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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 (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 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. Social Bookmarking                   What's this? Submitted June 13, 2002 Accepted August 14, 2002 Fibrates down-regulate IL-1-stimulated C-reactive protein gene expression in hepatocytes by reducing nuclear p50-NFB ~C/EBP-ß complex formation Robert Kleemann*, Philippe P Gervois, Lars Verschuren, Bart Staels, Hans M Princen, and Teake Kooistra VBO, TNO-PG, Leiden, The Netherlands Department of Atherosclerosis, Institute Pasteur, Lille, France; Department of Atherosclerosis, Institute Pasteur, Lille, France * Corresponding author; email: R.Kleemann{at}pg.tno.nl. 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 induced by interleukins-1 and -6 (IL-1 and IL-6) under inflammatory situations, such as the acute phase. Fibrates are hypolipidemic drugs that act via 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 via two overlapping response elements, the binding sites for CCAAT-box/enhancer-binding protein-ß(C/EBP-ß) and p50-nuclear factor-B (p50-NFB). Co-transfection of C/EBP-ß and p50-NFB enhances CRP promoter activity and co-immunoprecipitation experiments indicate that the increase in CRP promoter activity by IL-1 is related to generation and nuclear accumulation of C/EBP-ß~p50-NFB complexes. Interestingly, PPAR- activators reduce the formation of nuclear C/EBP-ß~p50-NFB complexes, and thereby CRP promoter activity, by two mechanisms. Firstly, PPAR- increases IB- expression and thus prevents p50-NFB translocation to the nucleus. Secondly, fibrates decrease hepatic C/EBP-ß and p50-NFB protein levels in mice in a PPAR--dependent way. Our findings identify C/EBP-ß and p50-NFB as novel targets for PPAR- and provide a molecular explanation for the reduction of plasma CRP levels by fibrates. 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. Gervois Systemic and Distal Repercussions of Liver-Specific Peroxisome Proliferator-Activated Receptor-{alpha} Control of the Acute-Phase Response Endocrinology, June 1, 2008; 149(6): 3215 - 3223. [Abstract] [Full Text] [PDF] J. Shen, D. K. Arnett, L. D. Parnell, J. M. Peacock, C.-Q. Lai, J. E. Hixson, M. Y. Tsai, M. A. Province, R. J. Straka, and J. M. 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