Identification of CCAAT/Enhancer-binding proteins as exchange protein activated by cAMP-activated transcription factors that mediate the induction of the SOCS-3 gene (original) (raw)

Yarwood, S.J., Borland, G., Sands, W.A. and Palmer, T.M.(2008) Identification of CCAAT/Enhancer-binding proteins as exchange protein activated by cAMP-activated transcription factors that mediate the induction of the SOCS-3 gene.Journal of Biological Chemistry, 283(11), pp. 6843-6853. (doi: 10.1074/jbc.M710342200)

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Abstract

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/EBP[beta] to the SOCS-3 promoter. Secondly, knockdown of C/EBP[beta] and [delta] isoforms abolished both SOCS-3 induction and inhibition of IL-6 signaling in response to cyclic AMP. Thirdly, overexpression of C/EBP[alpha], [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/EBP[beta] 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

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