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Binding of C/EBPβ to the C-Reactive Protein (CRP) Promoter in Hep3B Cells Is Associated with Transcription of CRP mRNA¹

Duprane Pedaci Young^2,*, Irving Kushner and David Samols^3,*

^* Department of Biochemistry, Case Western Reserve University, Cleveland, OH 44106; and Department of Medicine, Case Western Reserve University, MetroHealth Campus, Cleveland, OH 44109

Expression of the acute phase protein C-reactive protein (CRP) is tightly regulated in hepatocytes. Although very little CRP mRNA is transcribed normally, inflammatory stimuli are followed by a dramatic increase in mRNA synthesis and accumulation. IL-6 and IL-1β are believed to be the major cytokines responsible for induction of CRP and other acute phase proteins. Our previous studies, using transient transfection and EMSA experiments, implicated involvement of the transcription factors C/EBPβ, STAT3, Rel p50, and c-Rel in CRP induction. In the current study we used chromatin immunoprecipitation assays to determine the kinetics of transcription factor occupancy of these transcription factors on the endogenous CRP promoter. All of these transcription factors were found bound to the endogenous CRP promoter in the absence of cytokines, but cytokine treatment markedly increased binding of only C/EBPβ. In addition, c-Rel and TATA box-binding protein (TBP) appeared to occupy the promoter in parallel in the presence of cytokines. In the absence of cytokines, CRP mRNA accumulation was not measurable but began to increase by 3 h after exposure of cells to IL-1β plus IL-6, peaking at 12 h with secondary peaks at 18 and 24 h. The secondary peaks in mRNA expression paralleled the pattern of binding of c-Rel and TBP to the CRP promoter. We conclude that the CRP promoter has a low level of transcription factor occupancy in the absence of cytokines and induction occurs with binding of C/EBP, and that c-Rel and TBP are important for modulating CRP expression.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant AG02467 from the National Institutes of Health and Metabolism Training Program Grant T32 DK-007319-28.

² Current address: Department of Molecular Cardiology, Cleveland Clinic Lerner Research Institute, 9500 Euclid Avenue, Cleveland, OH 44195.

³ Address correspondence and reprint requests to David Samols, Department of Biochemistry, School of Medicine, 10900 Euclid Avenue, Case Western Reserve University, Cleveland, OH 44106-4935. E-mail address: dsamols{at}cwru.edu

⁴ Abbreviations used in this paper: CRP, C-reactive protein; TBP, TATA box-binding protein; ChIP, chromatin immunoprecipitation; LAP, liver-enriched activator protein; LIP, liver-enriched inhibitor protein.

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