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首页> 外文期刊>Cellular Signalling >Selective inhibition of cytokine-activated extracellular signal-regulated kinase by cyclic AMP via Epac1-dependent induction of suppressor of cytokine signalling-3
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Selective inhibition of cytokine-activated extracellular signal-regulated kinase by cyclic AMP via Epac1-dependent induction of suppressor of cytokine signalling-3

机译：环AMP通过Epac1依赖性细胞因子信号传导抑制因子3的诱导选择性抑制细胞因子激活的细胞外信号调节激酶

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摘要

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.
机译：在这里，我们证明人脐静脉内皮细胞（HUVECs）中环AMP（cAMP）水平的升高会特异性地减弱ERK1,2激活，从而响应瘦素或可溶性白介素IL-6受体-α/ IL-6（sIL-6R α/ IL-6）反信号复合物，但不是蛋白激酶C激活物佛波醇12-肉豆蔻酸酯13-乙酸酯。通过短期干扰（si）RNA介导的敲除或细胞因子信号传导抑制因子3（SOCS-3的遗传消除）消除了cAMP对sIL-6R alpha / IL-6刺激的ERK1,2和STAT3磷酸化的抑制作用）。不能通过抑制cAMP依赖性蛋白激酶（PKA）来逆转cAMP的抑制作用，但被耗尽由cAMP 1（Epac1）激活的细胞内cAMP传感器交换蛋白所阻断，这也是观察SOCS-3所必需的响应cAMP积累。有趣的是，ERK抑制阻止了cAMP升高抑制IL-6信号传导的能力。与此观察结果一致，HUVEC中的cAMP升高会产生短暂但稳定的ERK激活，随后磷酸化转录因子C / EBPβ，这两者均对PKA抑制有抵抗力。但是，siRNA耗竭和免疫印迹实验表明，在cAMP升高后，Epac1和Epac2均未参与PKA独立的ERK1,2活化。在一起，这些观察结果表明，尽管SOCS-3诱导以及随后对cAMP的应答由细胞因子介导的ERK1,2和STAT3磷酸化的抑制需要Epac1和ERK途径的短暂PKA独立激活，但这两个事件是由不同的控制的机制。此外，它揭示了一种新型的Epac依赖性机制，cAMP可以通过这种机制特异性抑制ERK响应细胞因子受体的活化。

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