Identification of CCAAT/enhancer-binding proteins as exchange protein activated by cAMP-activated transcription factors that mediate the induction of the SOCS-3 gene

J Biol Chem. 2008 Mar 14;283(11):6843-53. doi: 10.1074/jbc.M710342200. Epub 2008 Jan 14.


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/EBPbeta to the SOCS-3 promoter. Secondly, knockdown of C/EBPbeta and -delta isoforms abolished both SOCS-3 induction and inhibition of IL-6 signaling in response to cAMP. Thirdly, overexpression of C/EBPalpha, -beta, or -delta 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/EBPbeta or delta 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CCAAT-Enhancer-Binding Proteins / metabolism*
  • Cyclic AMP / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Endothelium, Vascular / cytology
  • Fibroblasts / metabolism
  • Gene Expression Regulation*
  • Interleukin-6 / metabolism
  • Mice
  • Models, Biological
  • Protein Isoforms
  • Signal Transduction
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins / metabolism*
  • Umbilical Veins / cytology


  • CCAAT-Enhancer-Binding Proteins
  • Interleukin-6
  • Protein Isoforms
  • Socs3 protein, mouse
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases