Cathepsin S provokes interleukin-6 (IL-6) trans-signaling through cleavage of the IL-6 receptor in vitro

• Published in: Scientific reports 2020-12, Vol.10 (1), p.21612-21612, Article 21612
• Main Authors: Flynn, Charlotte M., Garbers, Yvonne, Düsterhöft, Stefan, Wichert, Rielana, Lokau, Juliane, Lehmann, Christian H. K., Dudziak, Diana, Schröder, Bernd, Becker-Pauly, Christoph, Rose-John, Stefan, Aparicio-Siegmund, Samadhi, Garbers, Christoph
• Format: Article
• Language: English
• Subjects: 631/45; 631/45/127; 631/45/468; Animals; Biological activity; Cathepsin S; Cathepsins - physiology; Cysteine proteinase; Cytokines; Humanities and Social Sciences; Humans; Hydrolysis; In Vitro Techniques; Inflammation; Interleukin 6; Interleukin 6 receptors; Interleukin-6 - metabolism; Metalloproteinase; Mice; multidisciplinary; Proteolysis; Receptors, Interleukin-6 - metabolism; Science; Science (multidisciplinary); Serum levels; Signal Transduction - physiology
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-77884-4

The cytokine interleukin-6 (IL-6) fulfills its pleiotropic functions via different modes of signaling. Regenerative and anti-inflammatory activities are mediated via classic signaling, in which IL-6 binds to the membrane-bound IL-6 receptor (IL-6R). For IL-6 trans-signaling, which accounts for the pro-inflammatory properties of the cytokine, IL-6 activates its target cells via soluble forms of the IL-6R (sIL-6R). We have previously shown that the majority of sIL-6R in human serum originates from proteolytic cleavage and mapped the cleavage site of the IL-6R. The cleavage occurs between Pro-355 and Val-356, which is the same cleavage site that the metalloprotease ADAM17 uses in vitro. However, sIL-6R serum levels are unchanged in hypomorphic ADAM17 ex/ex mice, making the involvement of ADAM17 questionable. In order to identify other proteases that could be relevant for sIL-6R generation in vivo, we perform a screening approach based on the known cleavage site. We identify several candidate proteases and characterize the cysteine protease cathepsin S (CTSS) in detail. We show that CTSS is able to cleave the IL-6R in vitro and that the released sIL-6R is biologically active and can induce IL-6 trans-signaling. However, CTSS does not use the Pro-355/Val-356 cleavage site, and sIL-6R serum levels are not altered in Ctss −/− mice. In conclusion, we identify a novel protease of the IL-6R that can induce IL-6 trans-signaling, but does not contribute to steady-state sIL-6R serum levels.