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

The prototypical second messenger cyclic AMP 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 signalling-3\" (SOCS-3), a negative regulator of IL-6 receptor signaling. We have determined previously that SOCS-3 induction by cyclic AMP occurs independently of cyclic AMP-dependent protein kinase (PKA), instead requiring the recently identified cyclic AMP sensor \"exchange protein activated by cyclic AMP 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 (HUVECs) 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 cyclic AMP. Thirdly, overexpression of C/EBPalpha, beta or delta potentiated EPAC-mediated accumulation of SOCS-3. Finally, these effects were not restricted to HUVECs, as 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 cyclic AMP-mediated changes in gene expression independently of PKA.