Therapeutic Targeting of IL-6 Trans Signaling Counteracts STAT3 Control of Experimental Inflammatory Arthritis
Abstract
Cytokine control of the synovial infiltrate is a central process in the development of inflammatory arthritis. In this study, we combine genetic approaches and intervention strategies to describe a fundamental requirement for IL-6-mediated STAT3 signaling in orchestrating the inflammatory infiltrate in monoarticular and systemic models of experimental arthritis. STAT3 activation via the common gp130 signal-transducing receptor for all IL-6-related cytokines led to increased retention of neutrophils and T cells within the inflamed synovium, which included STAT3-regulated IL-17A-secreting T cells. Control of leukocyte infiltration was reliant upon IL-6 signaling via its soluble receptor (termed IL-6 trans signaling), as evidenced by selective blockade of this alternative IL-6 signaling pathway using an engineered variant of soluble gp130 (sgp130Fc). This therapeutic intervention led to substantial clinical improvement in mice with emerging or established incidence of systemic arthritis. These data illustrate that IL-6 control of STAT3 is critical for regulating the synovial infiltrate in inflammatory arthritis, and suggest that selective inhibition of IL-6 trans signaling may provide a more refined intervention strategy for blocking IL-6-driven proarthritic activities.
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AIA, which is IL-6-dependent, is enhanced in gp130Y757F/Y757F mice in a manner dependent on STAT3.
“It has not yet been reported whether gp130Y757F/Y757F mice spontaneously develop arthritis as F759 mice do, but AIA, which is also IL-6-dependent, is enhanced in gp130Y757F/Y757F mice in a manner dependent on STAT3 (259).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [259]
Cites
Bettelli, E., Carrier, Y., Gao, W., Korn, T., Strom, T. B., Oukka, M., Weiner, H. L., & Kuchroo, V. K. (2006) · Nature · doi:10.1038/nature04753 · Cited by 6,992 · see citing works
Ivanov, I. I., McKenzie, B. S., Zhou, L., Tadokoro, C. E., Lepelley, A., Lafaille, J. J., Cua, D. J., & Littman, D. R. (2006) · Cell · doi:10.1016/j.cell.2006.07.035 · Cited by 5,145 · see citing works
Veldhoen, M., Hocking, R. J., Atkins, C. J., Locksley, R. M., & Stockinger, B. (2006) · Immunity · doi:10.1016/j.immuni.2006.01.001 · Cited by 3,605 · see citing works
Principles of interleukin (IL)-6-type cytokine signalling and its regulation
HEINRICH, P. C., BEHRMANN, I., HAAN, S., HERMANNS, H. M., MÜLLER-NEWEN, G., & SCHAPER, F. (2003) · Biochemical Journal · doi:10.1042/bj20030407 · Cited by 3,272 · cited 1× · see citing works
“In either case, IL-6 engagement of its specific -subunit leads to gp130 homodimerization and activation of several signaling cascades, in particular the JAK-STAT1/3, Src homology region 2 domain-containing phosphatase 1-MAPK, and Src homology region 2 domain-containing phosphatase 1-PI3K pathways (10).”
BackgroundTebbutt, N. C., Giraud, A. S., Inglese, M., Jenkins, B., Waring, P., Clay, F. J., Malki, S., Alderman, B. M., Grail, D., Hollande, F., et al. (2002) · Nature Medicine · doi:10.1038/nm763 · Cited by 474 · see citing works
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IL-6 in inflammation, autoimmunity and cancer
Hirano, T. (2021) · International Immunology · doi:10.1093/intimm/dxaa078 · Cited by 1,453 · see citing works
“It has not yet been reported whether gp130 Y757F/Y757F mice spontaneously develop arthritis as F759 mice do, but AIA, which is also IL-6-dependent, is enhanced in gp130 Y757F/Y757F mice in a manner dependent on STAT3 (259).”
BackgroundRecent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer
Jones, S. A., & Jenkins, B. J. (2018) · Nature Reviews Immunology · doi:10.1038/s41577-018-0066-7 · Cited by 1,102 · see citing works
Self-citationRose-John, S. (2012) · International Journal of Biological Sciences · doi:10.7150/ijbs.4989 · Cited by 1,040 · see citing works
Self-citationTargeting IL-6 trans-signalling: past, present and future prospects
Rose-John, S., Jenkins, B. J., Garbers, C., Moll, J. M., & Scheller, J. (2023) · Nature Reviews Immunology · doi:10.1038/s41577-023-00856-y · Cited by 524 · see citing works
Self-citationPleiotropy and specificity: insights from the interleukin 6 family of cytokines
Murakami, M., Kamimura, D., & Hirano, T. (2019) · Immunity · doi:10.1016/j.immuni.2019.03.027 · Cited by 533 · see citing works
The role of IL-6 in host defence against infections: immunobiology and clinical implications
Rose-John, S., Winthrop, K., & Calabrese, L. (2017) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2017.83 · Cited by 424 · see citing works
Self-citationInterleukin-6: from basic biology to selective blockade of pro-inflammatory activities
Scheller, J., Garbers, C., & Rose-John, S. (2014) · Seminars in Immunology · doi:10.1016/j.smim.2013.11.002 · Cited by 308 · see citing works
Self-citationIL-6 <i>Trans</i>-Signaling Modulates TLR4-Dependent Inflammatory Responses via STAT3
Greenhill, C. J., Rose-John, S., Lissilaa, R., Ferlin, W., Ernst, M., Hertzog, P. J., Mansell, A., & Jenkins, B. J. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1002971 · Cited by 264 · see citing works
Self-citationIL‐6 Trans‐signaling Controls Liver Regeneration After Partial Hepatectomy
Fazel Modares, N., Polz, R., Haghighi, F., Lamertz, L., Behnke, K., Zhuang, Y., Kordes, C., Häussinger, D., Sorg, U. R., Pfeffer, K., et al. (2019) · Hepatology · doi:10.1002/hep.30774 · Cited by 113 · see citing works
Self-citationThe Regenerative Activity of Interleukin-6
Galun, E., & Rose-John, S. (2013) · Methods in Molecular Biology · doi:10.1007/978-1-62703-308-4_4 · Cited by 34 · see citing works
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- Authors
- Nowell, M. A., Williams, A. S., Carty, S. A., Scheller, J., Hayes, A. J., Jones, G. W., Richards, P. J., Slinn, S., Ernst, M., Jenkins, B. J., Topley, N., Rose-John, S., & Jones, S. A.
- Affiliations
- Cardiff University (GB)
- Christian-Albrechts-Universität zu Kiel (DE)
- Ludwig Cancer Research (BE)
- Monash Institute of Medical Research (AU)
- Department of Biochemistry, Christian-Albrechts-Universität zu Kiel , Kiel,
- Corresponding author
- Topley, Nicholas
- ORCID
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2009-01-01
- Volume
- 182
- Issue
- 1
- Pages
- 613-622
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2111091679
- Cited by
- 215
- References
- 5
- Citations by year
- 2026: 9 · 2025: 8 · 2024: 9 · 2023: 9 · 2022: 6 · 2021: 11 · 2020: 9 · 2019: 12 · 2018: 17 · 2017: 17 · 2016: 19 · 2015: 14 · 2014: 7 · 2013: 10 · 2012: 17
- FWCI
- 9.58
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Bristol Research (University of Bristol) (submittedVersion)
- Funders
- Versus Arthritis (17654)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Rheumatology › Rheumatoid Arthritis Research and Therapies
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Keywords
- IL-6 trans-signaling, STAT3 signaling, interleukin-6, gp130, inflammatory arthritis, neutrophils, T cells, IL-17A, systemic arthritis, monoarthritis
- MeSH terms
- Animals, Arthritis, Experimental, Cells, Cultured, Cricetulus, Cricetinae, Humans, Male, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Transgenic, Recombinant Fusion Proteins, Recurrence, Synovial Membrane, T-Lymphocytes, Signal Transduction, Interleukin-6, CHO Cells, Mice, Knockout, Inflammation Mediators, STAT3 Transcription Factor, Cytokine Receptor gp130, Mice
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