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Prepublished online as a Blood First Edition Paper on August 29, 2002; DOI 10.1182/blood-2002-06-1762. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-06-1762v1 101/2/545    most recent 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 Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Kleemann, R. Articles by Kooistra, T. Search for Related Content PubMed PubMed Citation Articles by Kleemann, R. Articles by Kooistra, T. Related Collections Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 January 2003, Vol. 101, No. 2, pp. 545-551 HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Fibrates down-regulate IL-1-stimulated C-reactive protein gene expression in hepatocytes by reducing nuclear p50-NFB-C/EBP- complex formation Robert Kleemann, Philippe P. Gervois, Lars Verschuren, Bart Staels, Hans M. G. Princen, and Teake Kooistra From the Gaubius Laboratory Nederlandse Organisatie voor toegepast natuurwetenschappelijk onderzoek (TNO) Prevention and Health, Leiden, The Netherlands; Département d'Athérosclérose, U.545 INSERM, Institut Pasteur de Lille; and Faculté de Pharmacie, Université de Lille II, France. C-reactive protein (CRP) is a major acute-phase protein in humans. Elevated plasma CRP levels are a risk factor for cardiovascular disease. CRP is predominantly expressed in hepatocytes and is induced by interleukin-1 (IL-1) and IL-6 under inflammatory situations, such as the acute phase. Fibrates are hypolipidemic drugs that act through the nuclear receptor peroxisome proliferator-activated receptor- (PPAR-). Fibrates have been shown to reduce elevated CRP levels in humans, but the molecular mechanism is unknown. In this study, we demonstrate that different PPAR- activators suppress IL-1-induced, but not IL-6-induced, expression of CRP in primary human hepatocytes and HuH7 hepatoma cells. Induction of CRP expression by IL-1 occurs at the transcriptional level. Site-directed mutagenesis experiments show that IL-1 induces CRP expression through 2 overlapping response elements, the binding sites for CCAAT-box/enhancer-binding protein- (C/EBP-) and p50-nuclear factor-B (p50-NFB). Cotransfection of C/EBP- and p50-NFB enhances CRP promoter activity, and coimmunoprecipitation experiments indicate that the increase in CRP promoter activity by IL-1 is related to the generation and nuclear accumulation of C/EBP--p50-NFB complexes. Interestingly, PPAR- activators reduce the formation of nuclear C/EBP--p50-NFB complexes, and thereby CRP promoter activity, by 2 mechanisms. First, PPAR- increases IB- expression and thus prevents p50-NFB translocation to the nucleus. Second, fibrates decrease hepatic C/EBP- and p50-NFB protein levels in mice in a PPAR--dependent way. Our findings identify C/EBP- and p50-NFB as novel targets for PPAR- and provide a molecular explanation for the reduction of plasma CRP levels by fibrates. © 2003 by The American Society of Hematology.   CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: R. M. Mansouri, E. Bauge, B. Staels, and P. 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