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

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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.