| Author |
Guo, Songbo Knittler, Katharina Bartsch, Jörg W. Rabe, Björn Murphy, Gillian Rose-john, Stefan Mauermann, Andre Von Der Heyde, Jan Meyer, Dörte Michalek, Matthias Eickholz, Peter Garbers, Christoph Schwarz, Jeanette Schumacher, Neele Chalaris, Athena Schacher, Beate Wolf, Janina |
| Description |
Author Affiliation: Schumacher N ( From the Institute of Biochemistry, Medical Faculty, University of Kiel, Rudolf-Höber-Str. 1, 24118 Kiel, Germany.); Meyer D ( From the Institute of Biochemistry, Medical Faculty, University of Kiel, Rudolf-Höber-Str. 1, 24118 Kiel, Germany.); Mauermann A ( From the Institute of Biochemistry, Medical Faculty, University of Kiel, Rudolf-Höber-Str. 1, 24118 Kiel, Germany.); von der Heyde J ( From the Institute of Biochemistry, Medical Faculty, University of Kiel, Rudolf-Höber-Str. 1, 24118 Kiel, Germany.); Wolf J ( From the Institute of Biochemistry, Medical Faculty, University of Kiel, Rudolf-Höber-Str. 1, 24118 Kiel, Germany.); Schwarz J ( From the Institute of Biochemistry, Medical Faculty, University of Kiel, Rudolf-Höber-Str. 1, 24118 Kiel, Germany.); Knittler K ( From the Institute of Biochemistry, Medical Faculty, University of Kiel, Rudolf-Höber-Str. 1, 24118 Kiel, Germany.); Murphy G ( the Department of Oncology, University of Cambridge, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, United Kingdom.); Michalek M ( From the Institute of Biochemistry, Medical Faculty, University of Kiel, Rudolf-Höber-Str. 1, 24118 Kiel, Germany.); Garbers C ( From the Institute of Biochemistry, Medical Faculty, University of Kiel, Rudolf-Höber-Str. 1, 24118 Kiel, Germany.); Bartsch JW ( the Department of Neurosurgery/Lab, Philipps-University Marburg, Baldingerstr., 35033 Marburg, Germany, and.); Guo S ( the Department of Neurosurgery/Lab, Philipps-University Marburg, Baldingerstr., 35033 Marburg, Germany, and.); Schacher B ( the Department of Periodontology, Center for Dentistry and Oral Medicine (Carolinum), Johann Wolfgang Goethe-University, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany.); Eickholz P ( the Department of Periodontology, Center for Dentistry and Oral Medicine (Carolinum), Johann Wolfgang Goethe-University, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany.); Chalaris A ( From the Institute of Biochemistry, Medical Faculty, University of Kiel, Rudolf-Höber-Str. 1, 24118 Kiel, Germany.); Rose-John S ( From the Institute of Biochemistry, Medical Faculty, University of Kiel, Rudolf-Höber-Str. 1, 24118 Kiel, Germany.); Rabe B ( From the Institute of Biochemistry, Medical Faculty, University of Kiel, Rudolf-Höber-Str. 1, 24118 Kiel, Germany, brabe@biochem.uni-kiel.de.) |
| Abstract |
Generation of the soluble interleukin-6 receptor (sIL-6R) is a prerequisite for pathogenic IL-6 trans-signaling, which constitutes a distinct signaling pathway of the pleiotropic cytokine interleukin-6 (IL-6). Although in vitro experiments using ectopically overexpressed IL-6R and candidate proteases revealed major roles for the metalloproteinases ADAM10 and ADAM17 in IL-6R shedding, the identity of the protease(s) cleaving IL-6R in more physiological settings, or even in vivo, remains unknown. By taking advantage of specific pharmacological inhibitors and primary cells from ADAM-deficient mice we established that endogenous IL-6R of both human and murine origin is shed by ADAM17 in an induced manner, whereas constitutive release of endogenous IL-6R is largely mediated by ADAM10. Although circulating IL-6R levels are altered in various diseases, the origin of blood-borne IL-6R is still poorly understood. It has been shown previously that ADAM17 hypomorphic mice exhibit unaltered levels of serum sIL-6R. Here, by quantification of serum sIL-6R in protease-deficient mice as well as human patients we also excluded ADAM10, ADAM8, neutrophil elastase, cathepsin G, and proteinase 3 from contributing to circulating sIL-6R. Furthermore, we ruled out alternative splicing of the IL-6R mRNA as a potential source of circulating sIL-6R in the mouse. Instead, we found full-length IL-6R on circulating microvesicles, establishing microvesicle release as a novel mechanism for sIL-6R generation. |
