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

Abstract

Interleukin-6 (IL-6) is a key immunomodulatory cytokine that affects the pathogenesis of diverse diseases, including autoimmune diseases, chronic inflammatory conditions and cancer. Classical IL-6 signalling involves the binding of IL-6 to the membrane-bound IL-6 receptor α-subunit (hereafter termed ‘mIL-6R’) and glycoprotein 130 (gp130) signal-transducing subunit. By contrast, in IL-6 trans-signalling, complexes of IL-6 and the soluble form of IL-6 receptor (sIL-6R) signal via membrane-bound gp130. A third mode of IL-6 signalling — known as cluster signalling — involves preformed complexes of membrane-bound IL-6–mIL-6R on one cell activating gp130 subunits on target cells. Antibodies and small molecules have been developed that block all three forms of IL-6 signalling, but in the past decade, IL-6 trans-signalling has emerged as the predominant pathway by which IL-6 promotes disease pathogenesis. The first selective inhibitor of IL-6 trans-signalling, sgp130, has shown therapeutic potential in various preclinical models of disease and olamkicept, a sgp130Fc variant, had promising results in phase II clinical studies for inflammatory bowel disease. Technological developments have already led to next-generation sgp130 variants with increased affinity and selectivity towards IL-6 trans-signalling, along with indirect strategies to block IL-6 trans-signalling. Here, we summarize our current understanding of the biological outcomes of IL-6-mediated signalling and the potential for targeting this pathway in the clinic.

A Facile Strategy for Multiplex Protein Detection by a Fluorescent Microsphere-Based Digital Immunoassay

“…The proposed FMDIA can easily realize the simultaneous detection of multiple proteins in a single sample because it only needs to add SA-MBs to separate all the different color-coded fluorescent microspheres for analysis. As a pleiotropic cytokine, interleukin-6 (IL-6) has been clinically associated with the occurrence of various diseases. , Previous studies have shown that IL-6 may serve as complementary hepatocellular carcinoma (HCC) markers and play a synergistic role with AFP in the early diagnosis of HCC. , Therefore, the capacity of the proposed FMDIA in the simultaneous detection of multiple proteins was explored using AFP and IL-6 as models, and the principle of simultaneous detection of multiple proteins is schematically displayed in Figure a. First, the capture antibodies of AFP were chemically conjugated to r-QDMS, and the capture antibodies of IL-6 were chemically conjugated to g-FMS.…”

“…As a pleiotropic cytokine, interleukin-6 (IL-6) has been clinically associated with the occurrence of various diseases. 38,39 Previous studies have shown that IL-6 may serve as complementary hepatocellular carcinoma (HCC) markers and play a synergistic role with AFP in the early diagnosis of HCC. 40,41 Therefore, the capacity of the proposed FMDIA in the simultaneous detection of multiple proteins was explored using AFP and IL-6 as models, and the principle of simultaneous detection of multiple proteins is schematically displayed in Figure 4a.…”

Proteogenomic Data Integration Reveals CXCL10 as a Potentially Downstream Causal Mediator for IL-6 Signaling on Atherosclerosis

“…Third, tocilizumab blocks both the classical and trans-IL-6 signaling. 54 Whether this is the case for most of the variants used as proxies for IL-6R signaling (selected based on their effects on CRP, primarily reflecting classical signaling) remains untested. Animal studies have shown decreases in CXCL10 levels and T-cell recruitment after targeted pharmacological inhibition of the trans-signaling cascade.…”

Effect of Ligustrazine on Lipopolysaccharide-induced Inflammatory Response of Vascular Endothelial Cells and its Possible Mechanism

“…Figure 1 depicts the concentration-dependent increase in cell viability caused by Lig therapy, in contrast to the suppressive impact seen with LPS treatment. Current investigations suggest that inflammatory cytokines, namely ICAM-1 (Buckley et al, 2022), interleukin-6 (IL-6) (Rose-John et al, 2023), and MCP-1 (Bittar et al, 2020), synthesized during the inflammatory response, can precipitate EC injury and dysfunction. ICAM-1, an indispensable adhesion molecule belonging to the immunoglobulin superfamily, typically exhibits diminished expression levels in a quiescent state but can be upregulated by various factors, thereby contributing to the adhesion of diverse leukocytes (Kucukal et al, 2020).…”