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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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.
“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]
The “IL-6 Trans-signaling is pro-inflammatory” section distinguishes pro-inflammatory trans-signaling through sIL-6R from regenerative or anti-inflammatory classic signaling through membrane-bound IL-6R. The blood-buffer section also discusses how receptor and cytokine availability, including unknown local levels, affect signaling. The “Transgenic strategies” section says prolonged signaling changes cellular responses, but does not establish signal duration as a determinant of whether IL-6 is protective or pathogenic. Page numbers are unavailable in our copy. (LLM, conf=0.84)
Experimental — accuracy not yet measuredHyIL-6 triggers signaling in all cells expressing gp130, producing a more robust and homogenous signaling output.
“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
The Introduction (page not provided) says that gp130-expressing cells can be stimulated through IL-6 trans-signaling even without membrane IL-6R. The section “Protein tools to study IL-6 trans-signaling” reports that Hyper-IL-6 is 100–1,000 times more active than separate IL-6 and sIL-6R on gp130-expressing cells, supporting a more robust response. It does not establish that the signaling output is homogeneous across those cells. (LLM, conf=0.87)
Experimental — accuracy not yet measuredClassic and trans-signaling promote anti- and pro-inflammatory responses, respectively.
“This is in line with the view that classic and trans-signaling promote anti- and pro-inflammatory responses, respectively (85)”
From T <sub>H</sub> 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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“It was shown that this local regulation of sIL-6R activity and IL-6 trans-signaling contributes to the status of the T-cell response [31].”
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Self-citationDann, S. M., Spehlmann, M. E., Hammond, D., Iimura, M., Hase, K., Choi, L. J., Hanson, E. M., & Eckmann, L. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.10.6816 · Cited by 176 · cited 2× · see citing works
“Activities of IL-6 can be regenerative and protective during infection and inflammation [76, 77, 96].”
BackgroundPeters, M., Schirmacher, P., Goldschmitt, J., Odenthal, M., Peschel, C., Fattori, E., Ciliberto, G., Dienes, H., Buschenfelde, K. Z. Z., & Rose-John, S. (1997) · Journal of Experimental Medicine · doi:10.1084/jem.185.4.755 · Cited by 176 · 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-citationCutting Edge: Soluble IL-6R Is Produced by IL-6R Ectodomain Shedding in Activated CD4 T Cells
Briso, E. M., Dienz, O., & Rincón, M. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.11.7102 · Cited by 165 · cited 1× · see citing works
“Interestingly, sIL-6R is produced by naïve and memory CD4-T-cells when the T-cell receptor is activated [30].”
BackgroundAudet, J., Miller, C., Rose‐John, S., Piret, J. M., & Eaves, C. J. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.98.4.1757 · Cited by 137 · see citing works
Self-citationSuthaus, J., Stuhlmann-Laeisz, C., Tompkins, V., Rosean, T. R., Klapper, W., Tosato, G., Janz, S., Scheller, J., & Rose-John, S. (2012) · Blood · doi:10.1182/blood-2011-09-377705 · Cited by 131 · cited 2× · see citing works
“Furthermore, in mice transgenic for vIL-6 we observed development of a phenotype, which closely resembled multicentric Castleman disease [93].”
BackgroundSelf-citationMaione, D., Carlo, E. D., Li, W., Musiani, P., Modesti, A., Peters, M., Rose‐John, S., Rocca, C. D., Tripodi, M., Lazzaro, D., et al. (1998) · The EMBO Journal · doi:10.1093/emboj/17.19.5588 · Cited by 128 · cited 1× · see citing works
“It turned out that only double transgenic IL-6/sIL-6R mice showed massive extramedullary hematopoiesis [40] together with hepatocellular proliferation [41, 42].”
BackgroundSelf-citationDevelopment of progressive kidney damage and myeloma kidney in interleukin-6 transgenic mice
Fattori, E., Rocca, C. D., Costa, P., Giorgio, M., Dente, B., Pozzi, L., & Ciliberto, G. (1994) · Blood · doi:10.1182/blood.v83.9.2570.2570 · Cited by 124 · see citing works
STAT3 activation via interleukin 6 trans-signalling contributes to ileitis in SAMP1/Yit mice
Mitsuyama, K., Matsumoto, S., Rose‐John, S., Suzuki, A., Hara, T., Tomiyasu, N., Handa, K., Tsuruta, O., Funabashi, H., Scheller, J., et al. (2006) · Gut · doi:10.1136/gut.2005.079343 · Cited by 120 · cited 1× · see citing works
“Intestinal Inflammation DSS-colitis, SAMP/YIT mouse model [98, 99]”
Self-citationDifferential shedding of the two subunits of the interleukin‐6 receptor
Müllberg, J., Dittrich, E., Graeve, L., Gerhartz, C., Yasukawa, K., Taga, T., Kishimoto, T., Heinrich, P. C., & Rose‐John, S. (1993) · FEBS Letters · doi:10.1016/0014-5793(93)80507-q · Cited by 116 · cited 1× · see citing works
“The soluble forms of sgp130 were found not to be generated by proteolytic cleavage [35] but rather by translation from alternatively spliced mRNA [36].”
BackgroundSelf-citationProtein kinase C activity is rate limiting for shedding of the interleukin-6 receptor
Müllberg, J., Schooltink, H., Stoyan, T., Heinrich, P. C., & Rose‐John, S. (1992) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(92)92272-y · Cited by 116 · cited 1× · see citing works
“Stimulation of the cells with the phorbol ester PMA induced complete loss of the IL-6R from the cell surface within 1 h [14, 20].”
BackgroundSelf-citationSleep enhances IL‐6 trans‐signaling in humans
Dimitrov, S., Lange, T., Benedict, C., Nowell, M. A., Jones, S. A., Scheller, J., Rose‐John, S., Born, J., Dimitrov, S., Lange, T., et al. (2006) · The FASEB Journal · doi:10.1096/fj.06-5754fje · Cited by 115 · cited 1× · see citing works
“It is thought that regulated generation of the sIL-6R occurs through shedding rather than through differential splicing [16].”
BackgroundSelf-citationvan Dam, M., Müllberg, J., Schooltink, H., Stoyan, T., Brakenhoff, J. P. J., Graeve, L., Heinrich, P. C., & Rose‐John, S. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)82467-x · Cited by 113 · see citing works
Self-citationIL-6 Receptor Independent Stimulation of Human gp130 by Viral IL-6
Müllberg, J., Geib, T., Jostock, T., Hoischen, S. H., Vollmer, P., Voltz, N., Heinz, D. W., Galle, P. R., Klouche, M., & Rose‐John, S. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.164.9.4672 · Cited by 110 · see citing works
Self-citationStudies on the structure and regulation of the human hepatic interleukin‐6 receptor
Rose‐John, S., Schooltink, H., Lenz, D., Erich, H. I. P. P., Dufhues, G., SCHMITZ, H., Schiel, X., Hirano, T., Kishimoto, T., & Heinrich, P. C. (1990) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1990.tb15548.x · Cited by 108 · cited 1× · see citing works
“This could be explained by the fact that the affinity of IL-6 to IL-6R is in the range of 1 nM whereas the complex of IL-6/IL-6R binds with 100 times higher affinity to gp130 [46].”
BackgroundSelf-citationIn Vivo and In Vitro Activities of the gp130-Stimulating Designer Cytokine Hyper-IL-6
Peters, M., Blinn, G., Solem, F. K., Fischer, M., Büschenfelde, K. M. Z., & Rose‐John, S. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.161.7.3575 · Cited by 104 · see citing works
Self-citationPore-forming toxins trigger shedding of receptors for interleukin 6 and lipopolysaccharide.
Walev, I., Vollmer, P., Palmer, M., Bhakdi, S., & Rose‐John, S. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.15.7882 · Cited by 102 · cited 1× · see citing works
“Subsequent studies established that treatment of cells with C-reactive protein (CRP) [22], bacterial toxins [23] and cholesterol depleting agents [24] as well as treatment of cells with bacterial metalloproteinases [25] induced shedding of the IL-6R.”
BackgroundSelf-citationRichards, P. J., Nowell, M. A., Horiuchi, S., McLoughlin, R. M., Fielding, C. A., Grau, S., Yamamoto, N., Ehrmann, M., Rose‐John, S., Williams, A. S., et al. (2006) · Arthritis & Rheumatism · doi:10.1002/art.21818 · Cited by 99 · cited 2× · see citing works
“It was shown that like the soluble, entire extracellular form of sgp130, the shorter form gp130-RAPS could bind the IL-6/sIL-6R complex [34].”
BackgroundSelf-citationVollmer, P., Walev, I., Rose‐John, S., & Bhakdi, S. (1996) · Infection and Immunity · doi:10.1128/iai.64.9.3646-3651.1996 · Cited by 98 · cited 1× · see citing works
“Subsequent studies established that treatment of cells with C-reactive protein (CRP) [22], bacterial toxins [23] and cholesterol depleting agents [24] as well as treatment of cells with bacterial metalloproteinases [25] induced shedding of the IL-6R.”
BackgroundSelf-citationHitting a complex target: an update on interleukin-6 trans-signalling
Waetzig, G. H., & Rose-John, S. (2012) · Expert opinion on therapeutic targets · doi:10.1517/14728222.2012.660307 · Cited by 96 · cited 2× · see citing works
“These experiments allowed to decide whether the gp130 driven disease model was based on IL-6 classic signaling or IL-6 trans-signaling [54, 55].”
BackgroundMethodSelf-citationInterleukin‐6 serum levels in patients with gynecological tumors
Scambia, G., Testa, U., Panici, P. B., Martucci, R., Foti, E., Petrini, M., Amoroso, M., Masciullo, V., Peschle, C., & Mancuso, S. (1994) · International Journal of Cancer · doi:10.1002/ijc.2910570305 · Cited by 93 · cited 1× · see citing works
“In healthy subjects, IL-6 plasma levels are barely detectable and range between 2-6 pg/ml [62].”
BackgroundViswanathan, S., Benatar, T., Rose‐John, S., Lauffenburger, D. A., & Zandstra, P. W. (2002) · Stem Cells · doi:10.1634/stemcells.20-2-119 · Cited by 92 · cited 1× · see citing works
“Cells, which would only respond to IL-6 in the presence of the sIL-6R include hematopoietic stem cells [47], many if not all neural cells [48, 49], smooth muscle cells [50] and embryonic stem cells [51, 52].”
BackgroundSelf-citationDittrich, E., Rose‐John, S., Gerhartz, C., Müllberg, J., Stoyan, T., Yasukawa, K., Heinrich, P. C., & Graeve, L. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)32267-6 · Cited by 91 · see citing works
Self-citationVirokines in the Pathogenesis of Cancer: Focus on Human Herpesvirus 8
Klouche, M., Carruba, G., CASTAGNETTA, L. A. M., & Rose‐John, S. (2004) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1322.038 · Cited by 91 · cited 1× · see citing works
“Since vIL-6 is the only known cytokine, which can stimulate gp130 without the help of an additional receptor protein, we speculated that vIL-6 was a natural model for IL-6 trans-signaling [89-91].”
BackgroundSelf-citationPadberg, F., Feneberg, W. W., Schmidt, S., Schwarz, M., Körschenhausen, D. A., Greenberg, B. D., Nolde, T., Müller, N., Trapmann, H., König, N., et al. (1999) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(99)00120-4 · Cited by 88 · see citing works
Schirmacher, P., Peters, M., Ciliberto, G., Blessing, M., Lotz, J., Büschenfelde, K. M. Z., & Rose‐John, S. (1998) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)65605-2 · Cited by 87 · see citing works
Self-citationDimerization of the cytokine receptors gp130 and LIFR analysed in single cells
Giese, B., Roderburg, C., Sommerauer, M., Wortmann, S. B., Metz, S., Heinrich, P. C., & Müller‐Newen, G. (2005) · Journal of Cell Science · doi:10.1242/jcs.02628 · Cited by 81 · cited 2× · see citing works
“The dimerization of gp130 found in the absence of receptor stimulation [57, 58] apparently does not position the transmembrane domains and cytoplasmic domains of gp130 in a way that is sufficient to induce gp130 signaling.”
BackgroundADAM17-mediated shedding of the IL6R induces cleavage of the membrane stub by γ-secretase
Chalaris, A., Gewiese, J., Paliga, K., Fleig, L., Schneede, A., Krieger, K., Rose‐John, S., & Scheller, J. (2009) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2009.12.001 · Cited by 73 · cited 1× · see citing works
“Since shedding of the IL-6R is mainly governed by the protease ADAM17 [14, 80], we speculate that ADAM17 has a decisive role in inflammation and cancer [17] (Fig.”
BackgroundSelf-citationStuhlmann-Laeisz, C., Lang, S., Chalaris, A., Krzysztof, P., Enge, S., Eichler, J., Klingmüller, U., Samuel, M., Ernst, M., Rose-John, S., et al. (2006) · Molecular Biology of the Cell · doi:10.1091/mbc.e05-12-1129 · Cited by 71 · cited 3× · see citing works
“To address this question a gp130 cDNA was constructed, in which the entire region coding for the extracellular portion was replaced by DNA sequences coding for the leucine-zipper from the Jun protein [59, 60].”
BackgroundMethodSelf-citationThe interleukin 6 pathway and atherosclerosis
Scheller, J., & Rose‐John, S. (2012) · The Lancet · doi:10.1016/s0140-6736(12)61246-x · Cited by 68 · see citing works
Self-citationTGF-beta suppresses tumor progression in colon cancer by inhibition of IL–6 trans-signaling
Becker, C., Fantini, M. C., Schramm, C., Lehr, H., Wirtz, S. J., Becker, A., Burg, J., Strand, S., Kießlich, R., Huber, S., et al. (2004) · Zeitschrift für Gastroenterologie · doi:10.1055/s-2004-831593 · Cited by 67 · see citing works
Self-citationNo inhibition of IL-27 signaling by soluble gp130
Scheller, J., Schuster, B., Hölscher, C., Yoshimoto, T., & Rose‐John, S. (2004) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2004.11.098 · Cited by 66 · cited 3× · see citing works
“Interestingly, gp130 is also a receptor subunit of the receptor complexes for IL-11, ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), oncostatin M (OSM), cardiotrophin-1 (CT-1), cardiotrophin like cytokine (CLC) and IL-27.”
BackgroundInfluentialSelf-citationSodenkamp, J., Waetzig, G. H., Scheller, J., Seegert, D., Grötzinger, J., Rose‐John, S., Ehlers, S., & Hölscher, C. (2012) · Immunobiology · doi:10.1016/j.imbio.2012.01.015 · Cited by 66 · cited 1× · see citing works
“whereas treatment with neutralizing TNFα-antibodies resulted in a 10-100 fold increase in mycobacterial colony forming units in the respective organs [75].”
BackgroundSelf-citationZhang, J., Zhang, Y., Owczarek, C. M., Ward, L. D., Moritz, R. L., Simpson, R. J., Yasukawa, K., & Nicola, N. A. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.17.10798 · Cited by 63 · cited 2× · see citing works
“This form of sgp130 called gp130-RAPS only comprises the Ig-like N-terminal domain as well as the cytokine binding domain of gp130 and therefore has a molecular weight of only around 50 kDa [33].”
BackgroundMeads, M. B., & Medveczky, P. G. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m407382200 · Cited by 62 · see citing works
Finotto, S., Eigenbrod, T., Karwot, R., Boross, I., Doganci, A., Ito, H., Nishimoto, N., Yoshizaki, K., Kishimoto, T., Rose‐John, S., et al. (2007) · International Immunology · doi:10.1093/intimm/dxm037 · Cited by 60 · cited 1× · see citing works
“Asthma Late-phase murine asthma model after OVA sensitization [67, 102]”
BackgroundSelf-citationgp130 dimerization in the absence of ligand: Preformed cytokine receptor complexes
Tenhumberg, S., Schuster, B., Zhu, L., Kovaleva, M., Scheller, J., Kallen, K., & Rose‐John, S. (2006) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2006.05.173 · Cited by 58 · cited 2× · see citing works
“The dimerization of gp130 found in the absence of receptor stimulation [57, 58] apparently does not position the transmembrane domains and cytoplasmic domains of gp130 in a way that is sufficient to induce gp130 signaling.”
BackgroundSelf-citationAdam, N., Rabe, B., Suthaus, J., Grötzinger, J., Rose‐John, S., & Scheller, J. (2009) · Journal of Virology · doi:10.1128/jvi.01601-08 · Cited by 57 · cited 1× · see citing works
“This was confirmed by the structure of vIL-6 bound to the extracellular portion of gp130 [85] and by the definition of the amino acid sequences responsible for the ability of vIL-6 to directly bind to and activate gp130 [86].”
BackgroundSelf-citationHuman herpes virus 8 interleukin‐6 homologue triggers gp130 on neuronal and hematopoietic cells
Hoischen, S. H., Vollmer, P., März, P., Özbek, S., Götze, K. S. S., Peschel, C., Jostock, T., Geib, T., Müllberg, J., Mechtersheimer, S., et al. (2000) · European Journal of Biochemistry · doi:10.1046/j.1432-1327.2000.01389.x · Cited by 53 · cited 1× · see citing works
“Interestingly, it could be shown that vIL-6 directly bound to gp130 without the need of soluble of membrane bound IL-6R and that association with gp130 was sufficient to induce STAT3-dependent proliferation of cells [83, 84].”
BackgroundSelf-citationThe interleukin-6 pathway and atherosclerosis
Boekholdt, S. M., & Stroes, E. S. G. (2012) · The Lancet · doi:10.1016/s0140-6736(12)60361-4 · Cited by 48 · cited 1× · see citing works
“This effect of this single nucleotide polymorphism was explained with the loss of membrane bound IL-6R from hepatocytes, monocytes, and macrophages and a concomitant loss of IL-6 signaling in these cells [73].”
BackgroundSuthaus, J., Tillmann, A., Lorenzen, I., Bulanova, E., Rose‐John, S., & Scheller, J. (2010) · Molecular Biology of the Cell · doi:10.1091/mbc.e10-03-0240 · Cited by 44 · cited 2× · see citing works
“To address this question a gp130 cDNA was constructed, in which the entire region coding for the extracellular portion was replaced by DNA sequences coding for the leucine-zipper from the Jun protein [59, 60].”
BackgroundMethodSelf-citationKovaleva, M., Bußmeyer, I., Rabe, B., Grötzinger, J., Sudarman, E., Eichler, J., Conrad, U., Rose‐John, S., & Scheller, J. (2006) · Journal of Virology · doi:10.1128/jvi.00420-06 · Cited by 41 · see citing works
Self-citationThe human interleukin‐6 (IL‐6) receptor exists as a preformed dimer in the plasma membrane
Schuster, B., Meinert, W., Rose‐John, S., & Kallen, K. (2003) · FEBS Letters · doi:10.1016/s0014-5793(03)00154-6 · Cited by 40 · cited 1× · see citing works
“Interestingly, in a different study it had been observed that also the membrane bound IL-6R on cells was dimeric although the function of this dimerization so far remains unclear [61].”
BackgroundSelf-citationViral IL-6 Blocks Neutrophil Infiltration during Acute Inflammation1
Fielding, C., McLoughlin, R., Colmont, C. S., Kovaleva, M., Harris, D., Rose-John, S., Topley, N., & Jones, S. A. (2005) · Journal of Immunology · doi:10.4049/jimmunol.175.6.4024 · Cited by 39 · cited 1× · see citing works
“Indeed, it could be shown that vIL-6 affects neutrophil infiltration during acute inflammation in a similar way as the IL-6/sIL-6R complex [92].”
BackgroundSelf-citationViral Interleukin-6: Structure, pathophysiology and strategies of neutralization
Suthaus, J., Adam, N., Grötzinger, J., Scheller, J., & Rose‐John, S. (2010) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2010.10.016 · Cited by 38 · cited 1× · see citing works
“Since vIL-6 is the only known cytokine, which can stimulate gp130 without the help of an additional receptor protein, we speculated that vIL-6 was a natural model for IL-6 trans-signaling [89-91].”
BackgroundSelf-citationHuman herpesvirus 8-derived viral IL-6 induces PTX3 expression in Kaposi's sarcoma cells
Klouche, M., Brockmeyer, N. H., Knabbe, C., & Rose‐John, S. (2002) · AIDS · doi:10.1097/00002030-200205240-00001 · Cited by 38 · cited 1× · see citing works
“Since vIL-6 is the only known cytokine, which can stimulate gp130 without the help of an additional receptor protein, we speculated that vIL-6 was a natural model for IL-6 trans-signaling [89-91].”
BackgroundSelf-citationDiamant, M., Hansen, M., Rieneck, K., Svenson, M., Yasukawa, K., & Bendtzen, K. (1996) · Leukemia Research · doi:10.1016/0145-2126(95)00077-1 · Cited by 16 · cited 1× · see citing works
“The soluble forms of sgp130 were found not to be generated by proteolytic cleavage [35] but rather by translation from alternatively spliced mRNA [36].”
BackgroundDeLeo, F. R. (2007) · Blood · doi:10.1182/blood-2007-06-096677 · Cited by 14 · see citing works
Development of progressive kidney damage and myeloma kidney in interleukin-6 transgenic mice
Fattori, E., Rocca, C. D., Costa, P., et al. (1994) · Blood · doi:10.1182/blood.v83.9.2570.bloodjournal8392570 · Cited by 13 · cited 1× · see citing works
“The sIL-6R transgenic mice were crossed with mice, which were transgenic for human IL-6 [39].”
BackgroundAtreya, R. N., Finotto, S., Mudter, J., Mullberg, J., Jostock, T., Holtmann, M. H., Kishimoto, T., Galle, P. R., Rose‐John, S., & Neurath, M. F. (2000) · Gastroenterology · doi:10.1016/s0016-5085(00)85593-6 · Cited by 12 · see citing works
Self-citationSoluble cytokine-receptors are present in normal human urine
Novick, D., Engelmann, H., Wallach, D., & Rubinstein, M. (1989) · Cytokine · doi:10.1016/1043-4666(89)91511-1 · Cited by 7 · see citing works
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Targeting the IL-6/JAK/STAT3 signalling axis in cancer
Johnson, D. E., O'Keefe, R. A., & Grandis, J. R. (2018) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2018.8 · Cited by 3,110 · see citing works
IL-6 as a keystone cytokine in health and disease
Hunter, C. A., & Jones, S. A. (2015) · Nature Immunology · doi:10.1038/ni.3153 · Cited by 2,511 · see citing works
Chimeric antigen receptor T-cell therapy—assessment and management of toxicities
Neelapu, S. S., Tummala, S., Kebriaei, P., Wierda, W., Gutierrez, C., Locke, F. L., Komanduri, K. V., Lin, Y., Jain, N., Daver, N., et al. (2018) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2017.148 · Cited by 2,438 · see citing works
Shimabukuro‐Vornhagen, A., Gödel, P., Subklewe, M. S., Stemmler, H., Schlößer, H., Schlaak, M. S., Kochanek, M., Böll, B., & von Bergwelt‐Baildon, M. S. (2018) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-018-0343-9 · Cited by 1,673 · see citing works
“This soluble IL-6/IL-6 receptor complex binds to gp130 and therefore can also induce signaling in cell types that do not express membrane bound IL-6 receptors [59].”
BackgroundSARS-CoV-2 infection: The role of cytokines in COVID-19 disease
Costela-Ruiz, V. J., Montes, R. I., Puerta, J. M., Ruíz, C., & Melguizo‐Rodríguez, L. (2020) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2020.06.001 · Cited by 1,110 · see citing works
“It has been reported that it has regenerative and anti-inflammatory effects mediated by the conventional signaling process, although it also exerts proinflammatory effects mediated by trans-signaling, as in the case of viral infections [76].”
Teachey, D. T., Lacey, S. F., Shaw, P. A., Melenhorst, J. J., Maude, S. L., Frey, N., Pequignot, E., Gonzalez, V. E., Chen, F., Finklestein, J., et al. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-0040 · Cited by 1,102 · see citing works
“In other IL6-mediated diseases, IL6 levels often go up and sIL6R levels either increase or decrease after treatment as the interaction between IL6R and IL6 is blocked (21, 23, 24).”
BackgroundSelf-citationRole of interleukin-6 in cancer progression and therapeutic resistance
Kumari, N., Dwarakanath, B. S. R., Das, A., & Bhatt, A. N. (2016) · Tumor Biology · doi:10.1007/s13277-016-5098-7 · Cited by 1,096 · see citing works
“Like sIL-6R, a soluble form of the signal transducer protein gp130 (sgp130) is also present in the circulation at relatively high concentrations during inflammation and cancer [37, 39].”
BackgroundIL-6 pathway in the liver: From physiopathology to therapy
Schmidt-Arras, D., & Rose-John, S. (2016) · Journal of Hepatology · doi:10.1016/j.jhep.2016.02.004 · Cited by 881 · see citing works
Self-citationInflammation: The Common Pathway of Stress-Related Diseases
Liu, Y.-Z., Wang, Y.-X., & Jiang, C.-L. (2017) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2017.00316 · Cited by 800 · see citing works
“Moreover, evidence that disruption of IL-6 trans-signaling delays growth in established murine tumors demonstrates that IL-6 activities are important during neoplastic progression (Grivennikov et al., 2009; Rose-John, 2012).”
BackgroundIL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis
Rokavec, M., Öner, M. G., Li, H., Jackstadt, R., Jiang, L., Lodygin, D., Kaller, M., Horst, D., Ziegler, P. K., Schwitalla, S., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci73531 · Cited by 753 · see citing works
“However, the CRC cell lines with a mesenchymal phenotype, which consist only of tumor cells, showed elevated expression of the s–IL-6R, which is involved in IL-6 transsignal-ing (55) and is also under control of miR-34a.”
BackgroundIL-6 and related cytokines as the critical lynchpins between inflammation and cancer
Taniguchi, K., & Karin, M. (2014) · Seminars in Immunology · doi:10.1016/j.smim.2014.01.001 · Cited by 713 · see citing works
JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression
Owen, K. L., Brockwell, N. K., & Parker, B. S. (2019) · Cancers · doi:10.3390/cancers11122002 · Cited by 711 · see citing works
“transendothelial migration of tumor cells [107], the recruitment of neutrophils and macrophages into the TME through endothelial cell secretion of monocyte chemoattractant protein-1 (MCP-1) [108], M2 polarization of macrophages, inhibition of DC activation, and Treg differentiation [109].”
BackgroundThe two faces of IL-6 in the tumor microenvironment
Fisher, D. T., Appenheimer, M. M., & Evans, S. S. (2014) · Seminars in Immunology · doi:10.1016/j.smim.2014.01.008 · Cited by 693 · see citing works
Targeting inflammation in the treatment of type 2 diabetes: time to start
Donath, M. Y. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4275 · Cited by 690 · see citing works
A Review of SARS-CoV-2 and the Ongoing Clinical Trials
Tu, Y. F., Chien, C., Yarmishyn, A. A., Lin, Y., Luo, Y., Lin, Y.-T., Lai, W.-Y., Yang, D., Chou, S., Yang, Y., et al. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21072657 · Cited by 686 · see citing works
“Hence, specific blockade of IL-6-regulated signaling pathways represents a promising approach to attenuate inflammation-associated damage [78].”
BackgroundMendelian randomization in cardiometabolic disease: challenges in evaluating causality
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Interleukin-6 and its receptors: a highly regulated and dynamic system
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Self-citationThe Role of IL-6 in Skin Fibrosis and Cutaneous Wound Healing
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“IL-6 trans-signaling, whereby sIL-6Rα/IL-6 associates with gp130 and initiates JAK/STAT and MAPK signaling pathways [32], stimulates the migration of fibroblasts to sites of injury.”
BackgroundChanges in Nutritional Status Impact Immune Cell Metabolism and Function
Alwarawrah, Y., Kiernan, K., & MacIver, N. J. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01055 · Cited by 519 · see citing works
“IL-6 can signal through binding to the IL-6 receptor dimerized with gp130 on the surface of cells; however, IL-6 effects can also be mediated through trans-signaling, in which IL-6 binds to soluble IL-6 receptor, thereby permitting IL-6 to act on any cell that expresses gp130.”
BackgroundInfluentialInterleukin-6: Biology, signaling and strategies of blockade
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“During inflammation or infection, IL-6 is secreted by neutrophils, monocytes, macrophages, fibroblasts, endothelial cells, smooth muscle cells and T-cells [29].”
BackgroundSelf-citationSide-effect management of chimeric antigen receptor (CAR) T-cell therapy.
Schubert, M., Schmitt, M., Wang, L., Ramos, C., Jordan, K., Müller-Tidow, C., & Dreger, P. (2020) · Annals of Oncology · doi:10.1016/j.annonc.2020.10.478 · Cited by 423 · see citing works
Targeting cytokine and chemokine signaling pathways for cancer therapy
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The IL-1β, IL-6, and TNF cytokine triad is associated with post-acute sequelae of COVID-19
Schultheiß, C., Willscher, E., Paschold, L., Gottschick, C., Klee, B., Henkes, S.-S., Henkes, S.-S., Bosurgi, L., Sedding, D., Sedding, D., et al. (2022) · Cell Reports Medicine · doi:10.1016/j.xcrm.2022.100663 · Cited by 451 · see citing works
“38,80 The relevance of IL-6 trans -signaling for acute COVID-19 has recently been reported.”
The IL-6/gp130/STAT3 signaling axis: recent advances towards specific inhibition
Garbers, C., Aparicio-Siegmund, S., & Rose‐John, S. (2015) · Current Opinion in Immunology · doi:10.1016/j.coi.2015.02.008 · Cited by 432 · see citing works
“The soluble IL-6R: a buffer in the blood In healthy individuals levels of IL-6 in the plasma are extremely low, close to the detection limit of 1 pg/ml [23].”
BackgroundSelf-citationUnderstanding the role of cytokines in the pathogenesis of rheumatoid arthritis
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Interleukin-6: an emerging regulator of pathological pain
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The Role of Pro-Inflammatory Cytokines in the Pathogenesis of Cardiovascular Disease
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Inflammation in obesity and diabetes: islet dysfunction and therapeutic opportunity
Donath, M. Y., Dalmas, É., Sauter, N. S., & Böni-Schnetzler, M. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.05.001 · Cited by 338 · see citing works
“However, this remains speculative, and due to the complex effects of IL-6, clinical translation should await the outcome of further studies clarifying the precise role of IL-6 in metabolism and the development of drugs, allowing IL-6 effects to be targeted to a specific tissue (Rose-John, 2012).”
BackgroundThe shedding protease ADAM17: Physiology and pathophysiology
Zunke, F., & Rose‐John, S. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2017.07.001 · Cited by 337 · see citing works
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Self-citationIL-6 biology: implications for clinical targeting in rheumatic disease
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“© 2017 Taylor & Francis immune defense against bacterial infection.15 These findings led to the conclusion that the IL-6 classic pathway is important for regenerative and protective function whereas the IL-6 trans-signaling pathway constitutes the pro-inflammatory activity of IL-6.”
BackgroundInfluentialThe role of cytokines in the development of atherosclerosis
Fatkhullina, A. R., Peshkova, I. O., & Koltsova, E. K. (2016) · Biochemistry (Moscow) · doi:10.1134/s0006297916110134 · Cited by 322 · see citing works
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Interleukin-6: from basic biology to selective blockade of pro-inflammatory activities
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“Levels of sIL-6R, however, are in the range of 50 ng/ml and levels of sgp130 are found to be between 250 and 400 ng/ml [79,80].”
BackgroundSelf-citationEffects of IL-1β, IL-6 and IL-8 on erythrocytes, platelets and clot viscoelasticity
Bester, J., & Pretorius, E. (2016) · Scientific Reports · doi:10.1038/srep32188 · Cited by 303 · see citing works
IL-6 signalling pathways and the development of type 2 diabetes
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“While it is generally believed that IL-6 classic signalling is involved in the anti-inflammatory and regenerative activities of IL-6, IL-6 trans-signalling is considered to be responsible for the pro-inflammatory responses caused by this cytokine (Rose-John 2012; Schaper and Rose-John 2015).”
BackgroundMasjedi, A., Hashemi, V., Hojjat-Farsangi, M., Ghalamfarsa, G., Azizi, G., Yousefi, M., & Jadidi-Niaragh, F. (2018) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2018.09.177 · Cited by 303 · see citing works
Diabetic Macular Edema: Current Understanding, Molecular Mechanisms and Therapeutic Implications
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“IL-6 signaling occurs through its membranebound receptor IL-6R (classical signaling) or through the soluble IL-6R (sIL-6R, transsignaling) [198,199].”
BackgroundThe Clinical Significance of Interleukin-6 in Heart Failure: Results from the BIOSTAT-CHF Study
Markousis‐Mavrogenis, G., Tromp, J., Ouwerkerk, W., Devalaraja, M., Anker, S. D., Cleland, J. G. F., Dickstein, K., Filippatos, G. S., van der Harst, P., Lang, C. C., et al. (2019) · European Journal of Heart Failure · doi:10.1002/ejhf.1482 · Cited by 300 · see citing works
“3 The results of CANTOS and the accumulating evidence for the role of inflammation in HF resulted in renewed interest to investigate anti-inflammatory agents in HF. Interleukin-6 is a cytokine with both pro-inflammatory and anti-inflammatory properties.”
BackgroundThe role of cytokines in the regulation of NK cells in the tumor environment.
Konjević, G., Vuletić, A., Martinović, K. M., Larsen, A., & Jurišić, V. (2019) · Cytokine · doi:10.1016/j.cyto.2019.02.001 · Cited by 234 · see citing works
Chernyak, B. V., Popova, E. N., Prikhodko, A. S., Grebenchikov, O. A., Zinovkina, L. A., & Zinovkin, R. A. (2020) · Biochemistry (Moscow) · doi:10.1134/s0006297920120068 · Cited by 283 · see citing works
Cytokines and abnormal glucose and lipid metabolism
Shi, J., Fan, J., Su, Q., & Yang, Z. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00703 · Cited by 282 · see citing works
“While it is generally believed that the classic signaling is participated in the anti-inflammatory and regenerative activities of IL-6, the trans-signaling is involved in the pro-inflammatory responses induced by this cytokine (85, 86).”
Oxidative stress and the ageing endocrine system
Vitale, G., Salvioli, S., & Franceschi, C. (2013) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2013.29 · Cited by 269 · see citing works
Acute Inflammation in Tissue Healing
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Crosstalk of Inflammatory Cytokines within the Breast Tumor Microenvironment
Habanjar, O., Bingula, R., Decombat, C., Diab‐Assaf, M., Caldefie‐Chezet, F., & Delort, L. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24044002 · Cited by 272 · see citing works
Mahmud, F., Sarker, D. B., Jocelyn, J. A., & Sang, Q. A. (2024) · Cells · doi:10.3390/cells13211788 · Cited by 247 · see citing works
Immunopathogenesis of inflammatory bowel disease and mechanisms of biological therapies
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“Targeting IL-6 is already a reality in other chronic inflammatory diseases such as rheumatoid arthritis, where tocilizumab, an antibody against IL-6R, is already in use [40,41].”
BackgroundLiu, C., Lee, T.-L., Chen, Y., Liang, C., Wang, S.-H., Lue, J., Tsai, J., Lee, S.-W., Chen, S., Yang, Y.-F., et al. (2018) · Particle and Fibre Toxicology · doi:10.1186/s12989-018-0240-x · Cited by 231 · see citing works
“sgp130Fc specifically blocks IL-6 trans-signaling without affecting IL-6 classic signaling [29], but it did not affect ICAM-1 expression in cells according to Western blot (see Additional file 1: Fig.”
Iwasaki, M., Saito, J., Zhao, H., Sakamoto, A., Hirota, K., & Ma, D. (2020) · Inflammation · doi:10.1007/s10753-020-01337-3 · Cited by 229 · see citing works
The Role of IL-6 in Cancer Cell Invasiveness and Metastasis—Overview and Therapeutic Opportunities
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“In general, classic IL-6 signaling is responsible for the anti-inflammatory properties of IL-6, whereas trans-signaling is responsible for the pro-inflammatory actions of IL-6 [41].”
BackgroundIL-6/STAT3 Is a Promising Therapeutic Target for Hepatocellular Carcinoma
Xu, J., Lin, H., Wu, G., Zhu, M., & Li, M. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.760971 · Cited by 228 · see citing works
Cytokine-Induced Modulation of Colorectal Cancer
Mager, L. F., Wasmer, M.-H., Rau, T. T., & Krebs, P. (2016) · Frontiers in Oncology · doi:10.3389/fonc.2016.00096 · Cited by 215 · see citing works
“Soluble IL-6R, then, associates with the ubiquitously expressed glycoprotein 130 (IL-6 ST/GP130) (60).”
BackgroundInterleukin 6 and Rheumatoid Arthritis
Yoshida, Y., & Tanaka, T. (2014) · BioMed Research International · doi:10.1155/2014/698313 · Cited by 207 · see citing works
Immunological functions of liver sinusoidal endothelial cells
Knolle, P. A., & Wohlleber, D. (2016) · Cellular and Molecular Immunology · doi:10.1038/cmi.2016.5 · Cited by 202 · see citing works
The Two-Faced Cytokine IL-6 in Host Defense and Diseases
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“The IL-6/sIL-6R complex activates gp130-expressing cells, even if cells lack membrane IL-6R, a process known as trans-signaling [29].”
BackgroundPeripheral Markers of Depression
Nobis, A., Zalewski, D., & Waszkiewicz, N. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9123793 · Cited by 197 · see citing works
“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 176 · see citing works
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 · see citing works
“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 176 · see citing works
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 165 · see citing works
“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 168 · see citing works
“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 · see citing works
Shahini, A., & Shahini, A. (2022) · Journal of Cell Communication and Signaling · doi:10.1007/s12079-022-00695-x · Cited by 167 · see citing works
“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 · see citing works
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 162 · see citing works
“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 162 · see citing works
Interleukin-6 signalling in health and disease
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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 158 · see citing works
Favalli, E. (2020) · Rheumatology and Therapy · doi:10.1007/s40744-020-00219-2 · Cited by 142 · see citing works
“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 155 · see citing works
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 154 · see citing works
“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 · see citing works
“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 · see citing works
“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 · see citing works
“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 · see citing works
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“…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 146 · see citing works
“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 141 · see citing works
“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 142 · see citing works
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 149 · see citing works
Tocilizumab in the treatment of rheumatoid arthritis: an evidence-based review and patient selection
Biggioggero, M., Crotti, C., Becciolini, A., & Favalli, E. (2018) · Drug Design, Development and Therapy · doi:10.2147/dddt.s150580 · Cited by 125 · see citing works
“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 146 · see citing works
“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 145 · see citing works
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 139 · see citing works
“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 · see citing works
“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 136 · see citing works
Self-citationThe role of the interleukin (IL)-6/IL-6 receptor axis in cancer.
Taher, M. Y., Davies, D., & Maher, J. (2018) · Biochemical Society Transactions · doi:10.1042/bst20180136 · Cited by 115 · see citing works
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 133 · see citing works
“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 131 · see citing works
“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 · see citing works
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 · see citing works
“…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 · see citing works
“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 127 · see citing works
“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
- 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
- Health Sciences › Medicine › Oncology › 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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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.
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