期刊
CELLULAR SIGNALLING
卷 21, 期 11, 页码 1706-1715出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2009.07.009
关键词
Cyclic AMP; Exchange protein directly activated by cyclic AMP; Interleukin-6; Extracellular signal ling-regulated kinase; Suppressor of cytokine signalling
类别
资金
- British Heart Foundation [PG/08/125]
- U.K. Biotechnology and Biological Sciences Research Council [BB/DO15324/1]
- British Heart Foundation PhD [FS/04/074, FS/05/ 084/19458]
- BBSRC [BB/D015324/1] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/D015324/1] Funding Source: researchfish
- British Heart Foundation [PG/08/125/26415] Funding Source: researchfish
Here we demonstrate that elevation of cyclic AMP (cAMP) levels in human umbilical vein endothelial cells (HUVECs) specifically attenuates ERK1,2 activation in response to either leptin or a soluble interleukin IL-6 receptor-alpha/IL-6 (sIL-6R alpha/IL-6) trans-signalling complex but not protein kinase C activator phorbol 12-myristate 13-acetate. The inhibitory effects of cAMP on sIL-6R alpha/IL-6-stimulated phosphorylation of ERK1,2 and STAT3 were abolished by either short interfering (si) RNA-mediated knockdown or genetic ablation of suppressor of cytokine signalling-3 (SOCS-3). The inhibitory effect of cAMP could not be reversed by inhibition of cAMP-dependent protein kinase (PKA) but was blocked by depletion of the alternative intracellular cAMP sensor exchange protein activated by cAMP 1 (Epac1), which is also required to observe SOCS-3 accumulation in response to cAMP. Interestingly, the ability of cAMP elevation to inhibit IL-6 signalling was blocked by ERK inhibition. Consistent with this observation, cAMP elevation in HUVECs produced a transient yet robust activation of ERK, and subsequent phosphorylation of transcription factor C/EBP beta, both of which were resistant to PKA inhibition. However, siRNA depletion and immunoblotting experiments revealed that neither Epac1 nor Epac2 contributed to the PKA-independent activation of ERK1,2 observed following cAMP elevation. Together, these observations suggest that while SOCS-3 induction and subsequent inhibition of cytokine-mediated phosphorylation of ERK1,2 and STAT3 in response to cAMP require Epac1 and a transient PKA-independent activation of the ERK pathway, these two events are controlled by distinct mechanisms. In addition, it reveals a novel Epac-dependent mechanism by which cAMP can specifically inhibit ERK in response to cytokine receptor activation. (C) 2009 Elsevier Inc. All rights reserved.
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