HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Fibrates down-regulate IL-1–stimulated C-reactive protein gene expression in hepatocytes by reducing nuclear p50-NF B–C/EBP- complex formation

C-reactive protein (CRP) is a major acutephase 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 PPARactivators suppress IL1–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 factorB (p50-NF B). Cotransfection of C/EBPand p50-NF B 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-NF B complexes. Interestingly, PPARactivators reduce the formation of nuclear C/EBP– p50-NF B complexes, and thereby CRP promoter activity, by 2 mechanisms. First, PPARincreases I Bexpression and thus prevents p50-NF B translocation to the nucleus. Second, fibrates decrease hepatic C/EBPand p50-NF B protein levels in mice in a PPAR–dependent way. Our findings identify C/EBPand p50-NF B as novel targets for PPARand provide a molecular explanation for the reduction of plasma CRP levels by fibrates. (Blood. 2003;101:545-551)