Meprin Metalloproteases Generate Biologically Active Soluble Interleukin-6 Receptor to Induce Trans-Signaling

• Published in: Scientific reports Vol. 7; no. 1; p. 44053
• Main Authors: 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, Becker-Pauly, Christoph
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 09.03.2017
• Subjects: ADAM10 Protein - genetics; ADAM10 Protein - metabolism; ADAM17 Protein - genetics; ADAM17 Protein - metabolism; Amyloid Precursor Protein Secretases - genetics; Amyloid Precursor Protein Secretases - metabolism; Arthritis; Biological activity; Cell surface; Cytokines; HEK293 Cells; Humans; Inflammatory bowel diseases; Interleukin 6; Intestine; Leukocytes (granulocytic); Membrane Proteins - genetics; Membrane Proteins - metabolism; Metalloendopeptidases - genetics; Metalloendopeptidases - metabolism; Metalloproteinase; Neurodegeneration; Proteolysis; Receptors, Interleukin-6 - genetics; Receptors, Interleukin-6 - metabolism; Signal Transduction; Solubility
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep44053

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.