Rapamycin Induces Mitogen-activated Protein (MAP) Kinase Phosphatase-1 (MKP-1) Expression through Activation of Protein Kinase B and Mitogen-activated Protein Kinase Kinase Pathways
Rapamycin Induces Mitogen-activated Protein (MAP) Kinase Phosphatase-1 (MKP-1) Expression through Activation of Protein Kinase B and Mitogen-activated Protein Kinase Kinase Pathways
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DOI：
10.1074/jbc.m113.492702
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发表时间：
2013-11-22
影响因子：
4.8
通讯作者：
Samavati, Lobelia
中科院分区：
文献类型：
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作者：
Rastogi, Ruchi;Jiang, Zhongliang;Samavati, Lobelia
丝裂原活化蛋白激酶磷酸酶-1(MKP-1)又称双特异性磷酸酶-1(DUSP-1)，在MAPKs失活过程中起重要作用。几种具有免疫抑制特性的药物调节MKP-1的表达，作为其作用机制的一部分。我们研究了雷帕霉素和双重mTOR抑制剂(AZD2014)对MKP-1表达的影响。低剂量雷帕霉素导致AKT和ERK通路迅速激活，随后MKP-1表达增加。雷帕霉素处理导致CREB、转录因子1(ATF1)和ATF2的磷酸化，这三个转录因子与MKP-1启动子上的环状AMP反应元件结合。抑制MEK/ERK或AKT通路均可减弱雷帕霉素介导的MKP-1诱导。AZD2014没有激活AKT，但激活了ERK通路，导致适度的MKP-1诱导。使用来自野生型(WT)小鼠的骨髓来源的巨噬细胞(BMDM)或缺乏AKT1和AKT2亚型的小鼠，或者来自MEK1和MEK2靶向缺陷的BMDM，我们发现雷帕霉素治疗导致了WT BMDM中mkp1的表达增加，但在缺乏AKT1异构体或MEK1和MEK2的BMDM中未能做到这一点。重要的是，雷帕霉素可抑制脂多糖介导的p38的激活，减少一氧化氮和IL-6的产生。我们的工作为观察到的mTOR抑制的免疫调节作用提供了一个概念性框架。
Mitogen-activated protein kinase phosphatase-1 (MKP-1), also known as dual specificity phosphatase-1 (DUSP-1), plays a crucial role in the deactivation of MAPKs. Several drugs with immune-suppressive properties modulate MKP-1 expression as part of their mechanism of action. We investigated the effect of mTOR inhibition through rapamycin and a dual mTOR inhibitor (AZD2014) on MKP-1 expression. Low dose rapamycin led to a rapid activation of both AKT and ERK pathways with a subsequent increase in MKP-1 expression. Rapamycin treatment led to phosphorylation of CREB, transcription factor 1 (ATF1), and ATF2, three transcription factors that bind to the cyclic AMP-responsive elements on the Mkp-1 promoter. Inhibition of either the MEK/ERK or the AKT pathway attenuated rapamycin-mediated MKP-1 induction. AZD2014 did not activate AKT but activated the ERK pathway, leading to a moderate MKP-1 induction. Using bone marrow-derived macrophages (BMDMs) derived from wild-type (WT) mice or mice deficient in AKT1 and AKT2 isoforms or BMDM from targeted deficiency in MEK1 and MEK2, we show that rapamycin treatment led to an increased MKP1 expression in BMDM from WT but failed to do so in BMDMs lacking the AKT1 isoform or MEK1 and MEK2. Importantly, rapamycin pretreatment inhibited LPS-mediated p38 activation and decreased nitric oxide and IL-6 production. Our work provides a conceptual framework for the observed immune modulatory effect of mTOR inhibition.