Abstract
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.
Original language | English |
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Pages (from-to) | 6843-6853 |
Number of pages | 11 |
Journal | Journal of Biological Chemistry |
Volume | 283 |
Issue number | 11 |
DOIs | |
Publication status | Published - 14 Mar 2008 |
Keywords
- Animals
- CCAAT-Enhancer-Binding Proteins
- Cyclic AMP
- Cyclic AMP-Dependent Protein Kinases
- Endothelium, Vascular
- Fibroblasts
- Gene Expression Regulation
- Interleukin-6
- Mice
- Models, Biological
- Protein Isoforms
- Signal Transduction
- Suppressor of Cytokine Signaling Proteins
- Umbilical Veins