The soluble interleukin 6 receptor: advanced therapeutic options in inflammation
Abstract
Interleukin (IL)-6 binds to IL-6R and the complex of IL-6 and IL-6R associates with the receptor subunit gp130, which initiates signaling. gp130 is expressed on all cells. IL-6R is cleaved by the ADAM17, generating a soluble IL-6R (sIL-6R). The sIL-6R binds IL-6 and the complex of IL-6 and sIL-6R binds to gp130 even on cells that do not express IL-6R. This process, which has been called IL-6 trans-signaling, increases the spectrum of target cells for IL-6. We generated a protein, sgp130Fc, which inhibits IL-6 trans-signaling without affecting IL-6 classic signaling. Using the sgp130Fc protein we demonstrated that IL-6 classic signaling is antiinflammatory and protective, whereas IL-6 trans-signaling is proinflammatory. Blocking IL-6 trans-signaling does not compromise the defense of the body against bacterial infections. We suggest that sgp130Fc is a superior agent as compared to IL-6 or IL-6R antibodies to block IL-6. The sgp130Fc protein is in phase II clinical trials.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The trans-signaling mode plays crucial roles in chronic inflammation.
“Indeed, this mode plays crucial roles in chronic inflammation (33, 96).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [96]
sIL-6Rα is increased in several diseases, indicating that trans-signaling plays important roles in the progression of inflammation in many diseases including severe COVID-19.
“Notably, sIL-6Rα is increased in several diseases, indicating that trans-signaling plays important roles in the progression of inflammation in many diseases including severe COVID-19 (15, 96).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [96]
ADAM17 increases sIL-6Rα, which activates STAT3 through gp130 on a variety of non-immune cells including fibroblasts, endothelial cells and epithelial cells.
“Furthermore, ADAM17 increases sIL-6Rα, which activates STAT3 through gp130 on a variety of non-immune cells including fibroblasts, endothelial cells and epithelial cells (33, 96).”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [96]
For IL-6 action on non-immune cells, sIL-6Rα is required.
“For this action, sIL-6Rα is required.”
From IL-6 in inflammation, autoimmunity and cancer (2021) · cites this paper as [96]
Cites
Rose-John, S. (2012) · International Journal of Biological Sciences · doi:10.7150/ijbs.4989 · Cited by 1,040 · see citing works
Self-citationThe role of interleukin-6 signaling in nervous tissue
Rothaug, M., Becker-Pauly, C., & Rose-John, S. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2016.03.018 · Cited by 491 · see citing works
Ferreira, R. C., Freitag, D. F., Cutler, A. J., Howson, J. M. M., Rainbow, D. B., Smyth, D. J., Kaptoge, S., Clarke, P., Boreham, C., Coulson, R. M., et al. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003444 · Cited by 316 · see citing works
Kraakman, M. J., Kammoun, H. L., Allen, T. L., Deswaerte, V., Henstridge, D. C., Estevez, E., Matthews, V. B., Neill, B., White, D. A., Murphy, A. J., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.02.006 · Cited by 257 · see citing works
Self-citationBarkhausen, T., Tschernig, T., Rosenstiel, P., van Griensven, M., Vonberg, R.-P., Dorsch, M., Mueller-Heine, A., Chalaris, A., Scheller, J., Rose-John, S., et al. (2011) · Critical Care Medicine · doi:10.1097/ccm.0b013e318211ff56 · Cited by 169 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
IL-6 in inflammation, autoimmunity and cancer
Hirano, T. (2021) · International Immunology · doi:10.1093/intimm/dxaa078 · Cited by 1,453 · see citing works
“1B) (96).”
BackgroundInfluentialTargeting 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
Baran, P., Hansen, S., Waetzig, G. H., Akbarzadeh, M., Lamertz, L., Huber, H. J., Ahmadian, M. R., Moll, J. M., & Scheller, J. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra117.001163 · Cited by 235 · see citing works
Hou, X., Yin, S., Ren, R., Liu, S., Yong, L., Liu, Y., Li, Y., Zheng, M., Kunos, G., Gao, B., et al. (2021) · Hepatology · doi:10.1002/hep.31658 · Cited by 223 · see citing works
New insights into IL-6 family cytokines in metabolism, hepatology and gastroenterology
Giraldez, M. D., Carneros, D., Garbers, C., Rose-John, S., & Bustos, M. (2021) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-021-00473-x · Cited by 156 · see citing works
Self-citationIL-6 Revisited: From Rheumatoid Arthritis to CAR T Cell Therapy and COVID-19
Kishimoto, T., & Kang, S. (2022) · Annual Review of Immunology · doi:10.1146/annurev-immunol-101220-023458 · Cited by 140 · see citing works
Depression and Interleukin-6 Signaling: A Mendelian Randomization Study
Kelly, K. M., Smith, J. A., & Mezuk, B. (2021) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2021.02.019 · Cited by 117 · see citing works
Thériault, S., Dina, C., Messika-Zeitoun, D., Le Scouarnec, S., Capoulade, R., Gaudreault, N., Rigade, S., Li, Z., Simonet, F., Lamontagne, M., et al. (2019) · Circulation: Genomic and Precision Medicine · doi:10.1161/circgen.119.002617 · Cited by 90 · see citing works
The double-edged effects of IL-6 in liver regeneration, aging, inflammation, and diseases
Wang, M.-J., Zhang, H.-L., Chen, F., Guo, X.-J., Liu, Q.-G., & Hou, J. (2024) · Experimental Hematology & Oncology · doi:10.1186/s40164-024-00527-1 · Cited by 84 · see citing works
“During inflammation, the hepatic IL-6 levels can be increased to more than 100 ng/mL [51].”
Background
- Authors
- Rose‐John, S.
- Affiliations
- Christian-Albrechts-Universität zu Kiel (DE)
- Corresponding author
- Rose‐John, Stefan
- ORCID
- Rose‐John, Stefan
- Venue
- Clinical Pharmacology & Therapeutics
- Publisher
- Wiley
- Published
- 2017-07-29
- Volume
- 102
- Issue
- 4
- Pages
- 591-598
- ISSN
- 0009-9236 (ISSN-L)
- 1532-6535
- OpenAlex
- W2731047190
- Cited by
- 169
- References
- 5
- Citations by year
- 2026: 11 · 2025: 18 · 2024: 17 · 2023: 14 · 2022: 21 · 2021: 25 · 2020: 28 · 2019: 19 · 2018: 13 · 2017: 3
- FWCI
- 1.81
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Pharmacology & Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- BMBF (InTraSig, project B)
- 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
- soluble IL-6 receptor, IL-6 trans-signaling, gp130, sgp130Fc, ADAM17, IL-6 signaling, inflammation, anti-inflammatory therapy, IL-6 receptor antibody
- MeSH terms
- Animals, Humans, Inflammation, Recombinant Fusion Proteins, Drug Design, Signal Transduction, Interleukin-6, 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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
