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Targeting IL-6 trans-signalling: past, present and future prospects
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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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Self-citationIL-6 Controls the Innate Immune Response against Listeria monocytogenes via Classical IL-6 Signaling
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Self-citationRecent Advances in ADAM17 Research: A Promising Target for Cancer and Inflammation
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Self-citationIL‐6 trans‐signaling is essential for the development of hepatocellular carcinoma in mice
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Self-citationNeural activities of IL‐6‐type cytokines often depend on soluble cytokine receptors
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Self-citationDistinct Effects of IL-6 Classic and Trans -Signaling in Bone Fracture Healing
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Self-citationIL-6 Revisited: From Rheumatoid Arthritis to CAR T Cell Therapy and COVID-19
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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-citationProteolytic Origin of the Soluble Human IL-6R In Vivo and a Decisive Role of N-Glycosylation
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Self-citationThe interleukin 6 pathway and atherosclerosis
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Self-citationNo inhibition of IL-27 signaling by soluble gp130
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Self-citationIdentification of cardiac myocytes as the target of interleukin 11, a cardioprotective cytokine
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Self-citationIL-6 Trans-Signaling Drives Murine Crescentic GN
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Self-citationInterleukin‐6 Trans‐Signaling Exacerbates Inflammation and Renal Pathology in Lupus‐Prone Mice
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Self-citationInterleukin-11 promotes accessory cell-dependent B-cell differentiation in humans
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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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