Key Points
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IL-6 can signal via the membrane-bound and the soluble IL-6 receptor (IL-6R); classic signalling via the membrane-bound receptor is regenerative and protects from bacterial infections, whereas trans-signalling via the soluble receptor is proinflammatory
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The soluble gp130Fc fusion protein specifically blocks IL-6 trans-signalling without affecting classic signalling
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Preclinical models strongly suggest the efficacy of IL-6-directed therapies for a variety of immunological conditions
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The approval and use of tocilizumab, a first-in-class human monoclonal antibody directed at IL-6R, has demonstrated that this strategy is both highly effective and safe
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New agents with unique bioengineering features targeting either IL-6 or the soluble IL-6R, with varying selectivity for classic signalling and trans-signalling pathways, are entering clinical trials and offer alternative strategies for IL-6-based therapies
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Selective IL-6-based therapeutic targeting has several unique toxicity signatures, including paradoxical effects on surrogate markers of cardiovascular risk, and awaits clinical studies to determine net effects on morbidity and mortality
Abstract
IL-6 has been linked to numerous diseases associated with inflammation, including rheumatoid arthritis, inflammatory bowel disease, vasculitis and several types of cancer. Moreover, IL-6 is important in the induction of hepatic acute-phase proteins for the trafficking of acute and chronic inflammatory cells, the differentiation of adaptive T-cell responses, and tissue regeneration and homeostatic regulation. Studies have investigated IL-6 biology using cell-bound IL-6 receptors expressed predominantly on hepatocytes and certain haematopoietic cells versus activation mediated by IL-6 and soluble IL-6 receptors via a second protein, gp130, which is expressed throughout the body. Advances in this research elucidating the differential effects of IL-6 activation provide important insights into the role of IL-6 in health and disease, as well as its potential as a therapeutic target. Knowledge of the basic biology of IL-6 and its signalling pathways can better inform both the research agenda for IL-6-based targeted therapies as well as the clinical use of strategies affecting IL-6-mediated inflammation. This Review covers novel, emerging aspects of the biology of IL-6, which might lead to more specific blockade of IL-6 signalling without compromising the protective function of this cytokine in the body's defence against infections.
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Change history
19 September 2014
In the version of this article initially published online, findings from the Kuchroo et al. group were incorrectly reported in the 'Role in inflammation' section. This inaccuracy has been corrected for the HTML, PDF and print versions of the article.
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Acknowledgements
The work of S.R.-J. is supported by grants from the Deutsche Forschungsgemeinschaft Bonn, Germany (SFB654, project C5; SFB841, project C1; SFB877 project A1) and by the Cluster of Excellence 'Inflammation at Interfaces'.
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L.H.C. declares that he has acted as a consultant to Genentech Roche, Sanofi-Aventis, UCB, Bristol–Myers Squib and Pfizer, and has acted as a speaker for Genentech and Bristol–Myers Squib. S.R. J. declares that he is an inventor on patents owned by CONARIS Research Institute, which develops the sgp130Fc protein together with Ferring Pharmaceuticals, and he has stock ownership in CONARIS.
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Calabrese, L., Rose-John, S. IL-6 biology: implications for clinical targeting in rheumatic disease. Nat Rev Rheumatol 10, 720–727 (2014). https://doi.org/10.1038/nrrheum.2014.127
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DOI: https://doi.org/10.1038/nrrheum.2014.127
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