![]() Although previous studies on IL-6R cleavage almost exclusively relied on ectopically overexpressed receptors or proteases, the closely related proteases ADAM10 3 and ADAM17 were identified as IL-6R sheddases in vitro ( 8, 9). As IL-6R shedding can initiate pathogenic IL-6 trans-signaling, it is of high clinical relevance to identify the protease responsible for sIL-6R release. Ectodomain shedding of transmembrane proteins represents a swift and highly regulable response of the cell toward extracellular stimuli and is therefore ideally suited to counteract inflammatory insults ( 7). ![]() In humans, a soluble form of the IL-6R is generated by proteolytic release of the ectodomain as well as transcription from an alternatively spliced mRNA lacking the transmembrane region ( 5, 6). It has become evident in recent years that most of the pro-inflammatory and deleterious actions of IL-6, which includes generation of autoimmune Th17 cells, inhibition of T cell apoptosis, or proliferation of malignant epithelial cells, can in fact be attributed to IL-6 trans-signaling ( 4). This alternative IL-6 signaling pathway has been termed “IL-6 trans-signaling” and greatly expands the spectrum of IL-6 responsive cells ( 3). The resulting binary cytokine complex exhibits agonistic properties and is able to activate cells that only express gp130 but lack membrane-bound IL-6R. Alternatively, IL-6 can engage a soluble form of the IL-6R in solution with the same affinity as the membrane-bound receptor. ![]() Signaling via membrane-bound IL-6R is rather anti-inflammatory and has been shown to be critically involved in plasma cell differentiation, the acute phase response, and fever induction ( 2). In contrast to gp130, which is present on almost every cell of the body, IL-6R expression is much more restricted with mainly hepatocytes and certain leukocyte subtypes bearing IL-6R. The first route, termed “classic” IL-6 signaling, relies on IL-6 binding the membrane IL-6R receptor (IL-6R), which in turn leads to dimerization of the second receptor subunit glycoprotein 130 (gp130) and initiation of intracellular signaling cascades ( 1). The pleiotropic cytokine IL-6 can exert its signal via two extracellular routes. Instead, we found full-length IL-6R on circulating microvesicles, establishing microvesicle release as a novel mechanism for sIL-6R generation. Furthermore, we ruled out alternative splicing of the IL-6R mRNA as a potential source of circulating sIL-6R in the mouse. Here, by quantification of serum sIL-6R in protease-deficient mice as well as human patients we also excluded ADAM10, ADAM8, neutrophil elastase, cathepsin G, and proteinase 3 from contributing to circulating sIL-6R. It has been shown previously that ADAM17 hypomorphic mice exhibit unaltered levels of serum sIL-6R. Although circulating IL-6R levels are altered in various diseases, the origin of blood-borne IL-6R is still poorly understood. By taking advantage of specific pharmacological inhibitors and primary cells from ADAM-deficient mice we established that endogenous IL-6R of both human and murine origin is shed by ADAM17 in an induced manner, whereas constitutive release of endogenous IL-6R is largely mediated by ADAM10. Although in vitro experiments using ectopically overexpressed IL-6R and candidate proteases revealed major roles for the metalloproteinases ADAM10 and ADAM17 in IL-6R shedding, the identity of the protease(s) cleaving IL-6R in more physiological settings, or even in vivo, remains unknown. Generation of the soluble interleukin-6 receptor (sIL-6R) is a prerequisite for pathogenic IL-6 trans-signaling, which constitutes a distinct signaling pathway of the pleiotropic cytokine interleukin-6 (IL-6).
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