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Targeting IL-6 trans-signalling: past, present and future prospects
Open accessAbstract
Interleukin-6 (IL-6) is a key immunomodulatory cytokine that affects the pathogenesis of diverse diseases, including autoimmune diseases, chronic inflammatory conditions and cancer. Classical IL-6 signalling involves the binding of IL-6 to the membrane-bound IL-6 receptor α-subunit (hereafter termed ‘mIL-6R’) and glycoprotein 130 (gp130) signal-transducing subunit. By contrast, in IL-6 trans-signalling, complexes of IL-6 and the soluble form of IL-6 receptor (sIL-6R) signal via membrane-bound gp130. A third mode of IL-6 signalling — known as cluster signalling — involves preformed complexes of membrane-bound IL-6–mIL-6R on one cell activating gp130 subunits on target cells. Antibodies and small molecules have been developed that block all three forms of IL-6 signalling, but in the past decade, IL-6 trans-signalling has emerged as the predominant pathway by which IL-6 promotes disease pathogenesis. The first selective inhibitor of IL-6 trans-signalling, sgp130, has shown therapeutic potential in various preclinical models of disease and olamkicept, a sgp130Fc variant, had promising results in phase II clinical studies for inflammatory bowel disease. Technological developments have already led to next-generation sgp130 variants with increased affinity and selectivity towards IL-6 trans-signalling, along with indirect strategies to block IL-6 trans-signalling. Here, we summarize our current understanding of the biological outcomes of IL-6-mediated signalling and the potential for targeting this pathway in the clinic. This Review details the discovery of the interleukin-6 (IL-6) trans-signalling pathway and the subsequent development of biologics that specifically inhibit this pathway. Emerging evidence suggests that specifically targeting IL-6 trans-signalling can reduce pathological disease-promoting activities of IL-6 without blocking the protective actions of IL-6 in infection and tissue repair.
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“In MM cells, the JAK/STAT3 pathway is triggered by cytokines from the gp130 receptor family, such as IL-6, leukemia inhibitory factor (LIF), and oncostatin-M (OSM).”
From Multiple myeloma: signaling pathways and targeted therapy (2024) · cites this paper as [108]
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“Additionally, the binding of IL-6 to its receptor (IL-6R) leads to the activation of JAK1, which phosphorylates STAT3, thereby activating the JAK/STAT pathway [108].”
From Multiple myeloma: signaling pathways and targeted therapy (2024) · cites this paper as [108]
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“Soluble gp130Fc, named olamkicept or TJ301, is consists of two soluble human gp130 proteins fused with the Fc of human IgG, and selectively targets the IL-6-sIL-6R complex [79].”
From The double-edged effects of IL-6 in liver regeneration, aging, inflammation, and diseases (2024) · cites this paper as [79]
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“As IL-6 classic signaling plays crucial roles in the initiation of inflammation and the host defense against pathogen infection, global blockade of IL-6 signaling may reduce the induction of hepatic acute-phase proteins upon infection, such as Listeria monocytogenes [79].”
From The double-edged effects of IL-6 in liver regeneration, aging, inflammation, and diseases (2024) · cites this paper as [79]
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Tissue-based map of the human proteome
Uhlén, M., Fagerberg, L., Hallström, B. M., Lindskog, C., Oksvold, P., Mardinoglu, A., Sivertsson, Å., Kampf, C., Sjöstedt, E., Asplund, A., et al. (2015) · Science · doi:10.1126/science.1260419 · Cited by 15,286
Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients
Hadjadj, J., Yatim, N., Barnabei, L., Corneau, A., Boussier, J., Smith, N., Péré, H., Charbit, B., Bondet, V., Chenevier-Gobeaux, C., et al. (2020) · Science · doi:10.1126/science.abc6027 · Cited by 2,984
The global burden of IBD: from 2015 to 2025
Kaplan, G. G. (2015) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2015.150 · Cited by 2,639
Grivennikov, S., Karin, E., Terzic, J., Mucida, D., Yu, G.-Y., Vallabhapurapu, S., Scheller, J., Rose-John, S., Cheroutre, H., Eckmann, L., et al. (2009) · Cancer Cell · doi:10.1016/j.ccr.2009.01.001 · Cited by 2,155
Self-citationHirano, T., Yasukawa, K., Harada, H., Taga, T., Watanabe, Y., Matsuda, T., Kashiwamura, S.-I., Nakajima, K., Koyama, K., Iwamatsu, A., et al. (1986) · Nature · doi:10.1038/324073a0 · Cited by 2,139
Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure
Giamarellos-Bourboulis, E. J., Netea, M. G., Rovina, N., Akinosoglou, K., Antoniadou, A., Antonakos, N., Damoraki, G., Gkavogianni, T., Adami, M.-E., Katsaounou, P., et al. (2020) · Cell Host & Microbe · doi:10.1016/j.chom.2020.04.009 · Cited by 2,045 · cited 1×
“Dysregulated IL-6 signalling is a hallmark of infections, including SARS-CoV-2, that are characterized by hyperinflammation 137–145 , with high IL-6 levels in patients with COVID-19 being implicated in the depletion of CD4 + T cells, CD8 + T cells and natural killer cells 146 .”
Abani, O., Abbas, A., Abbas, F., Abbas, M., Abbasi, S., Abbass, H., Abbott, A., Abdallah, N., Abdelaziz, A., Abdelfattah, M., et al. (2021) · The Lancet · doi:10.1016/s0140-6736(21)00676-0 · Cited by 1,983
Interleukin-6 receptor antagonists in critically ill patients with Covid-19.
The REMAP-CAP Investigators (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2100433 · Cited by 1,962
Impaired immune and acute-phase responses in interleukin-6-deficient mice
Kopf, M., Baumann, H., Freer, G., Freudenberg, M., Lamers, M., Kishimoto, T., Zinkernagel, R., Bluethmann, H., & Köhler, G. (1994) · Nature · doi:10.1038/368339a0 · Cited by 1,768 · cited 2×
“Studies in IL-6-deficient mice showed that IL-6 contributes to the pathogenesis of many inflammatory diseases, including bacterial and viral infections 66 , arthritis 67,68 , experimental colitis 69 and multiple sclerosis 70 .”
Gauldie, J., Richards, C. D., Harnish, D. C., Lansdorp, P. M., & Baumann, H. J. (1987) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.84.20.7251 · Cited by 1,635
Research works printed but not linked: 1
- Kang, S., Narazaki, M., Metwally, H. & Kishimoto, T. Historical overview of the interleukin-6 family cytokine. J. Exp. Med. 2020, 5 (2020).
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Yang, Y., Wan, L., Qin, Y., Guo, J. Z., Wang, Y., Ji, K., Hu, S., & Feng, M. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1907563
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Self-citationZhao, M., Li, Z., Li, J., Zhang, X., Li, X., Cui, Y., Fan, Y., & Sun, Y. (2026) · Nano Today · doi:10.1016/j.nantod.2026.103132
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Melisi, F., Pasquale, L. S., Peluso, T., Graziano, C., Iannarone, C., Vicario, M., Iesu, M. R. D., Izzo, M., Ricciardi, R., Bocchetti, M., et al. (2026) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2026.113383
Russell, A. L., Patel, V., Gober, I. G., Nasser, L., Shah, M., Vadalia, C., Kline, K. E., Parthasarathy, M., Vagni, V., Scott, J. A., et al. (2026) · Neurotrauma Reports · doi:10.1177/2689288x261467218
Schlei, J., Franke, K. F., Holzmann, D., Wittich, C., Floss, D. M., Rafii, P., Brors, K., & Scheller, J. (2026) · ACS Synthetic Biology · doi:10.1021/acssynbio.6c00029
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Yang, Y., Chen, Y., Zhao, H., Wang, Z., Yu, M., Shao, X., Zhu, Y., Han, P., Han, T., Cui, W., et al. (2026) · PLoS Pathogens · doi:10.1371/journal.ppat.1014367
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Wu, X., Wang, H., Zhang, L., Wang, B., Tan, X., Zhu, L., Nie, J., & Liu, D. (2026) · Microbiology Spectrum · doi:10.1128/spectrum.03825-25
Sun, X., Kuang, X., Sun, S., Cui, Y., Xu, X., Dong, J., & Lin, F. (2026) · Frontiers in Medicine · doi:10.3389/fmed.2026.1937471
SMITH, L. L. (2026) · Journal of Clinical Medicine · doi:10.3390/jcm15218538
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Brüggemann, E., & Garbers, C. (2026) · Biochimie · doi:10.1016/j.biochi.2026.09.015
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Cho, E., Compton, S. L. E., Yang, S., Tejani, M. A., Zakari, A., Brown, J. C., & Spielmann, G. (2026) · Cancer Control · doi:10.1177/10732748261493127
Ameen, A. A. J. (2026) · Al-Mustansiriyah Journal of Sciences · doi:10.23851/mjs.v37i3.1920
Wang, J., Li, T., Zhuang, R., He, B., Yang, M., Hao, Y., Yu, N., Zheng, Y., & Cao, Y. (2026) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2026.101532
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Dyachenko, E. I., & Bel’skaya, L. V. (2026) · Eurasian Journal of Medicine and Oncology · doi:10.36922/ejmo026310388
García, F. G. S., Santos, S. R. D. L., Hernández, V. S., & Huerta, F. J. (2026) · Personalized Medicine in Psychiatry · doi:10.1016/j.pmip.2026.100198
Rieneck, E., Haak, J. R., Asgarov, K., Pallandre, J., Wundrack, N., Ettich, J., Miri, N., Floss, D. M., Scheller, J., Garbers, C., et al. (2026) · Communications Biology · doi:10.1038/s42003-026-11014-0
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Kamel, M. M., Zaki, H. F., Saleh, R. A., Henry, S. R., Ibrahim, M. K., Bakr, M. M., Abouhussein, D. M. N., & Rabie, M. A. (2026) · Pharmacia · doi:10.3897/pharmacia.73.e205623
Lax, K., Glass, J., Aliste, A., Sharma, A., & Sharma, S. (2026) · Eye and Vision · doi:10.1186/s40662-026-00513-0
潘, 治. (2026) · Journal of Clinical Personalized Medicine · doi:10.12677/jcpm.2026.55391
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Rana, M. M., Cottingham, A. L., Kolhatkar, S., Xu, F., Najafabadi, A. H., & Pearson, R. M. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.10.22.760948
Zhang, R., Zhang, X., He, X., & Xiang, M. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1983756
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Hao, C., Zheng, S., Fan, E., Brooks, S. E., & Fan, X. (2026) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2026.113725
Jinlong, L., Kong, H., Long, Y., Wei, X., 周连群, & Wang, Q. (2026) · Talanta · doi:10.1016/j.talanta.2026.130841
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Ridker, P. M., Lincoff, A. M., Marx, N., Návar, A. M., Sattar, N. A., Tuttle, K. R., Budoff, M., Bøttcher, M., Cavender, M. A., Choudhury, R. P., et al. (2026) · New England Journal of Medicine · doi:10.1056/nejmoa2612126
Metadata
- Authors
- Rose-John, S., Jenkins, B. J., Garbers, C., Moll, J. M., & Scheller, J.
- Affiliations
- Hudson Institute of Medical Research (AU)
- Otto-von-Guericke-Universität Magdeburg (DE)
- Heinrich Heine University Düsseldorf (DE)
- Corresponding author
- Scheller, Jürgen
- Venue
- Nature Reviews Immunology
- Published
- 2023-04-17
- Volume
- 23
- Issue
- 10
- Pages
- 666-681
- ISSN
- 1474-1733 (ISSN-L)
- 1474-1741
- PMC
- PMC10108826
- OpenAlex
- W4366085911
- Semantic Scholar
- 5ffbde604bb1ef36987e5c29a105b9a8541a3137
- Cited by
- 524
- References
- 213
- Citations by year
- 2026: 146 · 2025: 184 · 2024: 151 · 2023: 43
- FWCI
- 16.99
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature reviews. Immunology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Defense (LC170062)
- Deutsche Forschungsgemeinschaft (CRC877, SFB 877, CRC 841, 125440785)
- Deutsche Krebshilfe
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Keywords
- interleukin-6, IL-6 trans-signalling, soluble IL-6 receptor, gp130, sgp130, IL-6 receptor alpha, inflammatory bowel disease, autoimmune disease, chronic inflammation, cancer, cytokine therapy
- MeSH terms
- Humans, Neoplasms, Interleukin-6, Cytokines, Receptors, Interleukin-6, Cytokine Receptor gp130
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