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.

• Authors: Stefan Rose-John, Brendan J Jenkins, Christoph Garbers, Jens M Moll, Jürgen Scheller
• Journal: Nature reviews. Immunology (Nat Rev Immunol) Vol. 23 Issue 10 Pg. 666-681 (10 2023) ISSN: 1474-1741 [Electronic] England
• PMID: 37069261 (Publication Type: Journal Article, Review, Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't)
• Copyright: © 2023. Springer Nature Limited.

Chemical References

• Cytokine Receptor gp130
• Interleukin-6
• Receptors, Interleukin-6
• Cytokines

Topics

• Humans
• Cytokine Receptor gp130 (metabolism)
• Interleukin-6
• Receptors, Interleukin-6
• Cytokines (therapeutic use)
• Neoplasms (drug therapy)