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Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer

Abstract

The IL-6 family of cytokines consists of IL-6, IL-11, IL-27, IL-31, oncostatin M (OSM), leukaemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), cardiotrophin 1 (CT-1) and cardiotrophin-like cytokine factor 1 (CLCF1). Membership of this cytokine family is defined by usage of common β-receptor signalling subunits, which activate various intracellular signalling pathways. Each IL-6 family member elicits responses essential to the physiological control of immune homeostasis, haematopoiesis, inflammation, development and metabolism. Accordingly, distortion of these cytokine activities often promotes chronic disease and cancer; the pathological importance of this is exemplified by the successful treatment of certain autoimmune conditions with drugs that target the IL-6 pathway. Here, we discuss the emerging roles for IL-6 family members in infection, chronic inflammation, autoimmunity and cancer and review therapeutic strategies designed to manipulate these cytokines in disease.

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Fig. 1: Cytokine receptor usage by the IL-6 family of cytokines.
Fig. 2: The intrinsic and extrinsic properties of IL-6 family cytokines in cancer.
Fig. 3: The IL-6 cytokine family as therapeutic targets.

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Acknowledgements

The authors thank R. Smith for editing and proofing the manuscript. S.A.J. holds research grants from Arthritis Research UK, GlaxoSmithKline and Kidney Research UK and additional funding support from the Systems Immunity University Research Institute at Cardiff University. B.J.J. is recipient of a Senior Medical Research Fellowship from the National Health and Medical Research Council of Australia (NHMRC) and is supported by research grants from the NHMRC, Cancer Council of Victoria and Avner Pancreatic Cancer Foundation. An Operational Infrastructure Support Program funded by the Victorian State Government supports research at the Hudson Institute of Medical Research.

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Nature Reviews Immunology thanks S. Rose-John and the other, anonymous reviewer(s) for their contribution to the peer review of this manuscript.

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Both authors contributed to the discussion of content, writing, review and editing of the manuscript.

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Correspondence to Simon A. Jones or Brendan J. Jenkins.

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B.J.J. has received funding support from Immix Biopharma and Opsona Therapeutics. S.A.J. has received funding support from Ferring Pharmaceuticals, GlaxoSmithKline, Hoffman-La Roche and NovImmune SA, and during the past 5 years, he has acted as an advisory consultant for Chugai Pharmaceuticals, Eleven Biotherapeutics, Genentech, Janssen Pharmaceuticals, Johnson & Johnson, NovImmune SA, Roche and Sanofi Regeneron.

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Glossary

Lymphokines

A subset of cytokines that are released by lymphocytes.

Adipokines

A subset of cytokines that are secreted by adipose tissue and are sometimes called adipocytokines.

Myokines

Cytokines produced and released by myocytes in response to muscle contraction.

Janus kinase–signal transducer and activator of transcription pathway

(JAK–STAT pathway). A cytokine receptor signalling mechanism used by certain cytokines to sense and interpret environmental cues during inflammation and immune homeostasis.

Pattern recognition receptors

Innate sensors that detect bacteria, viruses, fungi and other endogenous ligands generally associated with tissue damage.

Tumour microenvironment

A cellular and non-cellular compartment associated with a tumour that comprises the extracellular matrix, surrounding blood and lymphatic vessels, immune (inflammatory) cells, fibroblasts, neuroendocrine cells and adipocytes.

Cachexia

A wasting or weakening of the body owing to chronic illness or cancer.

Nanobody

An engineered single-domain antibody.

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Jones, S.A., Jenkins, B.J. Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer. Nat Rev Immunol 18, 773–789 (2018). https://doi.org/10.1038/s41577-018-0066-7

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