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

Abstract

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 ADAM17ex/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.

Targeting IL-6 trans-signalling: past, present and future prospects

“…In humans but not in mice, a soluble form of the IL-6R can also be generated by translation from a differentially spliced mRNA, although this only accounts for about 15% of the sIL-6R found in the blood 42 , 43 . Other proteases such as meprin-α and meprin-β 44 , rhomboid-related protein 2 45 , 46 , cathepsin S 47 and cathepsin G 48 are capable of mediating the shedding of the sIL-6R, although the biological importance of these secondary sheddases has not been analysed. The sIL-6R was shown to bind IL-6 with similar affinity as mIL-6R 39 , 40 .…”

Critical roles of PU.1/cathepsin S activation in regulating inflammatory responses of macrophages in periodontitis

“…32 On the other hand, CatS was found to cleave the IL-6 receptor and thus provoke IL-6 trans-signaling. 33 Taken together, these findings suggest the complex mutual regulating mechanism between CatS and IL-6.…”

“…IL‐6‐STAT3 was reported to promote CatS activity, reducing the MHC II ab dimer levels in DCs, and eventually suppressing CD4+ T cell‐mediated immune responses 32 . On the other hand, CatS was found to cleave the IL‐6 receptor and thus provoke IL‐6 trans‐signaling 33 . Taken together, these findings suggest the complex mutual regulating mechanism between CatS and IL‐6.…”

All Roads Lead to Cathepsins: The Role of Cathepsins in Non-Alcoholic Steatohepatitis-Induced Hepatocellular Carcinoma

“…Cathepsins can be expressed and secreted by immune cells and they have physiological functions in the immune system [ 117 ]. Cathepsins have been found to play a part in toll-like receptor signaling and cytokine activation/inhibition [ 118 , 119 ]. In addition, cathepsins, mainly CTSS, play an important role in the processing and presenting of antigens in the antigen-presenting cells, e.g., macrophages and dendritic cells [ 120 ].…”