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New insights into IL-6 family cytokines in metabolism, hepatology and gastroenterology

Nature Reviews Gastroenterology & Hepatology volume 18, pages 787–803 (2021)Cite this article

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Abstract

IL-6 family cytokines are defined by the common use of the signal-transducing receptor chain glycoprotein 130 (gp130). Increasing evidence indicates that these cytokines are essential in the regulation of metabolic homeostasis as well as in the pathophysiology of multiple gastrointestinal and liver disorders, thus making them attractive therapeutic targets. Over the past few years, therapies modulating gp130 signalling have grown exponentially in several clinical settings including obesity, cancer and inflammatory bowel disease. A newly engineered gp130 cytokine, IC7Fc, has shown promising preclinical results for the treatment of type 2 diabetes, obesity and liver steatosis. Moreover, drugs that modulate gp130 signalling have shown promise in refractory inflammatory bowel disease in clinical trials. A deeper understanding of the main roles of the IL-6 family of cytokines during homeostatic and pathological conditions, their signalling pathways, sources of production and target cells will be crucial to the development of improved treatments. Here, we review the current state of the role of these cytokines in hepatology and gastroenterology and discuss the progress achieved in translating therapeutics targeting gp130 signalling into clinical practice.

Key points

  • Evidence from animal and human studies supports the role of IL-6 family cytokines in regulating metabolic, hepatic and gastroenterology homeostasis.

  • Activation of gp130 signalling can be detrimental in some contexts and contribute to metabolic, liver and gastrointestinal disorders such as obesity, chronic liver damage, inflammatory bowel disease (IBD) and cancer.

  • Further insights into the involvement of IL-6 family cytokines in homeostasis and the pathophysiology of different disorders are required to develop treatments with adequate risk–benefit profiles.

  • Some therapies targeting gp130 signalling (for example, spg130Fc and JAK inhibitors) are promising novel disease-modifying biological treatments for refractory IBD.

  • Preclinical studies have shown that engineered IL-6 family cytokines such as IC7Fc are promising for the treatment of type 2 diabetes, obesity and liver steatosis.

  • New approaches such as gp130–cytokine fusion proteins, soluble antagonist receptors and more selective or tissue-specific inhibitors of gp130 signalling might improve the effectiveness and safety profile of this class of therapy.

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Fig. 1: IL-6 family signalling complex.
Fig. 2: Modes of IL-6 and IL-11 signalling.
Fig. 3: Signalling of other members of the IL-6 family cytokines.
Fig. 4: Intracellular signalling mechanisms linked to gp130.
Fig. 5: gp130 cytokines involved in the pathophysiology of human metabolic, liver and gastrointestinal disorders.
Fig. 6: Therapeutic interventions that target gp130 signalling.
Fig. 7: Adverse effects of anti-IL-6 drugs and anti-JAK inhibitors.

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Acknowledgements

D.C. is supported by a predoctoral iPFIS (IFI 19/00048) funded by the Spanish Institute of Health Carlos III (co-funded by the European Social Fund). M.D.G. acknowledges support from a Juan Rodes contract (JR18/00026) funded by the Spanish Institute of Health Carlos III (co-funded by the European Social Fund). This study is supported by MINECO/AEI/FEDER, UE PID2019-110587RB-I00 from the Ministry of Economy and Competitiveness (co-funded by the European Social Fund) and Andalusian Ministry of Economy, Innovation, Science and Employment (P18-RT-4775). S.R.- J. is funded by the German Research Foundation (DFG, project number 80750187 – SFB 841 (project C1). S.R.- J. and C.G. are funded by the German Research Foundation (DFG, project number 125440785 – SFB 877 (projects A1, A10 and A14)).

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  1. These authors contributed equally: Maria D. Giraldez, David Carneros.

Authors and Affiliations

  1. Institute of Biomedicine of Seville (IBIS), Spanish National Research Council (CSIC), University of Seville, Virgen del Rocio University Hospital, Seville, Spain

    Maria D. Giraldez, David Carneros & Matilde Bustos

  2. Department of Pathology, Medical Faculty, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany

    Christoph Garbers

  3. Institute of Biochemistry, Kiel University, Kiel, Germany

    Stefan Rose-John

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All the authors contributed to all aspects of the article.

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Correspondence to Matilde Bustos.

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Competing interests

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 the company I-Mab. S.R.-J. has stock ownership in CONARIS. C.G. has received a research grant from Corvidia Therapeutics (Waltham, MA, USA) and has acted as a consultant for AbbVie. All other authors declare no competing interests.

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Giraldez, M.D., Carneros, D., Garbers, C. et al. New insights into IL-6 family cytokines in metabolism, hepatology and gastroenterology. Nat Rev Gastroenterol Hepatol 18, 787–803 (2021). https://doi.org/10.1038/s41575-021-00473-x

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