sIL‐6R: more than an agonist?

Abstract

On target cells, interleukin‐6 (IL‐6) interacts with its receptor complex consisting of the membrane‐bound IL‐6 receptor (IL‐6R) and the signal transducing protein gp130. IL‐6R can exist as a soluble protein (sIL‐6R), which binds the ligand IL‐6. This soluble complex can bind to gp130 on cells that lack the membrane‐bound IL‐6R and initiate signaling. This process is named transsignaling. The significance of transsignaling via sIL‐6R is underlined by different publications and exceeds very probably the significance of the membrane‐bound IL‐6R. It is the general assumption that sIL‐6R acts as an agonist in combination with IL‐6 resulting in an enhancement of the IL‐6 effects. In this article, we suppose ‘non‐agonistic’ properties. There are several publications that give reasons to speculate that sIL‐6R (a) has IL‐6‐antagonistic effects, (b) has orphan properties and (c) interacts with yet unknown binding partners different from IL‐6. Knowledge about additional properties of sIL‐6R will enlarge the biologic understanding of this molecule and might give an explanation for the sometimes contrasting effects of the cytokine IL‐6.

Cutting Edge: Inhibition of IL-6 Trans-Signaling Protects from Malaria-Induced Lethality in Mice

“…sIL-6Ra levels may also maintain the half-life of effective IL-6, as demonstrated previously (15). However, IL-6 trans-signaling can be inhibited when soluble GP130 (sGP130) binds and, thereby, inactivates the IL-6/sIL-6Ra complex (16). In this study, we show that IL-6 trans-signaling contributes to malaria-induced lethality.…”

“…IL-6 trans-signaling can be inhibited by sGP130, which is derived by shedding of the ectodomain from membrane GP130 and alternative splicing (13,16). This sGP130 is able to bind the IL-6/sIL-6Ra complex, thus preventing IL-6 trans-signaling (16).…”

“…(Supplemental Fig. 1J, 1K) Approximately 70% of circulating IL-6 was estimated to bind to sIL-6Ra (16), and the IL-6/sIL-6Ra complex is known to induce IL-6 trans-signaling in all cells via membrane-bound GP130. Therefore, it is conceivable that a lethal outcome of malaria is due to the P. chabaudi-induced increase in circulating endogenous sIL-6Ra in control IL-6Ra FL mice causing increased IL-6 trans-signaling.…”

Stężenie interleukiny-6, receptora dla interleukiny-6 i glikoproteiny 130 oraz cytokin zależnych od limfocytów Th17 u pacjentek z cukrzycą ciążową

“…In contrast, sgp130 is considered an antagonist to the sIL-6R/IL-6 complex, preventing sIL-6R/IL-6 from binding to the membrane receptor [4,6]. While IL-6 plasma levels change remarkably over time, sIL-6R and sgp130 concentrations fluctuate much less, and give more precise information about the activation of IL-6 pathway [2,4,5]. Though characterised as both a pro- [7][8][9] and anti-inflammatory [10,11] cytokine, IL-6 has been identified as a potential mediator linking chronic low-grade inflammation with insulin resistance [12].…”

“…Soluble forms of IL-6R (sIL-6R) and gp130 (sgp130), which can be detected in the blood, are biologically active, but exert opposite functions. In the extracellular compartment, sIL-6R acts as an agonist to IL-6 by forming sIL-6R/ /IL-6 complex, which can bind to membrane gp130 and initiate the signal transduction that accounts for most of the biological activity of IL-6 [5]. In contrast, sgp130 is considered an antagonist to the sIL-6R/IL-6 complex, preventing sIL-6R/IL-6 from binding to the membrane receptor [4,6].…”