Arnold, Philipp, Boll, Inga, Rothaug, Michelle, Schumacher, Neele, Schmidt, Frederike, Wichert, Rielana, Schneppenheim, Janna, Lokau, Juliane, Pickhinke, Ute, Koudelka, Tomas, Tholey, Andreas, Rabe, Björn, Scheller, Jürgen, Lucius, Ralph, Garbers, Christoph, Rose-John, Stefan and Becker-Pauly, Christoph (2017) Meprin Metalloproteases Generate Biologically Active Soluble Interleukin-6 Receptor to Induce Trans-Signaling. Scientific Reports, 7 . p. 44053. DOI 10.1038/srep44053.

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Abstract

Soluble Interleukin-6 receptor (sIL-6R) mediated trans-signaling is an important pro-inflammatory stimulus associated with pathological conditions, such as arthritis, neurodegeneration and inflammatory bowel disease. The sIL-6R is generated proteolytically from its membrane bound form and A Disintegrin And Metalloprotease (ADAM) 10 and 17 were shown to perform ectodomain shedding of the receptor in vitro and in vivo. However, under certain conditions not all sIL-6R could be assigned to ADAM10/17 activity. Here, we demonstrate that the IL-6R is a shedding substrate of soluble meprin α and membrane bound meprin β, resulting in bioactive sIL-6R that is capable of inducing IL-6 trans-signaling. We determined cleavage within the N-terminal part of the IL-6R stalk region, distinct from the cleavage site reported for ADAM10/17. Interestingly, meprin β can be shed from the cell surface by ADAM10/17 and the observation that soluble meprin β is not capable of shedding the IL-6R suggests a regulatory mechanism towards trans-signaling. Additionally, we observed a significant negative correlation of meprin β expression and IL-6R levels on human granulocytes, providing evidence for in vivo function of this proteolytic interaction.

Document Type:	Article
Research affiliation:	Kiel University > Kiel Marine Science OceanRep > The Future Ocean - Cluster of Excellence
Refereed:	Yes
Open Access Journal?:	Yes
Publisher:	Nature Research
Projects:	Future Ocean
Date Deposited:	08 Jan 2018 11:13
Last Modified:	06 Feb 2020 09:02
URI:	https://oceanrep.geomar.de/id/eprint/41255

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