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

TLDR: The key roles of the IL-6 cytokine family in regulating innate and adaptive immunity, as well as other physiological responses are considered, which highlight the potential of targeting IL- 6 family members to treat 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.

Figures

Figure 2: The intrinsic and extrinsic properties of IL-6 family cytokines in cancer

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Citation for final published version:
Jones, Simon A. and Jenkins, Brendan J. 2018. Recent insights into targeting the IL-6 cytokine
family in inflammatory diseases and cancer. Nature Reviews Immunology 18 , pp. 773-789.
10.1038/s41577-018-0066-7 file
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Recent insights into targeting the IL-6 cytokine family in inflammatory
diseases and cancer
Simon A. Jones
1,2
& Brendan J. Jenkins
3,4
Affiliations
1. Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, CF14 4XN,
Wales, UK
2. Systems Immunity, University Research Institute, School of Medicine, Cardiff University,
Cardiff, CF14 4XN, Wales, UK
3. Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research,
Clayton, Victoria 3168, Australia
4. Department of Molecular and Translational Science, Faculty of Medicine, Nursing and Health
Sciences, Monash University, Clayton, Victoria 3800, Australia
Correspondence
Professor Brendan J Jenkins (brendan.jenkins@hudson.org.au)
Professor Simon A Jones (JonesSA@cardiff.ac.uk)

Abstract
The interleukin-6 (IL-6) family of cytokines consists of IL-6, IL-11, IL-27, IL-31, oncostatin M
(OSM), leukemia 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 significance 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.

Jones & Jenkins, 2018 Nature Reviews Immunology
The IL-6 cytokine family in health and disease
3
[H1] Introduction
Cytokines contribute to all aspects of human biology and have evolved to enable the sensing
and interpretation of environmental cues relevant to the maintenance of normal host
physiology
1
. Although these secretory proteins are best known for their role as custodians of
immune homeostasis and the inflammatory response to infection, trauma or injury, their
diverse functions also affect embryonic development, cognitive function and behaviour, tissue
integrity, and ageing. In this regard, cytokines often display pleiotropic or overlapping functional
properties
1
.
The interleukin-6 (IL-6) cytokine family comprises IL-6, IL-11, IL-27, IL-31, oncostatin M
(OSM), leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-1)
and cardiotrophin-like cytokine factor 1 (CLCF1), and among all cytokine families it arguably
displays the highest degree of functional pleiotropy and redundancy in eliciting responses
relevant to health and disease
2
. Members of this family play prominent roles in chronic
inflammation, autoimmunity, infectious disease and cancer (BOX 1), where they often act as
diagnostic or prognostic indicators of disease activity and response to therapy
1,3-6
. Moreover,
IL-6 family cytokines are now viewed as major therapeutic targets for clinical intervention
3-9
.
This is epitomized by the treatment of chronic immune-related conditions, such as inflammatory
arthritis, giant cell arteritis and Castleman’s disease, with drugs that target IL-6
5,10-12
. In this
Review, we will draw on recent advances to provide a timely update on the biology of IL-6
family cytokines and their clinical potential as therapeutic targets or disease modifiers in
autoimmunity, inflammation, infection and cancer.
[H1] What constitutes IL-6 family membership?
IL-6 remains the archetypal member of the IL-6 cytokine family, and regulates a diverse array of
functions relevant to haematopoiesis, tissue homeostasis, metabolism and immunity (BOX 1 &

Jones & Jenkins, 2018 Nature Reviews Immunology
The IL-6 cytokine family in health and disease
4
BOX 2)
5,13
. Since the discovery of IL-6, subsequent investigations have revealed a high degree of
functional redundancy amongst IL-6 family cytokines
14
. As a consequence, cytokines within this
family are often described with activities attributed to lymphokines [G], adipokines [G] or
myokines [G], which reflect their broad expression and cellular distribution among all major cell
types within the body. This redundancy is characterized by a precise hierarchical involvement in
inflammation, metabolism, development, tissue regeneration, neurogenesis and oncogenesis
(BOX 1 & BOX 2)
15
.
A defining feature of this cytokine family is its usage of common cytokine receptor
subunits. These receptor complexes comprise the shared signal-transducing receptor β-subunit,
glycoprotein 130kDa (gp130), together with either a ligand-binding non-signalling receptor
α-subunit or a signalling receptor β-subunit that resembles gp130
2,15,16
(FIG. 1). The receptor
signalling complexes for IL-6 and IL-11 contain a gp130 homodimer, whereas other family
members signal via a heterodimeric receptor complex containing gp130 and an alternative
signalling β-subunit (FIG. 1). The exception to this ‘gp130 rule’ is IL-31, which binds a cytokine
receptor complex containing the OSM receptor β-subunit (OSMR) and a cognate IL-31-binding
receptor termed cytokine-binding gp130-like protein (GPL, also known as IL-31RA)
17-19
.
Phylogenetic analysis of cytokine families reveals that members of the IL-6 family share a
close relationship with IL-12 family cytokines
20-22
. This link is illustrated by the heterodimeric
composition of IL-27 (comprising IL-27p28 (also termed IL-30) and Epstein-Barr virus-induced
protein-3; EBI3), which is structurally related to the IL-12 (IL-12p40–IL-12p35), IL-23 (IL-23p19–
IL-12p40), IL-35 (IL-12p40–EBI3), and IL-39 (IL-23p19–EBI3) heterodimers
23-25
. Interestingly, both
IL-27p28 and IL-35 can also signal via gp130
26,27
, although the biological significance of this
engagement with gp130 requires further substantiation, and thus their membership to the IL-6
family of cytokine is premature.

Frequently asked questions

Q1. What are the classes of drugs that modulate receptor signalling activity?

Classes of drugs include monoclonal antibodies and recombinant protein modalities for specific cytokines or cytokine receptors (shown in top target), and small molecule interventions that modulate receptor signalling activity or intracellular mechanisms linked to gp130 or JAK–STAT signalling (shown in bottom target). 

Q2. What is the role of IL-6 in the development of obesity-associated macrophages?

Signaling by IL-6 promotes alternative activation of macrophages to limitendotoxemia and obesity-associated resistance to insulin. 

Q3. What are the main reasons for the suspension of these studies?

adverse events including severe weight loss, hyperalgesia, coughing, muscle fatigue and pain have led to the suspension of these studies. 

Q4. What other modalities interfere with gp130 signalling?

Other modalities that interfere with gp130 signalling include madindoline-A, the small molecule inhibitor SC144, and the synthetic oxazolidinone derivative LMT-28 236-238 . 

Q5. What is the role of IL-6 family cytokines in the progression of chronic disease?

With impacts on stromal tissue cells, tissue-resident monocytes and activated inflammatory leukocytes, IL-6 family cytokines play vital roles in the initiation, maintenance and resolution of local and systemic inflammatory outcomes that promote tissue damage, activation of the acute phase response, development of autoimmune reactions, and metabolism (BOX 1 & BOX 2) 5,15,17,122-126, . 

Q6. What is the role of IL-27 in the regulation of Th17 cells?

IL-27 acts as a negative regulator of certain effector characteristics and inhibits the generation of Th17 cells through the actions of STAT1 68,103,109 . 

Q7. What role do Th17 cells play in maintaining mucosal barrier integrity and immunity?

Th17 cells play vital roles in maintaining mucosal barrier integrity and immunity, protection against fungal infections, and in the development of inflammation-associated tissue damage, and may reflect the contribution of IL-6 in maintaining tissue integrity and immune homeostasis at barrier surfaces 106-108 . 

Q8. What is the role of gp130 in the regulation of overlapping activities?

Use of the common gp130 receptor subunit contributes to the regulation of a wide range of overlapping activities that are controlled by IL-6 family cytokines. 

Q9. What is the role of interleukin in the development of T cells?

Interleukin 27 negatively regulates the development of interleukin17-producing T helper cells during chronic inflammation of the central nervous system. 

Q10. What is the role of IL-6 in the treatment of rheumatoi?

The IL-6 cytokine family in health and disease26therapeutic strategies based on the neuroprotective properties of LIF and the anti-inflammatory characteristics of IL-27 may offer more promising applications in the treatment of multiple sclerosis, rheumatoid arthritis and other autoimmune or inflammatory diseases155,232-234. 

Q11. What are the common therapeutic strategies that target IL-6 cytokine family members?

Drug strategies that target IL-6 cytokine family members fall into various categories: i), blocking monoclonal antibodies that directly act on either the cytokine or the cytokine receptor; ii), recombinant cytokine regimes; iii), small molecule therapies that interfere with cytokine receptor signalling through gp130 and the JAK–STAT pathway (FIG. 3). 

Q12. What are the key roles of IL-6 family cytokines in anti-microbial?

Studies on IL-6, IL-27, OSM and LIF highlight important roles for these cytokines in anti-microbial and anti-viral immunity, where they provide tissue protection from infection-related injury 68,71,76-79 . 

Q13. What are the other forms of cytokine receptor signalling?

These additional forms of cytokine receptor signalling contribute to the regulation of innate and adaptive immunity, and direct responses in target cells that lack specific receptors for these cytokines. 

Q14. What are the roles of IL-6-related cytokines in adaptive immunity?

While these activities often rely on the prior activation of innate immune responses in monocytes and specialized antigen-presenting cells, several IL-6 family cytokines (for example, IL-6 and IL-27) also act as lymphokines of adaptive immunity (BOX 1). 

Q15. What is the role of IL-6 in the immune response of the mouse?

J.S., Stumhofer, J.S., Passos, S., Ernst, M. & Hunter, C.A. IL-6 mediates thesusceptibility of glycoprotein 130 hypermorphs to Toxoplasma gondii. 

Q16. What is the inverse relationship between IL-27 and ectopic lymphoi?

Consistent with IL-27 being a negative regulator of ectopic lymphoneogenesis, this inverse relationship is also evident in Il27ra -/- mice where the experimental onset of inflammatory arthritis is associated with elevated synovial expression of various mediators implicated in lymphoid neogenesis, including homeostatic chemokines (for example, CXCL13, CC_chemokine ligand 21 (CCL21) and CCL19), pro-inflammatory cytokines (for example, IL-17 and IL-21), follicular dendritic cell markers (for example, CD21) and transcriptional regulators (for example, BCL-6)169. 

Q17. What is the role of gp130 in IL-6 signalling?

In this regard, the IL-6:sIL-6R complex is able to directly engage and activate membrane-bound gp130 to facilitate IL-6 signalling in cell types that would not normally respond to IL-6 29 . 

Q18. What is the primary mechanism for IL-6 involvement in chronic diseases?

trans-signalling serves to broaden the target cell repertoire of IL-6, and is considered the primary mechanism for IL-6 involvement in numerous chronic diseases and cancers5,29,37. 

Q19. What is the phenotype of a mouse lacking gp130?

In contrast to gp130, the receptor subunits specific to individual family members display a more restricted cellular expression profile, and the phenotype of mice lacking individual cytokine family members or their associated receptor subunits is often less severe than their apparent pleiotropic properties would suggest 28,30,76,91 .