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How Stress Controls the Inflammatory Cytokine Response

压力如何控制炎症细胞因子反应

基本信息

批准号：
255537323
负责人：
Professor Dr. Fred Schaper
金额：
--
依托单位：
Abteilung Systembiologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2014
资助国家：
德国
起止时间：
2013-12-31 至 2017-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/255537323?language=en
关键词：
How Stress Controls Inflammatory Cytokine

项目摘要

We examine the novel concept that the integrated cellular stress response plays a critical role in regulating inflammatory cytokine gene expression. Specifically, we aim to study how stress regulates the genes encoding tumor necrosis factor (TNF-alpha) and suppressor of cytokine signaling 3 (SOCS3), a broad negative regulator of inflammatory signaling. Jointly, we will investigate how this regulation is affected by the inflammatory cytokine IL-6, a major mediator of the acute-phase response, and by immunosuppressive glucocorticoids. The work is based on our discovery that multiple inflammatory cytokine genes contain potent intragenic RNA activators of PKR. Phosphorylation of eIF2-alpha by kinases, including the RNA-activated kinase, PKR, represses translation and is essential for mounting the integrated cellular stress response. IFN-gamma mRNA attenuates its own translation by locally activating PKR through a 5-proximal RNA structure. Efficient splicing of TNF-alpha mRNA requires a short 3-UTR element that activates PKR; activation of PKR induces eIF2-alpha phosphorylation strictly needed for splicing of this mRNA, revealing a novel, positive role for eIF2-alpha phosphorylation in mRNA splicing. SOCS3 is regulated by stress signaling via PKR and eIF2-alpha phosphorylation. SOCS3 protein is very short-lived, however, a more stable and more potent N-terminally truncated isoform, delta N-SOCS3, is induced strongly by PKR and by conditions that promote eIF2-alpha phosphorylation. We showed recently that glucocorticoids increase IL-6-dependent gene induction by inhibiting expression of SOCS3 protein while not affecting SOCS3 protein stability or level and stability of SOCS3 mRNA, suggestive of translational repression. We ask here whether the activation of PKR needed for stable delta N-SOCS3 synthesis is achieved through an intragenic SOCS3 RNA activator of PKR and whether glucocorticoids influence control via PKR and phosphorylation of eIF2-alpha.Activation of PKR and phosphorylation of eIF2-alpha control SOCS3 and TNF-alpha gene expression and both SOCS3 and TNF-alpha are regulated by IL-6 and glucocorticoids, creating a solid basis for this joint research. Findings emanating from this joint basic biological research focused on the mechanisms of stress signaling will impact on basic understanding of inflammatory processes essential for protective immunity and at the heart of many diseases.

我们研究了新的概念，整合的细胞应激反应在调节炎症细胞因子基因表达中起着至关重要的作用。具体来说，我们的目标是研究如何调节基因编码肿瘤坏死因子（TNF-α）和细胞因子信号转导抑制因子3（SOCS 3），炎症信号的广泛的负调节。我们将共同研究这种调节是如何受到炎性细胞因子IL-6（急性期反应的主要介质）和免疫抑制性糖皮质激素的影响。这项工作是基于我们的发现，多个炎症细胞因子基因含有PKR的有效基因内RNA激活剂。eIF 2-α被激酶磷酸化，包括RNA激活的激酶PKR，抑制翻译，并且对于建立整合的细胞应激反应是必需的。IFN-γ mRNA通过5-近端RNA结构局部激活PKR来减弱其自身的翻译。TNF-α mRNA的有效剪接需要激活PKR的短3-UTR元件; PKR的激活诱导eIF 2-α磷酸化，这是该mRNA剪接所严格需要的，揭示了eIF 2-α磷酸化在mRNA剪接中的新的积极作用。SOCS 3通过PKR和eIF 2-α磷酸化受到应激信号的调节。SOCS 3蛋白的寿命非常短，然而，PKR和促进eIF 2-α磷酸化的条件强烈诱导更稳定和更有效的N-末端截短同种型Δ N-SOCS 3。我们最近发现，糖皮质激素通过抑制SOCS 3蛋白的表达增加IL-6依赖性基因诱导，而不影响SOCS 3蛋白的稳定性或SOCS 3 mRNA的水平和稳定性，提示翻译抑制。我们在此询问稳定的Δ N-SOCS 3合成所需的PKR的激活是否通过PKR的基因内SOCS 3 RNA激活剂实现，以及糖皮质激素是否通过PKR和eIF 2-α的磷酸化影响控制。PKR的激活和eIF 2-α的磷酸化控制SOCS 3和TNF-α基因表达，并且SOCS 3和TNF-α均受IL-6和糖皮质激素调节，为这项合作研究奠定了坚实的基础。这项联合基础生物学研究的结果集中在应激信号传导机制上，将影响对保护性免疫和许多疾病核心所必需的炎症过程的基本理解。