Molecular Principles of Interleukin-6/-11 Classic and Trans-Signalling

Interleukin-6/-11 经典和反式信号转导的分子原理

• 批准号: 438049395
• 负责人: Professor Dr. Jürgen Scheller
• 金额: --
• 依托单位: Institut für Biochemie und Molekularbiologie II
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2020
• 资助国家: 德国
• 起止时间: 2019-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/438049395?language=en
• 关键词: Molecular; Principles; Interleukin; 11; Classic

Interleukin (IL-)6 and IL-11 critically regulate health and disease. For signalling, IL-6 and IL-11 bind to non-signal transducing IL-6 receptor (IL-6R) and IL-11R, respectively, followed by complex formation with the signal-transducing glycoprotein 130 (gp130) receptor. Besides the membrane-bound IL-6R, a soluble form of the IL-6R (sIL-6R) is produced by proteolytic shedding and by differential splicing. Interaction of IL-6 with membrane-bound IL-6R and gp130 is called classic signalling, whereas binding of the complex of IL-6 and soluble IL-6R (sIL-6R) to gp130 is called trans-signalling. The IL-6R is mainly found on hepatocytes and immune cells, thereby restricting the scope of IL-6 target cells via classic signalling, which induces the acute-phase response and is considered to exert mainly anti-bacterial functions. Trans-signalling via the sIL-6R can activate virtually all cell types, since gp130 is ubiquitously expressed. IL-6 trans-signalling mainly regulates pro-inflammatory responses and blocking of trans-signalling using soluble gp130 (sgp130) has been shown to be effective in a variety of preclinical chronic and autoimmune diseases. For IL-11, we have recently described IL-11 trans-signalling. Overall, IL-11 has mainly regenerative functions. Since sgp130 specifically inhibits IL-6 and IL-11 trans-signalling, IL-6 and IL-11 classic signalling is largely unaffected. As a consequence, bacterial defence is largely not affected by sgp130 as observed shown for global blockade of IL-6 signalling. Sgp130Fc is a 10-100-fold more potent, dimerized variant of sgp130 incorporating the Fc part of an IgG1 antibody and is currently under clinical phase II development for chronic inflammatory bowel disease. Our recent finding that sgp130Fc is able to bind to membrane-bound IL-6:IL-6R complexes raised the question, why sgp130Fc did not inhibit classic signalling? Our hypothesis is, that this apparently unsolved question might be explained by the unique receptor activation mode of IL-6 based on a particular receptor arrangement on the plasma membrane. These characteristics might allow binding of natural sgp130 or sgp130Fc to membrane-bound IL-6:IL-6R complexes in the absence but not in the presence of cell surface gp130. Therefore we seek to address three central questions in IL-6 biology to unravel the mechanistic principles of IL-6 classic-signaling: 1. Molecular activation mode of the gp130 receptor in classic and trans-signaling, 2. Classic and Trans-signaling: mutually exclusive? and 3. Design and characterization of a novel IL-6-selective trans-signaling inhibitor which did not interfere with IL-11 Trans-signaling.

白细胞介素（IL-）6和IL-11在健康和疾病中起着重要的调节作用。对于信号传导，IL-6和IL-11分别结合非信号转导IL-6受体（IL-6R）和IL-11R，然后与信号转导糖蛋白130 （gp130）受体形成复合物。除了膜结合的IL-6R外，IL-6R的可溶性形式（sIL-6R）是通过蛋白水解脱落和差异剪接产生的。IL-6与膜结合的IL-6R和gp130的相互作用称为经典信号传导，而IL-6和可溶性IL-6R复合物（sIL-6R）与gp130的结合称为反式信号传导。IL-6R主要存在于肝细胞和免疫细胞上，通过经典信号传导限制IL-6靶细胞的作用范围，诱导急性期反应，被认为主要发挥抗菌功能。通过sIL-6R的反式信号传导可以激活几乎所有的细胞类型，因为gp130是普遍表达的。IL-6反式信号主要调节促炎反应，使用可溶性gp130 （sgp130）阻断反式信号传导已被证明在多种临床前慢性和自身免疫性疾病中有效。对于IL-11，我们最近描述了IL-11的转信号。总的来说，IL-11主要具有再生功能。由于sgp130特异性抑制IL-6和IL-11反式信号传导，IL-6和IL-11经典信号传导在很大程度上不受影响。因此，细菌防御在很大程度上不受sgp130的影响，正如在IL-6信号的全球阻断中所观察到的那样。Sgp130Fc是sgp130的10-100倍强效二聚体变体，包含IgG1抗体的Fc部分，目前正处于慢性炎症性肠病的临床II期开发中。我们最近发现sgp130Fc能够结合膜结合IL-6:IL-6R复合物，这提出了一个问题，为什么sgp130Fc不抑制经典信号传导？我们的假设是，这个显然未解决的问题可能是由基于质膜上特定受体排列的IL-6独特的受体激活模式来解释的。这些特性可能允许天然sgp130或sgp130Fc在细胞表面gp130不存在的情况下与膜结合的IL-6:IL-6R复合物结合。因此，我们寻求解决IL-6生物学中的三个核心问题，以揭示IL-6经典信号传导的机制原理：gp130受体在经典和反式信号传导中的分子激活模式，2。经典信号和反式信号：相互排斥？和3。不干扰IL-11反式信号传导的新型il -6选择性反式信号传导抑制剂的设计和表征。