Different Soluble Forms of the Interleukin-6 Family Signal Transducer gp130 Fine-tune the Blockade of Interleukin-6 Trans-signaling

Abstract

Soluble forms of the IL-6 receptor (sIL-6R) bind to the cytokine IL-6 with similar affinity as the membrane-bound IL-6R. IL-6⅐sIL-6R complexes initiate IL-6 trans-signaling via activation of the ubiquitously expressed membrane-bound ␤-receptor glycoprotein 130 (gp130). Inhibition of IL-6 trans-signaling has been shown to be favorable in numerous inflammatory diseases. Furthermore, different soluble forms of gp130 (sgp130) exist that, together with the sIL-6R, are thought to form a buffer for IL-6 in the blood. However, a functional role for the different sgp130 forms has not been described to date. Here we demonstrate that the metalloproteases ADAM10 and ADAM17 can produce sgp130 by ectodomain shedding of gp130, even though this mechanism only accounts for a minor proportion of sgp130 in the circulation. We further show that full-length sgp130 and the shorter forms sgp130-rheumatoid arthritis-associated peptide (RAPS) and sgp130-E10 are differentially expressed in a cell type-specific manner. Remarkably, full-length sgp130 is expressed by monocytes, but this expression is completely lost during differentiation into macrophages in vitro. Using genetically engineered murine pre-B cells that secrete different forms of sgp130, we found that these secreted sgp130 proteins are able to prevent trans-signaling-driven cell proliferation of the secreting cells, whereas conditioned supernatant from these cells failed to block IL-6 trans-signaling in other cells. Thus, our data suggest that the different sgp130 forms are released from cells into their immediate surroundings and appear to form cell-associated gradients to modulate their own susceptibility for IL-6 trans-signaling.IL-6 is a pleiotropic cytokine with pro-and anti-inflammatory functions (1-4). Classic signaling via the membranebound IL-6R 3 accounts for the regenerative properties of IL-6; trans-signaling via sIL-6R is rather pro-inflammatory (2, 4). In both cases, IL-6 binds initially to the (s)IL-6R, and the IL-6⅐(s)IL-6R complex recruits two signal-transducing gp130 ␤-receptors. This final IL-6⅐(s)IL-6R/gp130 complex formation initiates the activation of intracellular signaling pathways, among them Jak/STAT, PI3K, MAPK, and Src/Yes-associated protein (YAP) (5).Soluble forms of gp130 (sgp130) exist in human serum at concentrations of up to 400 ng/ml (6) and have been shown to act as natural inhibitors of IL-6 trans-signaling (7), although, at high concentrations, they can interfere with classic signaling as well (8). Interestingly, specific inhibition of trans-signaling with an Fc-dimerized version of sgp130 (sgp130Fc) has been shown to be beneficial in numerous inflammatory diseases and cancer (9, 10). sgp130Fc is currently in clinical development as a drug candidate to treat inflammatory bowel diseases (11).gp130 is a transmembrane protein with three N-terminal Iglike domains followed by three fibronectin-type III domains. sgp130 forms with molecular weights of 50, 90, and 110 kDa have been detected in human body fluids (6, 12, 13). Where and how these thre...

Circular RNA circCRIM1 inhibits invasion and metastasis in lung adenocarcinoma through the microRNA (miR)‐182/miR‐93‐leukemia inhibitory factor receptor pathway

“…As a member of the gp130 receptor family, LIFR is structurally similar to gp130, which is an interleukin‐6 signal transducer . After Leukemia inhibitory factor (LIF) forms multimeric complexes with gp130, LIF binds the complexes and subsequently activates the JAK/STAT, MAPK, and PI3K/AKT signaling pathways .…”

Analysis of the genetic variants associated with circulating levels of sgp130. Results from the IMPROVE study

“…The soluble gp130 (sgp130) is a master regulator of cytokine-mediated inflammatory, regenerative, and proliferative effects [1][2][3]. Three main sgp130 isoforms, with molecular weights between 50 and 110 KDa, can be detected in the circulation: sgp130-RAPS [4], sgp130-E10 [5], and full length sgp130 [6] produced by alternative splicing, alternative intronic polyadenylation [5], and Members of the IMPROVE study group are listed below Supplementary information The online version of this article (https:// doi.org/10.1038/s41435-019-0090-z) contains supplementary material, which is available to authorized users.…”

“…shedding of the membrane gp130 receptor in a cell specific manner [3]. Biological assays commonly used to measure sgp130 do not differentiate among these three isoforms.…”

Can we design a better anti-cytokine therapy?

“…The events downstream of the classic pathway, mediated by IL-6/IL6-R/gp130, or trans-signaling via IL-6/sIL6-R/gp130 interaction include activation of JAKs and STAT-3 transcription factor, as well as STAT-independent signal transduction involving MAPK and PI3K cascades [62]. Full-length and shorter forms of sgp130 are differentially expressed in a celltype-specific manner, enabling these cells to modulate their own susceptibility for IL-6 trans-signaling [63]. Systemic levels of sIL-6R and sgp130 under normal conditions by far exceed the concentration of IL-6 and, therefore, constitute the buffer for IL-6 bioactivity in the blood.…”