The role of IL-6 in host defence against infections: immunobiology and clinical implications

Key Points

  • IL-6 is a pleotrophic cytokine with a central role in the integrated immune defence network against infections

  • IL-6 can act via either classic or trans-signalling pathways, which have differential effects on immunocompetence

  • Studies of genetically modified animal models suggest that IL-6 has a role in both the innate and adaptive immune responses that protect the host from a variety of infections

  • Primary immunodeficiency diseases in which IL-6 has been affected either directly or indirectly also provide insights into the role of IL-6 in host defence, especially against bacterial and fungal pathogens

  • Clinical data on IL-6-targeting drugs, largely derived from studies of tocilizumab, suggest that serious and opportunistic infections occur with a frequency similar to that seen with other non-IL-6-targeting biologic agents

  • Neutralizing IL-6 might affect the clinical presentation of serious infections but has minimal effects on response to commonly administered vaccines

Abstract

IL-6 is a pleiotropic cytokine with broad-ranging effects within the integrated immune response. One of the roles of IL-6 is to support immunocompetence, defined as the ability of a host to respond to infections. Understanding the precise role of this cytokine in immunocompetence requires a critical appraisal of data derived from both preclinical and clinical studies. Primary immunodeficiency diseases involving IL-6 or its signalling pathways reveal that IL-6 is critical in the defence against numerous types of pathogens. Studies of IL-6 signalling in preclinical models reveal that selective inhibition of either classic IL-6 signalling or IL-6 trans-signalling has differential effects on the host response to different types of infections. Knowledge of such variation might inform bioengineering of new IL-6-targeting molecules and potentially enable modulation of their toxicity. Clinical studies of IL-6 inhibitors, mainly tocilizumab, reveal that their use is associated with an increased rate of both serious and opportunistic infections generally in the range observed with other non-IL-6 directed biologic therapies. Targeting IL-6 has several other important clinical implications related to diagnosis, management and prevention of infectious diseases.

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Figure 1: Mechanisms of action of various agents that target IL-6 and IL-6 activation pathways.
Figure 2: Estimated serious infection rates among clinical trials of biologics in rheumatoid arthritis.

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All authors researched the data for the article, provided substantial contributions to discussions of its content, wrote the article and undertook review and/or editing of the manuscript before submission.

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Correspondence to Leonard Calabrese.

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L.H.C. declares that he has acted as a consultant for Bristol–Myers Squib, Genentech-Roche, Jansen, Pfizer, Regeneron, Sanofi-Aventis and UCB, and has acted as a speaker for Bristol–Myers Squib, Genentech, Jansen and UCB. S.R.-J. has acted as a consultant and speaker for AbbVie, Chugai, Genentech Roche, Pfizer and Sanofi. He also declares that he is an inventor on patents owned by CONARIS Research Institute, which develops the sgp130Fc protein olamkicept together with Ferring Pharmaceuticals and he has stock ownership in CONARIS. K.W. declares that he has acted as a consultant to AbbVie, Bristol–Myers Squib, Genentech-Roche, Lilly, Pfizer and UCB, and received a research grant from Bristol–Myers Squib.

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Rose-John, S., Winthrop, K. & Calabrese, L. The role of IL-6 in host defence against infections: immunobiology and clinical implications. Nat Rev Rheumatol 13, 399–409 (2017). https://doi.org/10.1038/nrrheum.2017.83

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