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Review
. 2020 Aug 20:9:F1000 Faculty Rev-1013.
doi: 10.12688/f1000research.26058.1. eCollection 2020.

Interleukin-6 signalling in health and disease

Stefan Rose-John  1
Affiliations
Review

Interleukin-6 signalling in health and disease

Stefan Rose-John. F1000Res. .

Abstract

Biochemically, interleukin-6 belongs to the class of four-helical cytokines. The cytokine can be synthesised and secreted by many cells. It acts via a cell surface-expressed interleukin-6 receptor, which is not signalling competent. This receptor, when complexed with interleukin-6, associates with the signalling receptor glycoprotein 130 kDa (gp130), which becomes dimerised and initiates intracellular signalling via the Janus kinase/signal transducer and activator of transcription and rat sarcoma proto oncogene/mitogen-activated protein kinase/phosphoinositide-3 kinase pathways. Physiologically, interleukin-6 is involved in the regulation of haematopoiesis and the coordination of the innate and acquired immune systems. Additionally, interleukin-6 plays an important role in the regulation of metabolism, in neural development and survival, and in the development and maintenance of various cancers. Although interleukin-6 is mostly regarded as a pro-inflammatory cytokine, there are numerous examples of protective and regenerative functions of this cytokine. This review will explain the molecular mechanisms of the, in part opposing, activities of the cytokine interleukin-6.

Keywords: ADAM17; IL-6; IL-6R; gp130; sIL-6R; sgp130Fc; trans-signalling.

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Conflict of interest statement

Competing interests: Stefan Rose-John has acted as a consultant and speaker for AbbVie, Amgen, Janssen, Chugai, Roche, Genentech Roche, Pfizer, Eli Lilly, and Sanofi. He also declares that he is an inventor on patents owned by CONARIS Research Institute, which develops the sgp130Fc protein (olamkicept), and he has stock ownership in CONARIS.No competing interests were disclosed.No competing interests were disclosed.No competing interests were disclosed.

Figures

Figure 1.
Figure 1.. Four-helical topology of the interleukin-6 (IL-6) protein.
IL-6 belongs to the family of four-helical cytokines. The figure shows the four helices with the connecting loops. The A–B and the C–D loops are long enough to reach the length of a helix, whereas the B–C loop is short. Consequently, IL-6 has an up-up-down-down topology, meaning that helices A and B point upwards, whereas helices C and D point downwards. This topology is common to most cytokines such as IL-2, IL-4, IL-7, IL-11, IL-15, leukaemia inhibitory factor, oncostatin M, growth hormone, leptin, and many others.
Figure 2.
Figure 2.. Stimulation of target cells by interleukin-6 (IL-6).
IL-6 (orange) first binds to the IL-6 receptor (IL-6R) (red). The complex of IL-6 and IL-6R associates with glycoprotein 130 kDa (gp130) (blue), which dimerises and leads to intracellular signalling. It is important to note that IL-6 and IL-6R alone exhibit no measurable affinity to gp130. Only the complex of IL-6 and IL-6R binds to and activates gp130. Therefore, IL-6 cannot stimulate cells that do not express IL-6R. Signalling occurs via the signal transducer and activator of transcription (STAT) 1/STAT3, Yamaguchi sarcoma viral oncogene homolog (YES)/YES-associated protein (YAP), phosphoinositide-3 kinase (PI3K)/AKT, and rat sarcoma proto oncogene (RAS)/mitogen-activated protein kinase (MAPK) pathways. JAK, Janus kinase.
Figure 3.
Figure 3.. Designer proteins to probe for modes of interleukin-6 (IL-6) signalling.
( A) Hyper-IL-6 is a fusion protein between IL-6 and soluble IL-6 receptor (sIL-6R). ( B) sgp130Fc is a fusion protein of the extracellular portion of glycoprotein 130 kDa (gp130) and the constant part of a human immunoglobulin G1 (IgG1) antibody. ( C) IL-6 can signal via the membrane-bound IL-6R (classical signalling) and via the sIL-6R (trans-signalling). Hyper-IL-6 can be used to mimic IL-6 trans-signalling. ( B) The sg130Fc protein does not interfere with classical IL-6 signalling, but it specifically blocks IL-6 trans-signalling.
Figure 4.
Figure 4.. Pro- and anti-inflammatory activities of interleukin-6 (IL-6).
Left, anti-inflammatory and protective activities of the cytokine IL-6 are associated with signalling via the membrane-bound IL-6 receptor (IL-6R). Right, pro-inflammatory activities of the cytokine IL-6 are associated with signalling via the soluble IL-6R (sIL-6R). The membrane-bound metalloprotease a disintegrin and metalloprotease 17 (ADAM17) orchestrates the pro- and anti-inflammatory activities of IL-6. Treg, regulatory T cell.
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