Interleukin-6 (IL-6) is a cytokine largely induced during infection, inflammation, and cancer. In the liver, IL-6 induces the synthesis of acute-phase proteins, which are believed to support the response of the body during infection and inflammation. Moreover, IL-6 has been reported to be a growth factor in multiple myeloma. IL-6 on cells binds to an IL-6 receptor (IL-6R) forming an IL-6/IL-6R complex, which associates with a homodimer of a second receptor subunit, gp130, to initiate signaling. Gp130 is present on all cells of the body, whereas IL-6R is only expressed on hepatocytes, some leukocytes, and some epithelial cells. Since gp130 has no measurable affinity for IL-6, cells which do not express IL-6R are unresponsive to the cytokine. A soluble form of IL-6R, which is found in the blood, can still bind IL-6 and the complex of IL-6/sIL-6R can bind to cellular gp130 also on cells without IL-6R expression. This signaling mechanism has been called trans-signaling. Interestingly, a soluble form of gp130 (sgp130) blocks IL-6 trans-signaling without affecting classic IL-6 signaling via the membrane-bound IL-6R. We used a dimerized version of sgp130 fused to the Fc portion of an IgG1 antibody (sgp130Fc) to discriminate between classic and trans-signaling of IL-6. It turned out that proinflammatory activities of IL-6 are mediated via trans-signaling, whereas anti-inflammatory or regenerative activities are mediated via classic signaling. These results are important for strategies to inhibit IL-6 signaling in autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, and inflammation-associated colorectal cancer.

Keywords:
Cancer, IL-6, IL-6R, Inflammation, Shedding, Soluble receptor, Trans-signaling
1.
Taga T, Kishimoto T: gp130 and the interleukin-6 family of cytokines. Annu Rev Immunol 1997;15:797–819.
2.
Jones S, Scheller J, Rose-John S: Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J Clin Invest 2011;121:3375–3383.
3.
Heinrich PC, Behrmann I, Haan S, Hermanns HM, Muller-Newen G, Schaper F: Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J 2003;374:1–20.
4.
Garbers C, Hermanns H, Schaper F, Müller-Newen G, Grötzinger J, Rose-John S, Scheller J: Interleukin 6-type cytokines: cross-talk and dynamics of signal transduction. Cytokine Growth Factor Rev 2012;23:85–97.
5.
Kopf M, Bachmann MF, Marsland BJ: Averting inflammation by targeting the cytokine environment. Nat Rev Drug Discov 2010;9:703–718.
6.
Cressman DE, Greenbaum LE, DeAngelis RA, Ciliberto G, Furth EE, Poli V, Taub R: Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice. Science 1996;274:1379–1383.
7.
Wallenius V, Wallenius K, Ahren B, Rudling M, Carlsten H, Dickson SL, Ohlsson C, Jansson JO: Interleukin-6-deficient mice develop mature-onset obesity. Nat Med 2002;8:75–79.
8.
März P, Cheng JC, Gadient RA, Patterson P, Stoyan T, Otten U, Rose-John S: Sympathetic neurons can produce and respond to interleukin-6. Proc Natl Acad Sci USA 1998;95:3251–3256.
9.
Müllberg J, Geib T, Jostock T, Hoischen SH, Vollmer P, Voltz N, Heinz D, Galle PR, Klouche M, Rose-John S: IL-6-receptor independent stimulation of human gp130 by viral IL-6. J Immunol 2000;164:4672–4677.
10.
Suthaus J, Stuhlmann-Laeisz C, Tompkins VS, Rosean TR, Klapper W, Tosato G, Janz S, Scheller J, Rose-John S: HHV-8-encoded viral IL-6 collaborates with mouse IL-6 in MCD-like development in mice. Blood, in press
11.
Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S: The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Ata 2011;1813:878–888.
12.
Waetzig GH, Rose-John S: Hitting a complex target: an update on interleukin-6 trans-signalling. Expert Opin Ther Targets 2012;16:225–236.
13.
Boulanger MJ, Chow DC, Brevnova EE, Garcia KC: Hexameric structure and assembly of the interleukin-6/IL-6 alpha-receptor/gp130 complex. Science 2003;300:2101–2104.
14.
Rose-John S, Schooltink H: Cytokines are a therapeutic target for the prevention of inflammation-induced cancers. Recent Results Cancer Res 2007;174:57–66.
15.
Romano M, Sironi M, Toniatti C, Polentarutti N, Fruscella P, Ghezzi P, Faggioni R, Luini W, van Hinsbergh V, Sozzani S, Bussolino F, Poli V, Ciliberto G, Mantovani A: Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment. Immunity 1997;6:315–325.
16.
Klouche M, Bhakdi S, Hemmes M, Rose-John S: Novel path of activation of primary human smooth muscle cells: upregulation of gp130 creates an autocrine activation loop by IL-6 and its soluble receptor. J Immunol 1999;163:4583–4589.
17.
Rabe B, Chalaris A, May U, Waetzig GH, Seegert D, Williams AS, Jones SA, Rose-John S, Scheller J: Transgenic blockade of interleukin 6 transsignaling abrogates inflammation. Blood 2008;111:1021–1028.
18.
Taga T: IL6 signalling through IL6 receptor and receptor-associated signal transducer, gp130. Res Immunol 1992;143:737–739.
19.
Tajima S, Tsuji K, Ebihara Y, Sui X, Tanaka R, Muraoka K, Yoshida M, Yamada K, Yasukawa K, Taga T, Kishimoto T, Nakahata T: Analysis of interleukin 6 receptor and gp130 expressions and proliferative capability of human CD34+ cells. J Exp Med 1996;184:1357–1364.
20.
Becker C, Fantini MC, Wirtz S, Nikolaev A, Lehr HA, Galle PR, Rose-John S, Neurath MF: IL-6 signaling promotes tumor growth in colorectal cancer. Cell Cycle 2005;4:217–220.
21.
Novick D, Engelmann H, Wallach D, Rubinstein M: Soluble cytokine receptors are present in normal human urine. J Exp Med 1989;170:1409–1414.
22.
Honda M, Yamamoto S, Cheng M, Yasukawa K, Suzuki H, Saito T, Osugi Y, Tokunaga T, Kishimoto T: Human soluble IL-6 receptor: its detection and enhanced release by HIV infection. J Immunol 1992;148:2175–2180.
23.
Keul R, Heinrich PC, Muller-newen G, Muller K, Woo P: A possible role for soluble IL- 6 receptor in the pathogenesis of systemic onset juvenile chronic arthritis. Cytokine 1998;10:729–734.
24.
Papadaki H, Kyriakou D, Foudoulakis A, Markidou F, Alexandrakis M, Eliopoulos GD: Serum levels of soluble IL-6 receptor in multiple myeloma as indicator of disease activity. Acta Haematol 1997;97:191–195.
25.
Rose-John S, Heinrich PC: Soluble receptors for cytokines and growth factors: generation and biological function. Biochem J 1994;300:281–290.
26.
Chen Q, Wang WC, Bruce R, Li H, Schleider DM, Mulbury MJ, Bain MD, Wallace PK, Baumann H, Evans SS: Central role of IL-6 receptor signal-transducing chain gp130 in activation of L-selectin adhesion by fever-range thermal stress. Immunity 2004;20:59–70.
27.
Jones GW, McLoughlin RM, Hammond VJ, Parker CR, Williams JD, Malhotra R, Scheller J, Williams AS, Rose-John S, Topley N, Jones SA: Loss of CD4+ T cell IL-6R expression during inflammation underlines a role for IL-6 trans signaling in the local maintenance of Th17 cells. J Immunol 2010;184:2130–2139.
28.
Lust JA, Donovan KA, Kline MP, Greipp PR, Kyle RA, Maihle NJ: Isolation of an mRNA encoding a soluble form of the human interleukin-6 receptor. Cytokine 1992;4:96–100.
29.
Muller-Newen G, Kohne C, Keul R, Hemmann U, Muller-Esterl W, Wijdenes J, Brakenhoff JP, Hart MH, Heinrich PC: Purification and characterization of the soluble interleukin-6 receptor from human plasma and identification of an isoform generated through alternative splicing. Eur J Biochem 1996;236:837–842.
30.
Mullberg J, Schooltink H, Stoyan T, Gunther M, Graeve L, Buse G, Mackiewicz A, Heinrich PC, Rose-John S: The soluble interleukin-6 receptor is generated by shedding. Eur J Immunol 1993;23:473–480.
31.
Matthews V, Schuster B, Schutze S, Bussmeyer I, Ludwig A, Hundhausen C, Sadowski T, Saftig P, Hartmann D, Kallen KJ, Rose-John S: Cellular cholesterol depletion triggers shedding of the human interleukin-6 receptor by ADAM10 and ADAM17 (TACE). J Biol Chem 2003;278:38829–38839.
32.
Seals DF, Courtneidge SA: The ADAMs family of metalloproteases: multidomain proteins with multiple functions. Genes Dev 2003;17:7–30.
33.
Müllberg J, Oberthur W, Lottspeich F, Mehl E, Dittrich E, Graeve L, Heinrich PC, Rose-John S: The soluble human IL-6 receptor: mutational characterization of the proteolytic cleavage site. J Immunol 1994;152:4958–4968.
34.
Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, Castner BJ, Stocking KL, Reddy P, Srinivasan S, Nelson N, Boiani N, Schooley KA, Gerhart M, Davis R, Fitzner JN, Johnson RS, Paxton RJ, March CJ, Cerretti DP: A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature 1997;385:729–733.
35.
Moss ML, Jin SL, Milla ME, Bickett DM, Burkhart W, Carter HL, Chen WJ, Clay WC, Didsbury JR, Hassler D, Hoffman CR, Kost TA, Lambert MH, Leesnitzer MA, McCauley P, McGeehan G, Mitchell J, Moyer M, Pahel G, Rocque W, Overton LK, Schoenen F, Seaton T, Su JL, Becherer JD, et al: Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha. Nature 1997;385:733–736.
36.
Peschon JJ, Slack JL, Reddy P, Stocking KL, Sunnarborg SW, Lee DC, Russell WE, Castner BJ, Johnson RS, Fitzner JN, Boyce RW, Nelson N, Kozlosky CJ, Wolfson MF, Rauch CT, Cerretti DP, Paxton RJ, March CJ, Black RA: An essential role for ectodomain shedding in mammalian development. Science 1998;282:1281–1284.
37.
Scheller J, Chalaris A, Garbers C, Rose-John S: ADAM17: a molecular switch to control inflammation and tissue regeneration. Trends Immunol 2011;32:380–387.
38.
Jones SA, Novick D, Horiuchi S, Yamamoto N, Szalai AJ, Fuller GM: C-reactive protein: a physiological activator of interleukin 6 receptor shedding. J Exp Med 1999;189:599–604.
39.
Walev I, Vollmer P, Palmer M, Bhakdi S, Rose-John S: Pore-forming toxins trigger shedding of receptors for interleukin 6 and lipopolysaccharide. Proc Natl Acad Sci USA 1996;93:7882–7887.
40.
Chalaris A, Rabe B, Paliga K, Lange H, Laskay T, Fielding CA, Jones SA, Rose-John S, Scheller J: Apoptosis is a natural stimulus of IL6R shedding and contributes to the proinflammatory trans-signaling function of neutrophils. Blood 2007;110:1748–1755.
41.
Gomez MI, Sokol SH, Muir AB, Soong G, Bastien J, Prince AS: Bacterial induction of TNF-alpha converting enzyme expression and IL-6 receptor alpha shedding regulates airway inflammatory signaling. J Immunol 2005;175:1930–1936.
42.
DeLeo FR: Attractive shedding. Blood 2007;110:1711–1712.
43.
Garbers C, Janner N, Chalaris A, Moss ML, Floss DM, Meyer D, Koch-Nolte F, Rose-John S, Scheller J: Species specificity of ADAM10 and ADAM17 proteins in interleukin-6 (IL-6) trans-signaling and novel role of ADAM10 in inducible IL-6 receptor shedding. J Biol Chem 2011;286:14804–14811.
44.
Cui X, Hawari F, Alsaaty S, Lawrence M, Combs CA, Geng W, Rouhani FN, Miskinis D, Levine SJ: Identification of ARTS-1 as a novel TNFR1-binding protein that promotes TNFR1 ectodomain shedding. J Clin Invest 2002;110:515–526.
45.
Cui X, Rouhani FN, Hawari F, Levine SJ: An aminopeptidase, ARTS-1, is required for interleukin-6 receptor shedding. J Biol Chem 2003;278:28677–28685.
46.
Jostock T, Mullberg J, Ozbek S, Atreya R, Blinn G, Voltz N, Fischer M, Neurath MF, Rose-John S: Soluble gp130 is the natural inhibitor of soluble interleukin-6 receptor transsignaling responses. Eur J Biochem 2001;268:160–167.
47.
Atreya R, Mudter J, Finotto S, Müllberg J, Jostock T, Wirtz S, Schütz M, Bartsch B, Holtmann M, Becker C, Strand D, Czaja J, Schlaak JF, Lehr HA, Autschbach F, Schürmann G, Nishimoto N, Yoshizaki K, Ito H, Kishimoto T, Galle PR, Rose-John S, Neurath MF: Blockade of IL-6 transsignaling abrogates established experimental colitis in mice by suppression of the antiapoptotic resistance of lamina propria T cells. Nat Med 2000;6:583–588.
48.
Mitsuyama K, Matsumoto S, Rose-John S, Suzuki A, Hara T, Tomiyasu N, Handa K, Tsuruta O, Funabashi H, Scheller J, Toyonaga A, Sata M: STAT3 activation via interleukin-6 trans-signaling contributes to ileitis in SAMP1/Yit mice. Gut 2006;55:1263–1269.
49.
Becker C, Fantini MC, Schramm C, Lehr HA, Wirtz S, Nikolaev A, Burg J, Strand S, Kiesslich R, Huber S, Ito H, Nishimoto N, Yoshizaki K, Kishimoto T, Galle PR, Blessing M, Rose-John S, Neurath MF: TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling. Immunity 2004;21:491–501.
50.
Matsumoto S, Hara T, Mitsuyama K, Yamamoto M, Tsuruta O, Sata M, Scheller J, Rose-John S, Kado S, Takada T: Essential roles of IL-6 trans-signaling in colonic epithelial cells, induced by the IL-6/soluble-IL-6 receptor derived from lamina propria macrophages, on the development of colitis-associated premalignant cancer in a murine model. J Immunol 2010;184:1543–1551.
51.
Grivennikov S, Karin E, Terzic J, Mucida D, Yu GY, Vallabhapurapu S, Scheller J, Rose-John S, Cheroutre H, Eckmann L, Karin M: IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 2009;15:103–113.
52.
Bollrath J, Phesse TJ, von Burstin VA, Putoczki T, Bennecke M, Bateman T, Nebelsiek T, Lundgren-May T, Canli O, Schwitalla S, Matthews V, Schmid RM, Kirchner T, Arkan MC, Ernst M, Greten FR: gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis. Cancer Cell 2009;15:91–102.
53.
Schiechl G, Bauer B, Fuss I, Lang SA, Moser C, Ruemmele P, Rose-John S, Neurath MF, Geissler EK, Schlitt HJ, Strober W, Fichtner-Feigl S: Tumor development in murine ulcerative colitis depends on MyD88 signaling of colonic F4/80+CD11b(high)Gr1(low) macrophages. J Clin Invest 2011;121:1692–1708.
54.
Kopf M, Baumann H, Freer G, Freudenberg M, Lamers M, Kishimoto T, Zinkernagel R, Bluethmann H, Kohler G: Impaired immune and acute-phase responses in interleukin-6-deficient mice. Nature 1994;368:339–342.
55.
Lesina M, Kurkowski MU, Ludes K, Rose-John S, Treiber M, Kloppel G, Yoshimura A, Reindl W, Sipos B, Akira S, Schmid RM, Algul H: Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell 2011;19:456–469.
56.
Lo CW, Chen MW, Hsiao M, Wang S, Chen CA, Hsiao SM, Chang JS, Lai TC, Rose-John S, Kuo ML, Wei LH: IL-6 trans-signaling in formation and progression of malignant ascites in ovarian cancer. Cancer Res 2011;71:424–434.
57.
Bromberg J: Stat proteins and oncogenesis. J Clin Invest 2002;109:1139–1142.
58.
Bromberg J, Wang TC: Inflammation and cancer: IL-6 and STAT3 complete the link. Cancer Cell 2009;15:79–80.
59.
Rebouissou S, Amessou M, Couchy G, Poussin K, Imbeaud S, Pilati C, Izard T, Balabaud C, Bioulac-Sage P, Zucman-Rossi J: Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours. Nature 2009;457:200–204.
60.
Stuhlmann-Laeisz C, Lang S, Chalaris A, Krzysztof P, Enge S, Eichler J, Klingmuller U, Samuel M, Ernst M, Rose-John S, Scheller J: Forced dimerization of gp130 leads to constitutive STAT3 activation, cytokine-independent growth, and blockade of differentiation of embryonic stem cells. Mol Biol Cell 2006;17:2986–2995.
61.
Suthaus J, Tillmann A, Lorenzen I, Bulanova E, Rose-John S, Scheller J: Forced homo- and heterodimerization of all gp130-type receptor complexes leads to constitutive ligand-independent signaling and cytokine-independent growth. Mol Biol Cell 2010;21:2797–2807.
62.
Pilati C, Amessou M, Bihl MP, Balabaud C, Nhieu JT, Paradis V, Nault JC, Izard T, Bioulac-Sage P, Couchy G, Poussin K, Zucman-Rossi J: Somatic mutations activating STAT3 in human inflammatory hepatocellular adenomas. J Exp Med 2011;208:1359–1366.
63.
Kimura A, Kishimoto T: IL-6: regulator of Treg/Th17 balance. Eur J Immunol 2010;40:1830–1835.
64.
Hata H, Sakaguchi N, Yoshitomi H, Iwakura Y, Sekikawa K, Azuma Y, Kanai C, Moriizumi E, Nomura T, Nakamura T, Sakaguchi S: Distinct contribution of IL-6, TNF-alpha, IL-1, and IL-10 to T cell-mediated spontaneous autoimmune arthritis in mice. J Clin Invest 2004;114:582–588.
65.
Tawara K, Oxford JT, Jorcyk CL: Clinical significance of interleukin (IL)-6 in cancer metastasis to bone: potential of anti-IL-6 therapies. Cancer Manag Res 2011;3:177–189.
66.
Yamamoto K, Rose-John S: Therapeutic blockade of interleukin-6 in chronic inflammatory disease. Clin Pharmacol Ther 2012;91:574–576.
67.
Tanaka T, Narazaki M, Kishimoto T: Therapeutic targeting of the interleukin-6 receptor. Annu Rev Pharmacol Toxicol 2012;52:199–219.
68.
Nishimoto N, Kanakura Y, Aozasa K, Johkoh T, Nakamura M, Nakano S, Nakano N, Ikeda Y, Sasaki T, Nishioka K, Hara M, Taguchi H, Kimura Y, Kato Y, Asaoku H, Kumagai S, Kodama F, Nakahara H, Hagihara K, Yoshizaki K, Kishimoto T: Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease. Blood 2005;106:2627–2632.
69.
Chalaris A, Garbers C, Rabe B, Rose-John S, Scheller J: The soluble interleukin 6 receptor: generation and role in inflammation and cancer. Eur J Cell Biol 2011;90:484–494.
70.
Peters M, Odenthal M, Schirmacher P, Blessing M, Ciliberto G, Meyer zum Büschenfelde KH, Rose-John S: Soluble IL-6 Receptor leads to a paracrine modulation of the hepatic acute phase response in double transgenic mice. J. Immunol 1997;159:1474–1481.
71.
Garbers C, Thaiss W, Jones GW, Waetzig GH, Lorenzen I, Guilhot F, Lissilaa R, Ferlin WG, Grotzinger J, Jones SA, Rose-John S, Scheller J: Inhibition of classic signaling is a novel function of soluble glycoprotein 130 (sgp130), which is controlled by the ratio of interleukin 6 and soluble interleukin 6 receptor. J Biol Chem 2011;286:42959–42970.
72.
Sodenkamp J, Waetzig GH, Scheller J, Seegert D, Grotzinger J, Rose-John S, Ehlers S, Holscher C: Therapeutic targeting of interleukin-6 trans-signaling does not affect the outcome of experimental tuberculosis. Immunobiology 2012, E-pub ahead of print.
73.
Barkhausen T, Tschernig T, Rosenstiel P, van Griensven M, Vonberg RP, Dorsch M, Mueller-Heine A, Chalaris A, Scheller J, Rose-John S, Seegert D, Krettek C, Waetzig GH: Selective blockade of interleukin-6 trans-signaling improves survival in a murine polymicrobial sepsis model. Crit Care Med 2011;39:1407–1413.
© 2012 S. Karger AG, Basel
2012
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.