase of C/EBP{delta} protein in the nuclear extracts. IL-6 also increased PAI-1 and C/EBP{delta} 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{delta} binding site. Vascular protection by statins may be partly mediated through regulation of CEBP{delta} 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{delta} binding site. Mevastatin attenuated IL-6–mediated increase of C/EBP{delta} protein in the nuclear extracts. C/EBP{delta} 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:


Home page
 CLIN APPL THROMB HEMOSTHome page
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]

Home page
 Am. J. Physiol. Cell Physiol.Home page
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]

Home page
 Cancer Epidemiol. Biomarkers Prev.Home page
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]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
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]

Home page
 Mol. Cell. Biol.Home page
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]


ATVB Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search
Copyright © 2005 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited.