Interleukin-6 influences stress-signalling by reducing the expression of the mTOR-inhibitor REDD1 in a STAT3-dependent manner
Interleukin-6 influences stress-signalling by reducing the expression of the mTOR-inhibitor REDD1 in a STAT3-dependent manner
复制标题
DOI：
10.1016/j.cellsig.2016.04.004
复制
发表时间：
2016-08-01
影响因子：
4.8
通讯作者：
Dittrich, Anna
中科院分区：
文献类型：
--
作者：
Pinno, Jessica;Bongartz, Hannes;Dittrich, Anna
白细胞介素 6 (IL-6) 是一种多效性细胞因子，也是哺乳动物雷帕霉素靶点 (mTOR) 的强激活剂。相比之下，mTOR 活性受到发育和 DNA 损伤反应调节 1 (REDD1) 的负向调节。 REDD1 的表达是由糖皮质激素和 DNA 损伤剂等细胞应激源诱导的。我们发现 IL-6 可以降低基础以及应激诱导的 REDD1 的表达。 IL-6 对 REDD1 表达的减少与蛋白酶体或 caspase 介导的 REDD1 蛋白降解无关。相反，IL-6 会减少 REDD1 mRNA 的诱导。 IL-6 对 REDD1 表达的调节独立于磷脂酰肌醇 3 激酶 (PI3K) 和丝裂原激活蛋白激酶 (MAPK) 信号传导，但取决于信号转导器和转录激活剂 3 (STAT3) 的表达和激活。此外，IL-6 降低基础 REDD1 表达与 IL-6 诱导的 mTOR 信号传导激活相关。抑制 STAT3 激活可阻断 IL-6 诱导的 mTOR 激活。总之，我们提出了 IL-6 诱导的 mTOR 激活和 IL-6 依赖性应激诱导的 mTOR 活性抑制逆转的新的 STAT3 依赖性机制。 (C) 2016 Elsevier Inc. 保留所有权利。
Interleukin 6 (IL-6) is a pleiotropic cytokine and a strong activator of Mammalian Target of Rapamycin (mTOR). In contrast, mTOR activity is negatively regulated by Regulated in Development and DNA Damage Responses 1 (REDD1). Expression of REDD1 is induced by cellular stressors such as glucocorticoids and DNA damaging agents. We show that the expression of basal as well as stress-induced REDD1 is reduced by IL-6. The reduction of REDD1 expression by IL-6 is independent of proteasomal or caspase-mediated degradation of REDD1 protein. Instead, induction of REDD1 mRNA is reduced by IL-6. The regulation of REDD1 expression by IL-6 is independent of Phosphatidylinositide-3-Kinase (PI3K) and Mitogen-Activated Protein Kinase (MAPK) signalling but depends on the expression and activation of Signal Transducer and Activator of Transcription 3 (STAT3). Furthermore, the reduction of basal REDD1 expression by IL-6 correlates with IL-6-induced activation of mTOR signalling. Inhibition of STAT3 activation blocks IL-6-induced mTOR activation. In summary, we present a novel STAT3dependent mechanism of both IL-6-induced activation of mTOR and IL-6-dependent reversion of stress induced inhibition of mTOR activity. (C) 2016 Elsevier Inc. All rights reserved.