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IL-6 Trans-Signaling via the Soluble IL-6 Receptor: Importance for the Pro-Inflammatory Activities of IL-6
Open accessAbstract
Interleukin-6 (IL-6) is a cytokine with many activities. It has functions in the regulation of the immune system and the nervous system. Furthermore, IL-6 is involved in liver regeneration and in the metabolic control of the body. On target cells, IL-6 binds to an 80 kDa IL-6 receptor (IL-6R). The complex of IL-6 and IL-6R associates with a second protein, gp130, which thereupon dimerizes and initiates intracellular signaling. Whereas gp130 is expressed on all cells, IL-6R is only present on few cells in the body including hepatocytes and some leukocytes. Cells, which do not express IL-6R cannot respond to the cytokine, since gp130 alone has no measurable affinity for IL-6. Interestingly, a soluble form of IL-6R (sIL-6R) comprising the extracellular portion of the receptor can bind IL-6 with a similar affinity as the membrane bound IL-6R. The complex of IL-6 and sIL-6R can bind to gp130 on cells, which do not express the IL-6R, and which are unresponsive to IL-6. This process has been called trans-signaling. Here I will review published evidence that IL-6 trans-signaling is pro-inflammatory whereas classic IL-6 signaling via the membrane bound IL-6R is needed for regenerative or anti-inflammatory activities of the cytokine. Furthermore, the detailed knowledge of IL-6 biology has important consequences for therapeutic strategies aimed at the blockade of the cytokine IL-6.
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“Therefore, the balance between mbIL-6R and sIL-6R availability, along with signal duration and tissue context, determines whether IL-6 acts in a protective or pathogenic manner [40].”
From Exercise-Induced Muscle–Fat Crosstalk: Molecular Mediators and Their Pharmacological Modulation for the Maintenance of Metabolic Flexibility in Aging (2025) · cites this paper as [40]
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“HyIL-6 triggers signaling in all cells expressing gp130, producing a more robust and homogenous signaling output”
From CDK8 fine-tunes IL-6 transcriptional activities by limiting STAT3 resident time at the gene loci (2020) · cites this paper as Rose-John, 2012
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“This is in line with the view that classic and trans-signaling promote anti- and pro-inflammatory responses, respectively (85)”
From T H 17 cells require ongoing classic IL-6 receptor signaling to retain transcriptional and functional identity (2020) · cites this paper as [85]
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Nobis, A., Zalewski, D., & Waszkiewicz, N. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9123793 · Cited by 197
“The activation of soluble IL-6 receptors (sIL-6R) is responsible for IL-6 trans-signaling [44], which is characteristic of inflammation, while IL-6 classic signaling contributes to anti-inflammatory effects [97].”
BackgroundCook, S. A., & Schäfer, S. (2020) · Annual Review of Medicine · doi:10.1146/annurev-med-041818-011649 · Cited by 178
Interleukin-6 as a Multifunctional Regulator: Inflammation, Immune Response, and Fibrosis
Choy, E., & Rose-John, S. (2017) · Journal of Scleroderma and Related Disorders · doi:10.5301/jsrd.5000265 · Cited by 174
“Human endothelial cells express gp130 but not IL-6R (9, 37, 52), whereas sIL-6R–mediated trans-signaling is known to increase the expression of adhesion molecules by endothelial cells and the binding of neutrophils, thereby causing vascular inflammation (37).”
BackgroundInfluentialSelf-citationDurlacher, K., Hassan, A., Levi, R., Axelrod, J. H., Silver, J., & Naveh‐Many, T. (2018) · Kidney International · doi:10.1016/j.kint.2018.02.026 · Cited by 181
Immune‐suppressive effects of interleukin‐6 on T‐cell‐mediated anti‐tumor immunity
Tsukamoto, H., Fujieda, K., Senju, S., Ikeda, T., Oshiumi, H., & Nishimura, Y. (2017) · Cancer Science · doi:10.1111/cas.13433 · Cited by 168
“In addition to IL-6, elevated levels of sIL-6R have been proposed as a poor prognostic factor in patients with certain types of cancer,(27) because they promote IL-6 stabilization and amplify IL-6 signaling through protecting IL-6 from rapid degradation in vivo.(26) sIL-6R is produced by the shedding of membrane-bound…”
BackgroundMiao, L., Qi, J., Zhao, Q., Wu, Q.-N., Wei, D., Wei, X., Liu, J., Chen, J., Zeng, Z.-L., Ju, H., et al. (2019) · Theranostics · doi:10.7150/thno.37745 · Cited by 170
“immune responses and cancer progression [43].”
BackgroundA new era for the treatment of inflammatory autoimmune diseases by interleukin-6 blockade strategy
Tanaka, T., Narazaki, M., Ogata, A., & Kishimoto, T. (2014) · Seminars in Immunology · doi:10.1016/j.smim.2014.01.009 · Cited by 166
Shahini, A., & Shahini, A. (2022) · Journal of Cell Communication and Signaling · doi:10.1007/s12079-022-00695-x · Cited by 171
“1997; Rose-John 2012).”
BackgroundThe soluble interleukin 6 receptor: advanced therapeutic options in inflammation
Rose‐John, S. (2017) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.782 · Cited by 169
Self-citationIL ‐6 in diabetes and cardiovascular complications
Qu, D. C., Liu, J., Lau, C. W., & Huang, Y. (2014) · British Journal of Pharmacology · doi:10.1111/bph.12713 · Cited by 166
“The anti-inflammatory and regenerative activities of IL-6 are generally mediated by the classic signalling mode, whereas pro-inflammatory responses in many pathological conditions involve trans-signalling (Rabe et al., 2008; Rose-John, 2012).”
BackgroundThe genetics of asthma and the promise of genomics-guided drug target discovery
Elhusseini, Z. W., Gosens, R., Dekker, F. J., & Koppelman, G. H. (2020) · The Lancet Respiratory Medicine · doi:10.1016/s2213-2600(20)30363-5 · Cited by 172
Interleukin-6 signalling in health and disease
Rose‐John, S. (2020) · F1000Research · doi:10.12688/f1000research.26058.1 · Cited by 167
Self-citationPu, C., Liu, C., Liang, C., Yen, Y., Chen, S., Jiang‐Shieh, Y., Chien, C. L., Chen, Y.-C., & Chen, Y.-L. (2017) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2016.12.030 · Cited by 160
Current challenges and emerging opportunities of CAR-T cell therapies
Abreu, T. R., Fonseca, N. A., Gonçalves, N., & Moreira, J. N. (2019) · Journal of Controlled Release · doi:10.1016/j.jconrel.2019.12.047 · Cited by 159
Favalli, E. G. (2020) · Rheumatology and Therapy · doi:10.1007/s40744-020-00219-2 · Cited by 164
“The IL-6/sIL-6R/ gp130 complex then dimerizes as described above to initiate signaling in a much wider range of cells [19, 21].”
BackgroundInfluentialThe role of inflammation in diabetic eye disease
Mesquida, M., Drawnel, F., & Fauser, S. (2019) · Seminars in Immunopathology · doi:10.1007/s00281-019-00750-7 · Cited by 159
The Therapeutic Landscape of Rheumatoid Arthritis: Current State and Future Directions
Shams, S., Martinez, J. M., Dawson, J. R. D., Flores, J. C., Gabriel, M., Garcia, G., de Guevara, A. L., Murray, K. M., Pacifici, N. J., Vargas, M. V., et al. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.680043 · Cited by 162
“Studies have associated IL-6’s pro-inflammatory responses with signaling through its soluble receptor, whereas signaling through its transmembrane IL-6R, IL-6’s canonical signaling pathway, is needed for its regenerative or anti-inflammatory properties(Rose-John, 2012).”
BackgroundGupta, S., Hirota, M., Waugh, S. M., Murakami, I., Suzuki, T., Muraguchi, M., Shibamori, M., Ishikawa, Y., Jarvis, T. C., Carter, J. D., et al. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.532580 · Cited by 151
“This is also known as the trans-signaling pathway (8, 9).”
BackgroundHarbour, S. N., DiToro, D. F., Witte, S. J., Zindl, C. L., Gao, M., Schoeb, T. R., Jones, G. W., Jones, S. A., Hatton, R. D., & Weaver, C. T. (2020) · Science Immunology · doi:10.1126/sciimmunol.aaw2262 · Cited by 151
“This is in line with the view that classic and trans-signaling promote anti- and proinflammatory responses, respectively (84), and suggests that inhibiting classic signaling and, thus, the protective effects of IL-6 may exacerbate disease.”
BackgroundGarbers, C., Monhasery, N., Aparicio-Siegmund, S., Lokau, J., Baran, P., Nowell, M. A., Jones, S. A., Rose-John, S., & Scheller, J. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2014.05.018 · Cited by 155
“An increased proteolytic conversion of IL-6R due to the Asp358Ala SNP might therefore contribute to this increased buffer capacity of IL-6 and to overall reduced IL-6 activity [5,38].”
BackgroundSelf-citationNovel antiatherosclerotic therapies
Libby, P., & Everett, B. M. (2019) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.118.310958 · Cited by 145
Zhang, C., Xin, H., Zhang, W., Yazaki, P. J., Zhang, Z., Le, K., Li, W., Lee, H., Kwak, L. W., Forman, S. J., et al. (2016) · Immunity · doi:10.1016/j.immuni.2016.04.003 · Cited by 147
“…microenvironment conditions, IL-6R is known to be cleaved from the surface of the cell to form soluble IL-6Ra (sIL-6Ra), which nevertheless can activate IL-6 signaling and Stat3 by virtue of ‘‘IL-6 trans-signaling’’ (Neu- rath and Finotto, 2011; Rose-John, 2012; Rose-John and Neu- rath, 2004).”
BackgroundMolecular Mechanisms of Cancer-Induced Sleep Disruption
Walker, W. H., II, & Borniger, J. C. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20112780 · Cited by 149
“It is important to note that IL-6 signaling can occur via classical or trans-signaling pathways [140].”
BackgroundThe JAK/STAT Pathway in Skeletal Muscle Pathophysiology
Moresi, V., Adamo, S., & Berghella, L. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00500 · Cited by 145
“Frontiers in Physiology | www.frontiersin.org 7 April 2019 | Volume 10 | Article 500 the membrane bound IL-6R, which instead is needed for regenerative or anti-inflammatory activities of the cytokine (Scheller et al., 2011; Rose-John, 2012; Belizário et al., 2016).”
BackgroundPhysiological effects of modulating the interleukin-6 axis
Schett, G. A. (2018) · Rheumatology · doi:10.1093/rheumatology/kex513 · Cited by 148
The JAK-STAT pathway: from structural biology to cytokine engineering
Lv, Y., Qi, J., Babon, J. J., Cao, L., Fan, G.-H., Lang, J., Zhang, J., Mi, P., Kobe, B., & Wang, F. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01934-w · Cited by 157
Tocilizumab in the treatment of rheumatoid arthritis: an evidence-based review and patient selection
Biggioggero, M., Crotti, C., Becciolini, A., & Favalli, E. G. (2018) · Drug Design Development and Therapy · doi:10.2147/dddt.s150580 · Cited by 147
“52 IL-6 may interact with the membrane-bound subunit in the classical (cis-) signaling pathway which activates the acute-phase response and is involved in metabolic effects, infection defense, and tissue regeneration.”
Riegler, L. L., Jones, G. P., & Lee, D. W. (2019) · Therapeutics and Clinical Risk Management · doi:10.2147/tcrm.s150524 · Cited by 148
“Siltuximab is another monoclonal antibody that blocks IL-6 signaling by binding IL-6 itself and preventing it from activating immune effector cells through either the trans or cis mechanisms.(38) Siltuximab has a higher affinity for IL-6 than tocilizumab has for the IL-6R making it an attractive tool in managing CRS.”
BackgroundMethodPorter, R. J., Arends, M. J., Churchhouse, A. M. D., & Din, S. (2021) · Journal of Crohn s and Colitis · doi:10.1093/ecco-jcc/jjab102 · Cited by 149
Myokines and Resistance Training: A Narrative Review
Zunner, B. E. M., Wachsmuth, N. B., Eckstein, M. L., Scherl, L., Schierbauer, J., Haupt, S., Stumpf, C., Reusch, L., & Moser, O. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23073501 · Cited by 146
“Furthermore, there are different pathways following the activation of IL-6 receptor (IL-6R) that are responsible for either proinflammatory or anti-inflammatory effects of IL-6 [58,59].”
BackgroundDistinct Effects of IL-6 Classic and Trans -Signaling in Bone Fracture Healing
Prystaz, K., Kaiser, K., Kovtun, A., Haffner-Luntzer, M., Fischer, V., Rapp, A. E., Liedert, A., Strauss, G., Waetzig, G. H., Rose-John, S., et al. (2018) · The American Journal of Pathology · doi:10.1016/j.ajpath.2017.10.011 · Cited by 142
“25,27 To our knowledge, studies discriminating between the roles of both IL-6 signaling pathways in the in fl ammatory response to fracture and bone healing are lacking.”
BackgroundInfluentialSelf-citationProteolytic Cleavage Governs Interleukin-11 Trans-signaling
Lokau, J., Nitz, R., Agthe, M., Monhasery, N., Aparicio-Siegmund, S., Schumacher, N., Wolf, J., Möller‐Hackbarth, K., Waetzig, G. H., Grötzinger, J., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.01.053 · Cited by 135
Self-citationThe role of the interleukin (IL)-6/IL-6 receptor axis in cancer
Taher, M. Y., Davies, D. M., & Maher, J. F. (2018) · Biochemical Society Transactions · doi:10.1042/bst20180136 · Cited by 138
Diabetes and Sepsis: Risk, Recurrence, and Ruination
Frydrych, L. M., Fattahi, F., He, K., Ward, P. A., & Delano, M. J. (2017) · Frontiers in Endocrinology · doi:10.3389/fendo.2017.00271 · Cited by 141
“In the paradigm of inflammation within obesity, it is hypothesized that IL-6 enhances the prevailing inflammation, thus precipitating insulin resistance and leading to further micro- and macrovascular complications (245).”
BackgroundNițulescu, G. M., Păunescu, H., Moschos, S. A., Petrakis, D., Nițulescu, G., Ion, D., Spandidos, D. A., Νikolouzakis, Τ. Κ., Drakoulis, N., & Tsatsakis, A. M. (2020) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2020.4608 · Cited by 135
“Tocilizumab is a humanized monoclonal antibody (mAb) directed against the IL-6 receptor used as an effective therapeutic agent for rheumatoid arthritis patients who do not respond to methotrexate (176).”
InfluentialInterplay of skeletal muscle and adipose tissue: sarcopenic obesity.
Park, M., & Choi, K. M. (2023) · Metabolism: Clinical and Experimental · doi:10.1016/j.metabol.2023.155577 · Cited by 106
Santoro, A., Pini, E., Scurti, M., Palmas, M. G., Berendsen, A. A. M., Brzozowska, A., Pietruszka, B., Szczecińska, A., Cano, N., Meunier, N., et al. (2013) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2013.12.001 · Cited by 129
“…and anti-inflammatory effects, depending on the signalling pathway that is activated, i.e. ‘‘direct’’ through IL-6 receptor present in a limited number of cells or ‘‘trans-signalling’’ mediated by a previous binding to sIL-6R and then to gp130 present in a variety of cell types (Rose-John, 2012).”
Nääv, Å., Erlandsson, L., Isaxon, C., Frostner, E. Å., Ehinger, J. K., Sporre, M. K., Krais, A. M., Strandberg, B., Lundh, T., Elmér, E., et al. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00075 · Cited by 129
“It has effects on both cells from the immune system and other cell types, such as hepatocytes (48).”
BackgroundRoan, F., Stoklasek, T. A., Whalen, E., Molitor, J. A., Bluestone, J. A., Buckner, J. H., & Ziegler, S. F. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1501491 · Cited by 135
“as well as ILC2, which can also express significant levels of IL6Ra, may serve as sources of soluble IL-6Ra, which can amplify IL-6 responses in inflammatory conditions (75).”
Background
Metadata
- Authors
- Rose-John, S.
- Venue
- International Journal of Biological Sciences
- Publisher
- Ivyspring International Publisher
- Published
- 2012
- Volume
- 8
- Issue
- 9
- Pages
- 1237-1247
- ISSN
- 1449-2288 (ISSN-L)
- PMC
- PMC3491447
- OpenAlex
- W2100478793
- Cited by
- 1,040
- References
- 110
- Citations by year
- 2026: 87 · 2025: 98 · 2024: 77 · 2023: 73 · 2022: 94 · 2021: 108 · 2020: 107 · 2019: 76 · 2018: 72 · 2017: 65 · 2016: 49 · 2015: 48 · 2014: 54 · 2013: 30 · 2012: 1
- FWCI
- 4.28
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc
- Locations
- International Journal of Biological Sciences (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (SFB654, SFB841, project C1; SFB877, project A1, SFB 877, SFB841 project C1, SFB877, project A1, SFB 841)
- Exzellenzclusters Entzündungsforschung
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- interleukin-6, IL-6 trans-signaling, soluble IL-6 receptor, gp130, IL-6 receptor, pro-inflammatory activity, cytokine signaling, liver regeneration, anti-inflammatory activity, IL-6 inhibition, hepatocytes, leukocytes
- MeSH terms
- Animals, Humans, Mice, Transgenic, Models, Biological, Solubility, Signal Transduction, Interleukin-6, Receptors, Interleukin-6, Cytokine Receptor gp130, Mice
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