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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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“In addition to functioning as a membrane-bound receptor, IL-6R can also exist as a soluble form (sIL-6R), originating from the proteolysis catalyzed by the protease “a disintegrin and metalloproteinase domain-containing protein 17” (ADAM17) [52,53].”
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“IL-6 signaling can occur at local or systemic levels.(62)”
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“Conversely, an excess of sgp130, as provided by exogenous sgp130, prevents trans-signaling (Nowell et al., 2003; Rose-John, 2012).”
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“IL-6R expression, and thus IL-6 classic signaling, is largely restricted to immune cells and hepatocytes (Rose-John, 2012; Tanaka et al., 2014).”
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“Given that our study utilized Il6 gene knockout mice, which abrogates both the classical and trans-signaling functions of IL-6 [55], the specific signaling mechanism through which Il6 knockout leads to the attenuation of the STAT3-cGAS-STING pathway and the subsequent reduction in Aβ burden in Il6…”
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“IL-6 may have reached even higher levels at local areas in vessels, which may represent a local increase of trans-signalling, and a proinflammatory effect (Rose-John, 2012).”
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“ing or trans-signaling, respectively (Figure 1) [30].”
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“Its success in RA treatment underscores IL-6 ’ s signi fi cance, motivating the exploration of novel therapeutic avenues (9, 10).”
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“On the other hand, if the soluble IL-6 receptor/ IL-6 complex associates with gp130a, expressed on all cells, they immediately initiate an inflammatory cascade, so-called “trans-signaling” [44, 45].”
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“In physiological conditions, the concentration of sgp130 is around 400 ng ml−1 (Rose-John, 2012) and thus higher than the concentration of the IL-6/sIL-6R complex and also has a higher affinity for the IL-6/sIL-6R complex than the affinity of IL-6 for the sIL-6R.”
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“The dual role of this cytokine, at least in part, depends on the nature of the signaling pathway induced: IL-6 “classical” cis-signaling involving membrane IL-6R is believed to maintain body homeostasis, whereas IL-6 trans-signaling via the soluble IL-6 receptor mediates most pro-inflammatory responses (34, 35).”
BackgroundInflammation and immunity in the pathogenesis of hypoxic pulmonary hypertension
Ye, Y., Xu, Q., & Wuren, T. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1162556 · Cited by 54
Díaz-Torné, C., Ortiz, M. A., Moya, P., Hernández, M. V., Reina, D., Castellví, I., de Agustín, J., de la Fuente, D., Corominas, H., Sanmartí, R., et al. (2017) · Seminars in Arthritis & Rheumatism · doi:10.1016/j.semarthrit.2017.10.022 · Cited by 47
Reappraisal of Inflammatory Biomarkers in Heart Failure
Chaikijurajai, T., & Tang, W. H. W. (2020) · Current Heart Failure Reports · doi:10.1007/s11897-019-00450-1 · Cited by 54
Sudarsanam, H., Buhmann, R., & Henschler, R. (2022) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2022.886637 · Cited by 54
“IL-6/IL-6R binds to gp130 and initiates signaling through its intracellular domain via the JAK/STAT pathway (Rose-John et al., 2006; Rose-John, 2012).”
BackgroundHashimoto, S., Hashimoto, A., Muromoto, R., Kitai, Y., Oritani, K., & Matsuda, T. (2022) · Cells · doi:10.3390/cells11162618 · Cited by 51
“sIL6R released within the TME can induce STAT3 activation in gp130-expressing cells by trans-signaling [64].”
BackgroundIL-6 is produced by adipose-derived stromal cells and promotes osteogenesis
Huh, J.-E., & Lee, S. Y. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2013.06.025 · Cited by 52
“Thus, either the membrane-bound or the soluble IL-6R mediates the IL-6 signal in cells, as virtually all cells in the body express gp130 [17].”
BackgroundGrønhøj, M., Clausen, B., Fenger, C., Lambertsen, K., & Finsen, B. (2017) · Brain, behavior, and immunity · doi:10.1016/j.bbi.2017.05.019 · Cited by 51
Hong, R., Hu, Y., & Huang, H. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.627764 · Cited by 52
“IL-6 triggers the cytokine storm by binding to membrane-bound IL-6 receptors, which can form a complex with gp130 and initiate intracellular signaling in cells with/without membrane-bound IL-6 receptors (69, 70).”
BackgroundHop, H. T., Huy, T. X. N., Reyes, A. W. B., Arayan, L. T., Vu, S. H., Min, W., Lee, H.-J., Kang, C. K., Kim, D. H., Tark, D. S., et al. (2019) · Infection and Immunity · doi:10.1128/iai.00431-19 · Cited by 50
“Because the regulatory functions of IL-6 in the inflammatory response and lysosomemediated killing changed in a time-dependent manner, and because the binding of IL-6 to the IL-6R/Gp130 complex has been previously demonstrated to activate JAK/STAT pathways (16, 17), we speculated that the functional change in IL-6 in…”
BackgroundTargeting IL-6 or IL-6 Receptor in Rheumatoid Arthritis: What Have We Learned?
Avci, A. B., Feist, E., & Burmester, G. R. (2024) · BioDrugs · doi:10.1007/s40259-023-00634-1 · Cited by 50
“…such as rheumatoid arthritis, this elevation is more constrained, and serum levels of sIL-6R and sgp130 remain relatively consistent with serum IL-6 levels [11, 19, 20]. sIL-6R and sgp130 together serve as a buffer against high IL-6 levels and act as a barrier against inflammatory diseases.”
BackgroundAll roads lead to IL-6: A central hub of cardiometabolic signaling
Libby, P., & Rocha, V. Z. (2018) · International Journal of Cardiology · doi:10.1016/j.ijcard.2018.02.062 · Cited by 49
“The alpha subunit of the IL-6 receptor can undergo proteolytic cleavage by a metalloenzyme, ADAM-17, to release a soluble form into the fluid extracellular space [14].”
BackgroundPyroptosis: A New Insight Into Eye Disease Therapy
Zhang, Y., Jiao, Y., Li, X., Gao, S., Zhou, N., Duan, J., & Zhang, M. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.797110 · Cited by 51
Müller, S. A., Shmueli, M. D., Feng, X. M., Tüshaus, J., Schumacher, N., Clark, R., Smith, B. E., Chi, A., Rose‐John, S., Kennedy, M. E., et al. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00596-6 · Cited by 51
“gp130 is a cell surface cytokine receptor and has a dual role in IL-6 signaling [71, 78, 79].”
BackgroundSelf-citationNavigating IL-6: From molecular mechanisms to therapeutic breakthroughs
Swaroop, A. K., Negi, P., Kar, A., Mariappan, E., Natarajan, J., Namboori, P. K. K., & Selvaraj, J. (2024) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2023.12.007 · Cited by 48
Maes, M. H. J., Nowak, G., Caso, J. R., Leza, J. C., Song, C., Kubera, M., Klein, H. C., Gałecki, P., Noto, C. D. S., Glaab, E., et al. (2015) · Molecular Neurobiology · doi:10.1007/s12035-015-9183-5 · Cited by 50
Differential modulation of innate immunity in vitro by probiotic strains of Lactobacillus gasseri
Luongo, D., Miyamoto, J., Bergamo, P., Nazzaro, F., Baruzzi, F., Sashihara, T., Tanabe, S., & Rossi, M. (2013) · BMC Microbiology · doi:10.1186/1471-2180-13-298 · Cited by 48
The soluble interleukin-6 receptor and related proteins
Rose‐John, S. (2015) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2015.07.001 · Cited by 51
Self-citationIL-6 and diabetic kidney disease
Zhang, L., Xu, F., & Hou, L. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1465625 · Cited by 55
Characterization of the male ApcMin/+ mouse as a hypogonadism model related to cancer cachexia
White, J. P., Puppa, M. J., Narsale, A. A., & Carson, J. (2013) · Biology Open · doi:10.1242/bio.20136544 · Cited by 48
“We next treated Apc mice exhibiting initial body weight loss with an IL-6 receptor antibody for two weeks to block systemic IL-6 signaling including both classical and trans IL-6 signaling (Rose-John, 2012), during a pivotal time point in the progression of cachexia.”
MethodTemperature and adaptive immunity
Appenheimer, M. M., & Evans, S. S. (2018) · Handbook of clinical neurology · doi:10.1016/b978-0-444-63912-7.00024-2 · Cited by 48
CDK8 Fine-Tunes IL-6 Transcriptional Activities by Limiting STAT3 Resident Time at the Gene Loci
Martínez‐Fábregas, J., Wang, L., Pöhler, E., Cozzani, A., Wilmes, S., Kazemian, M., Mitra, S., & Moraga, I. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.108545 · Cited by 49
Combination of STING and TLR 7/8 Agonists as Vaccine Adjuvants for Cancer Immunotherapy
Bhatnagar, S., Revuri, V., Shah, M., Larson, P. G., Shao, Z., Yu, D., Prabha, S., Griffith, T. S., Ferguson, D. M., & Panyam, J. (2022) · Cancers · doi:10.3390/cancers14246091 · Cited by 46
Roles of Myeloid-Derived Suppressor Cells in Cancer Metastasis: Immunosuppression and Beyond
Khoshbin, A. P., Eskian, M., Keshavarz‐Fathi, M., & Rezaei, N. (2018) · Archivum Immunologiae et Therapiae Experimentalis · doi:10.1007/s00005-018-0531-9 · Cited by 46
Ni, R., Jiang, L., Zhang, C., Liu, M., Luo, Y., Hu, Z., Mou, X., & Zhu, Y. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24098358 · Cited by 49
Interleukin-6 and pulmonary hypertension: from physiopathology to therapy
Xu, W., Wu, Q. D., He, W., Wang, S., Zhao, Y., Huang, J.-X., Yan, X., & Jiang, R. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1181987 · Cited by 45
Aryappalli, P., Shabbiri, K., Masad, R. J., Al-Marri, R. H., Haneefa, S. M., Mohamed, Y. A., Arafat, K., Attoub, S., Cabral-Marques, O., Ramadi, K. B., et al. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20184340 · Cited by 45
“The membrane form of IL-6Rα is expressed only on hepatocytes and some immune cells, such as neutrophils and monocytes/macrophages, and has been suggested to be primarily important for the anti-inflammatory and regenerative activities of IL-6 [44].”
BackgroundOmere, C. I., Richardson, L., Saade, G. R., Bonney, E. A., Kechichian, T. B., & Menon, R. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00891 · Cited by 45
“In both cases, the binding between IL-6 and mIL-6R or sIL-6R is followed by homodimerization of the β-subunit of glycoprotein 130 (gp130) (Lee et al., 2011; Rose-John, 2012), the signal transduction subunit.”
BackgroundA 3D‐Bioprinted Multiple Myeloma Model
Wu, D., Wang, Z., Li, J., Song, Y. Y., Pérez, M. E. M., Wang, Z., Cao, X., Cao, C., Maharjan, S., Anderson, K. C., et al. (2021) · Advanced Healthcare Materials · doi:10.1002/adhm.202100884 · Cited by 47
Zeng, J., Chen, S., Li, C., Ye, Z., Lin, B., Liang, Y., Wang, B., Ma, Y., Chai, X., Zhang, X., et al. (2020) · Journal of Cancer · doi:10.7150/jca.37932 · Cited by 44
“It can not only act intrinsically on tumor cells to promote cell proliferation, survival, epithelial-mesenchymal transition (EMT), cancer stem cell (CSC) properties, migration, invasion, and metastasis [12-16], but also act extrinsically on other type of cells within the complex TME to sustain a pro-tumor microenviron…”
BackgroundAdams, R., Burnley, R. J., Valenzano, C. R., Qureshi, O. S., Doyle, C., Lumb, S., Lopez, M. D. C., Griffin, R., McMillan, D., Taylor, R. D., et al. (2017) · Scientific Reports · doi:10.1038/srep37716 · Cited by 44
Провоспалительные цитокины и заживление кожных ран у мышей
Nosenko, M. A., Амбарян, С. Г., & Друцкая, М. С. (2019) · Molecular Biology · doi:10.1134/s0026898419050136 · Cited by 46
A Potential Role of IL-6/IL-6R in the Development and Management of Colon Cancer
Turano, M., Cammarota, F., Duraturo, F., Izzo, P., & Rosa, M. D. (2021) · Membranes · doi:10.3390/membranes11050312 · Cited by 44
“It has also been suggested to be a potential therapeutic target in CRC [38,44,57].”
BackgroundResultInfluentialBlocking only the bad side of IL-6 in inflammation and cancer
Rose‐John, S. (2021) · Cytokine · doi:10.1016/j.cyto.2021.155690 · Cited by 44
Self-citationMeprin Metalloproteases Inactivate Interleukin 6
Keiffer, T. R., & Bond, J. S. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.546309 · Cited by 44
“IL-6 is a strong proinflammatory cytokine, although it can also act as an anti-inflammatory mediator in some contexts (1).”
BackgroundCrosstalk between FLS and chondrocytes is regulated by HIF-2α-mediated cytokines in arthritis
Huh, Y., Lee, G., Song, W.-H., Koh, J., & Ryu, J.-H. (2015) · Experimental and Molecular Medicine · doi:10.1038/emm.2015.88 · Cited by 43
Strand, V., Boklage, S., Kimura, T., Joly, F., Boyapati, A., & Msihid, J. (2020) · Arthritis Research & Therapy · doi:10.1186/s13075-020-02344-3 · Cited by 45
A New Approach to the Management of COVID-19. Antagonists of IL-6: Siltuximab
Villaescusa, L., Zaragozá, F., Gayo-Abeleira, I., & Zaragozá, C. (2022) · Advances in Therapy · doi:10.1007/s12325-022-02042-3 · Cited by 44
Jasiewicz, M., Knapp, M., Waszkiewicz, E., Ptaszyńska‐Kopczyńska, K., Szpakowicz, A., Sobkowicz, B., Musial, W. J., & Kamiński, K. A. (2015) · Cytokine · doi:10.1016/j.cyto.2015.06.018 · Cited by 43
Kaczmarski, P., Karuga, F. F., Szmyd, B. M., Sochal, M., Białasiewicz, P., Strzelecki, D., & Gabryelska, A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23169080 · Cited by 49
“IL-6 can activate neurons through membrane-bound (classic signaling) and soluble forms of IL-6R (trans-signaling) [61].”
BackgroundTargeting IL-6 for the treatment of rheumatoid arthritis: Phase II investigational drugs
Semerano, L., Thiolat, A., Minichiello, É., Clavel, G., Bessis, N., & Boissier, M. (2014) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2014.912276 · Cited by 42
“IL-6 trans-signaling conveys pro-inflammatory signals to cells that do not express mIL-6R and is therefore primarily implicated in local tissular inflammation [28].”
BackgroundGarbuzova-Davis, S. N., Ehrhart, J. C., Sanberg, P. R., & Borlongan, C. V. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19020423 · Cited by 42
“Numerous comprehensive reviews [112–117] discuss mediation of anti-inflammatory functions of IL-6 by the classic signaling pathway [112,113], whereas pro-inflammatory IL-6 responses are facilitated via the trans-signaling pathway [113,115,117].”
BackgroundInfluential
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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