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

白细胞介素（IL-）6和IL-11对健康和疾病起着重要的调节作用。对于信号传导，IL-6和IL-11分别与非信号转导IL-6受体（IL-6R）和IL-11R结合，随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之外，可溶形式的IL-6R（sIL-6R）通过蛋白水解脱落和差异剪接产生。IL-6与膜结合的IL-6R和gp130的相互作用被称为经典信号传导，而IL-6和可溶性IL-6R（sIL-6R）的复合物与gp130的结合被称为反式信号传导。IL-6R主要存在于肝细胞和免疫细胞上，从而通过经典信号传导限制IL-6靶细胞的范围，其诱导急性期反应，并被认为主要发挥抗菌功能。由于gp130广泛表达，通过sIL-6R的信号转导几乎可以激活所有类型的细胞。IL-6反式信号传导主要调节促炎反应，并且使用可溶性gp130（sgp130）阻断反式信号传导已显示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trans-signaling。总体而言，IL-11主要具有再生功能。由于sgp130特异性地抑制IL-6和IL-11的反式信号传导，因此IL-6和IL-11的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，如观察到的IL-6信号传导的全局阻断所示。Sgp130 Fc是一种10 - 100倍更有效的sgp130二聚体变体，其中包含IgG1抗体的Fc部分，目前正在进行慢性炎症性肠病的临床II期开发。我们最近发现sgp130 Fc能够与膜结合的IL-6：IL-6R复合物结合，这提出了一个问题，为什么sgp130 Fc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独特的受体激活模式的IL-6的基础上，一个特定的受体排列在质膜上。这些特征可能允许天然sgp130或sgp130Fc在不存在但不存在细胞表面gp130的情况下与膜结合的IL-6：IL-6R复合物结合。因此，我们试图解决IL-6生物学中的三个核心问题，以解开IL-6经典信号传导的机制原理：1。gp130受体在经典和反式信号转导中的分子激活模式。经典和跨信令：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。

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.