Print Email Facebook Twitter Fibrates down-regulate IL-1-stimulated C-reactive protein gene expression in hepatocytes by reducing nuclear p50-NFκB-C/EBP-β complex formation Title Fibrates down-regulate IL-1-stimulated C-reactive protein gene expression in hepatocytes by reducing nuclear p50-NFκB-C/EBP-β complex formation Author Kleemann, R. Gervois, P.P. Verschuren, L. Staels, B. Princen, H.M.G. Kooistra, T. Gaubius Instituut TNO Publication year 2003 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 Subject BiologyAnimalsAntilipemic AgentsBezafibrateC-Reactive ProteinCCAAT-Enhancer-Binding Protein-betaCell NucleusClofibric AcidDown-RegulationHepatocytesHumansInterleukin-1MiceMice, KnockoutNF-kappa BNF-kappa B p50 SubunitProtein BindingReceptors, Cytoplasmic and NuclearTranscription FactorsTranscription, GeneticTransfection To reference this document use: http://resolver.tudelft.nl/uuid:67a58c79-cbd9-439f-ac55-1be0cccc0303 DOI https://doi.org/10.1182/blood-2002-06-1762 TNO identifier 236938 ISSN 0006-4971 Source Blood, 101 (2), 545-551 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.