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Nucleic Acids Research, 2003, Vol. 31, No. 23 6722-6732
© 2003 Oxford University Press

Article

Interleukin-6 represses the transcription of the CCAAT/enhancer binding protein-{alpha} gene in hepatoma cells by inhibiting its ability to autoactivate the proximal promoter region

Pelagia Foka, Scott A. Irvine, Feray Kockar and Dipak P. Ramji*

Cardiff School of Biosciences, Cardiff University, Museum Avenue, PO Box 911, Cardiff CF10 3US, UK

*To whom correspondence should be addressed: Tel/Fax: +44 29 2087 6753; Email: ramji{at}cardiff.ac.uk
Present address:
Feray Kockar, Molecular Biology Section, Department of Biology, University of Balikesir, Balikesir, Turkey

The cytokine interleukin-6 (IL-6) plays key roles in the immune and inflammatory responses, acute-phase reaction and hematopoiesis. Such biological actions of IL-6 are characterised by both the activation and the inhibition of gene transcription. Unfortunately, in contrast to gene activation, the mechanism by which IL-6 suppresses transcription remains largely unclear. We have, therefore, investigated this aspect using the Xenopus laevis CCAAT/enhancer binding protein-{alpha} (C/EBP{alpha}) gene promoter as a model. We show by transient transfection assays of various promoter–luciferase DNA constructs into hepatoma cells that a C/EBP recognition sequence in the proximal promoter region is essential for the IL-6-mediated repression. Electrophoretic mobility shift assays showed that C/EBP{alpha} was the major protein that bound to this site and, consistent with its expression pattern, the binding was reduced when the cells were exposed to IL-6. Co-transfection assays revealed for the first time that the ability of C/EBP{alpha}, but not C/EBPß or Sp1, to transactivate the promoter was decreased dramatically when the cells were incubated with IL-6. These studies, therefore, identify a novel mechanism for IL-6-mediated repression of gene transcription that involves a reduction in C/EBP{alpha}-mediated activation.


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