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

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.

• Authors: Philipp Arnold, Inga Boll, Michelle Rothaug, Neele Schumacher, Frederike Schmidt, Rielana Wichert, Janna Schneppenheim, Juliane Lokau, Ute Pickhinke, Tomas Koudelka, Andreas Tholey, Björn Rabe, Jürgen Scheller, Ralph Lucius, Christoph Garbers, Stefan Rose-John, Christoph Becker-Pauly
• Journal: Scientific reports (Sci Rep) Vol. 7 Pg. 44053 (03 09 2017) ISSN: 2045-2322 [Electronic] England
• PMID: 28276471 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• IL6R protein, human
• Membrane Proteins
• Receptors, Interleukin-6
• Amyloid Precursor Protein Secretases
• Metalloendopeptidases
• meprin A
• ADAM10 Protein
• ADAM10 protein, human
• ADAM17 Protein
• ADAM17 protein, human

Topics

• ADAM10 Protein (genetics, metabolism)
• ADAM17 Protein (genetics, metabolism)
• Amyloid Precursor Protein Secretases (genetics, metabolism)
• HEK293 Cells
• Humans
• Membrane Proteins (genetics, metabolism)
• Metalloendopeptidases (genetics, metabolism)
• Receptors, Interleukin-6 (genetics, metabolism)
• Signal Transduction
• Solubility