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, LIF, and OSM.
“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]
In ‘The advent of IL-6 trans-signalling’ (page unavailable), the paper identifies LIF and OSM as gp130-dependent cytokines and describes JAK–STAT activation by IL-6 signalling. ‘Development of IL-6 signalling inhibitors’ discusses IL-6-dependent myeloma-cell proliferation, but the paper does not establish that all three cytokines trigger JAK/STAT3 in MM cells. (LLM, conf=0.86)
Experimental — accuracy not yet measuredBinding of IL-6 to IL-6R leads to activation of JAK1, which phosphorylates STAT3, activating the JAK/STAT pathway.
“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]
The Introduction describes IL-6 binding to membrane-bound IL-6R and forming a signalling complex with gp130. The advent of IL-6 trans-signalling section reports STAT3 phosphorylation and JAK–STAT activation following IL-6 signalling. However, our copy does not identify JAK1 specifically or state that JAK1 phosphorylates STAT3. (LLM, conf=0.86)
Experimental — accuracy not yet measuredOlamkicept (sgp130Fc) consists of two soluble human gp130 proteins fused with Fc of human IgG and selectively targets the IL-6-sIL-6R complex.
“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]
The ‘Preclinical and clinical development of olamkicept’ section identifies olamkicept as sgp130Fc. Figure 6 describes soluble gp130 fused to a human IgG1 Fc, and ‘An IL-6 trans-signalling inhibitor: sgp130Fc’ says the fusion protein interacts with IL-6–sIL-6R complexes. The passages do not establish the claimed count of two soluble gp130 proteins; the paper also notes interaction with IL-6–membrane IL-6R complexes, so binding is not exclusive to the soluble-receptor complex. (LLM, conf=0.84)
Experimental — accuracy not yet measuredGlobal blockade of IL-6 signaling may reduce induction of hepatic acute-phase proteins upon infection, such as Listeria monocytogenes.
“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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Self-citationADAM17 selectively activates the IL‐6 trans‐signaling/ERK MAPK axis in KRAS‐addicted lung cancer
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Self-citationNo inhibition of IL-27 signaling by soluble gp130
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Self-citationgp130 dimerization in the absence of ligand: Preformed cytokine receptor complexes
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Self-citationIL-6 Trans-Signaling Drives Murine Crescentic GN
Braun, G. S., Nagayama, Y., Maruta, Y., Heymann, F., van Roeyen, C. R. C., Klinkhammer, B. M., Boor, P., Villa, L., Salant, D. J., Raffetseder, U., et al. (2015) · Journal of the American Society of Nephrology · doi:10.1681/asn.2014111147 · Cited by 58 · see citing works
Self-citationInterleukin-11 promotes accessory cell-dependent B-cell differentiation in humans
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Interleukin-6 trans-signaling exacerbates inflammation and renal pathology in lupus-prone mice.
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Self-citationFOSL1 Promotes Kras-induced Lung Cancer through Amphiregulin and Cell Survival Gene Regulation
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Kinetics of cytokine receptor trafficking determine signaling and functional selectivity
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Self-citationThe IL-6-neutralizing sIL-6R/sgp130 buffer system is disturbed in patients with type 2 diabetes.
Aparicio-Siegmund, S., Garbers, Y., Flynn, C. M., Waetzig, G. H., Gouni-Berthold, I., Krone, W., Berthold, H., Laudes, M., Rose-John, S., & Garbers, C. (2019) · American Journal of Physiology. Endocrinology and Metabolism · doi:10.1152/ajpendo.00166.2019 · Cited by 45 · see citing works
Self-citationThe cytokine interleukin-11 crucially links bone formation, remodeling and resorption
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Self-citationHu, J., Zhang, Y., Chunxia, H., Feng, X., He, S., Zhang, Y., & Maze, M. (2022) · British Journal of Anaesthesia · doi:10.1016/j.bja.2022.08.019 · Cited by 42 · see citing works
ADAM17 orchestrates Interleukin-6, TNFα and EGF-R signaling in inflammation and cancer
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Self-citationEffect of interleukin 11 on normal and pathological thrombopoiesis
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The STAT3 beacon: IL-6 recurrently activates STAT 3 from endosomal structures
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A designer hyper interleukin 11 (H11) is a biologically active cytokine
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Self-citationGranulocytes Are Unresponsive to IL-6 Due to an Absence of gp130
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Koch, L., Kespohl, B., Agthe, M., Schumertl, T., Düsterhöft, S., Lemberg, M. K., Lokau, J., & Garbers, C. (2021) · The FASEB Journal · doi:10.1096/fj.202002087r · Cited by 36 · see citing works
Self-citationHeise, D., Soria, A. D., Hansen, S., Dambietz, C. A., Akbarzadeh, M., Berg, A. F., Waetzig, G. H., Jones, S. A., Dvorský, R., Ahmadian, M. R., et al. (2021) · Science Signaling · doi:10.1126/scisignal.abc3480 · Cited by 36 · see citing works
Self-citationExclusive inhibition of IL-6 trans-signaling by soluble gp130FlyRFc
Berg, A. F., Ettich, J., Weitz, H. T., Krusche, M., Floss, D. M., Scheller, J., & Moll, J. M. (2021) · Cytokine X · doi:10.1016/j.cytox.2021.100058 · Cited by 35 · see citing works
Self-citationKwok, H. F., Bøtkjær, K. A., Tape, C. J., Huang, Y., McCafferty, J., & Murphy, G. (2014) · Protein Engineering Design and Selection · doi:10.1093/protein/gzu010 · Cited by 32 · see citing works
Blockade of the protease ADAM17 ameliorates experimental pancreatitis
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Self-citationTranscytosis of IL-11 and Apical Redirection of gp130 Is Mediated by IL-11α Receptor.
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Self-citationMolecular basis for the mechanism of action of an anti‐TACE antibody
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“…studies employing ADAM17-neutralizing monoclonal antibodies that act via several modalities, including allosteric perturbation of the binding ability of its catalytic active site, or steric hindrance leading to competitive or noncompetitive inhibition of protein substrate binding 170,171 (Fig.”
A variant in IL6ST with a selective IL-11 signaling defect in human and mouse
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Self-citationRole of ubiquitination and proteolysis in the regulation of pro- and anti-apoptotic TNF-R1 signaling
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Therapeutic Potential of Combining IL-6 and TNF Blockade in a Mouse Model of Allergic Asthma
Namakanova, O. A., Gorshkova, E. A., Zvartsev, R. V., Nedospasov, S. A., Drutskaya, M. S., & Gubernatorova, E. O. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23073521 · Cited by 28 · see citing works
Identification of IL-6 Signalling Components as Predictors of Severity and Outcome in COVID-19
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Interleukin-11-driven gastric tumourigenesis is independent of trans-signalling
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Self-citationOverall interleukin-6 production exceeds 7 mg/day in multiple myeloma complicated by sepsis
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Interleukin-6 controls recycling and degradation, but not internalization of its receptors
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Self-citation
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Research works printed but not linked: 1
- [65]Kang S Narazaki M Metwally H Kishimoto T Historical overview of the interleukin-6 family cytokine J. Exp. Med. 2020 2020 5 PMC7201933 32267936
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Sorted by citations
Multiple myeloma: signaling pathways and targeted therapy
Lu, Q., Yang, D., Li, H., Niu, T., & Tong, A. (2024) · Molecular biomedicine · doi:10.1186/s43556-024-00188-w · Cited by 90 · see citing works
The double-edged effects of IL-6 in liver regeneration, aging, inflammation, and diseases
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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].”
BackgroundInfluential
- 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
- 212
- 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
- Health Sciences › Medicine › Oncology › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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