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J. Biol. Chem., Vol. 283, Issue 11, 6843-6853, March 14, 2008

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Identification of CCAAT/Enhancer-binding Proteins as Exchange Protein Activated by cAMP-activated Transcription Factors That Mediate the Induction of the SOCS-3 Gene^*

From the Molecular Pharmacology Group, Division of Biochemistry and Molecular Biology, Faculty of Biomedical and Life Sciences, University of Glasgow, Davidson Bldg., Glasgow G12 8QQ, United Kingdom

The prototypical second messenger cAMP is a key regulator of immune and inflammatory responses. Its ability to inhibit interleukin (IL)-6 responses is due to induction of suppressor of cytokine signaling-3 (SOCS-3), a negative regulator of IL-6 receptor signaling. We have determined previously that SOCS-3 induction by cAMP occurs independently of cAMP-dependent protein kinase, instead requiring the recently identified cAMP sensor exchange protein activated by cAMP 1 (EPAC1). Here we present evidence to suggest that the C/EBP family of transcription factors link EPAC1 activation to SOCS-3 induction. Firstly, selective activation of EPAC in human umbilical vein endothelial cells increased C/EBP DNA binding activity and recruitment of C/EBPβ to the SOCS-3 promoter. Secondly, knockdown of C/EBPβ and - isoforms abolished both SOCS-3 induction and inhibition of IL-6 signaling in response to cAMP. Thirdly, overexpression of C/EBP, -β, or - potentiated EPAC-mediated accumulation of SOCS-3. Finally, these effects were not restricted to human umbilical vein endothelial cells, because similar phenomena were observed in murine embryonic fibroblasts in which C/EBPβ or had been deleted. In summary, our findings constitute the first description of an EPAC-C/EBP pathway that can control cAMP-mediated changes in gene expression independently of protein kinase A.

Received for publication, December 19, 2007 , and in revised form, January 14, 2008.

^* This work was supported by the Biotechnology and Biological Sciences Research Council (Grant BB/D015324/1 to S. J. Y. and T. M. P.), the British Heart Foundation (Grant PG/05/026 to T. M. P. and S. J. Y.), and Tenovus Scotland (Grant S06/4 to S. J. Y.). 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 To whom correspondence may be addressed: Tel.: 44-141-330-3908; Fax: 44-141-330-4620; E-mail: S.Yarwood{at}bio.gla.ac.uk. ² To whom correspondence may be addressed: Tel.: 44-141-330-4626; Fax: 44-141-330-4620; E-mail: T.Palmer{at}bio.gla.ac.uk.

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