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Fibrates down-regulate IL-1-stimulated C-reactive protein gene expression in hepatocytes by reducing nuclear p50-NFκB-C/EBP-β complex formation

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Author: Kleemann, R. · Gervois, P.P. · Verschuren, L. · Staels, B. · Princen, H.M.G. · Kooistra, T.
Type:article
Date:2003
Institution: Gaubius Instituut TNO
Source:Blood, 2, 101, 545-551
Identifier: 236938
doi: doi:10.1182/blood-2002-06-1762
Keywords: Biology · Animals · Antilipemic Agents · Bezafibrate · C-Reactive Protein · CCAAT-Enhancer-Binding Protein-beta · Cell Nucleus · Clofibric Acid · Down-Regulation · Hepatocytes · Humans · Interleukin-1 · Mice · Mice, Knockout · NF-kappa B · NF-kappa B p50 Subunit · Protein Binding · Receptors, Cytoplasmic and Nuclear · Transcription Factors · Transcription, Genetic · Transfection

Abstract

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-α (PPAR-α). 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-α, 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 in-duces CRP expression through 2 overlapping response elements, the binding sites for CCAAT-box/enhancer-binding protein-β (C/EBP-β) and p50-nuclear factor-κB (p50-NFκB). Cotransfection of C/EBP-β and p50-NFκB 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-β-p50-NFκB complexes. Interestingly, PPAR-α activators reduce the formation of nuclear C/EBP-β- p50-NFκB complexes, and thereby CRP promoter activity, by 2 mechanisms. First, PPAR-α increases IκB-α expression and thus prevents p50-NFκB translocation to the nucleus. Second, fibrates decrease hepatic C/EBP-β and p50-NFκB protein levels in mice in a PPAR-α-dependent way. Our findings identify C/EBP-β and p50-NFκB as novel targets for PPAR-α and provide a molecular explanation for the reduction of plasma CRP levels by fibrates. © 2003 by The American Society of Hematology. Chemicals/CAS: bezafibrate, 41859-67-0; C reactive protein, 9007-41-4; ciprofibrate, 52214-84-3; fenofibric acid, 26129-32-8, 42017-89-0; peroxisome proliferator activated receptor alpha, 147258-70-6; pirinixic acid, 50892-23-4; simvastatin, 79902-63-9; Antilipemic Agents; Bezafibrate, 41859-67-0; C-Reactive Protein, 9007-41-4; CCAAT-Enhancer-Binding Protein-beta; ciprofibrate, 52214-84-3; Clofibric Acid, 882-09-7; Interleukin-1; NF-kappa B p50 Subunit; NF-kappa B; Receptors, Cytoplasmic and Nuclear; Transcription Factors