Preferences help
enabled [disable] Abstract
Number of results
2003 | 50 | 3 | 603-611
Article title

Interleukin-6 biology is coordinated by membrane bound and soluble receptors.

Title variants
Languages of publication
Cytokine receptors exist in membrane bound and soluble form. Both forms bind their ligands with comparable affinity. While most soluble receptors are antagonists in that they compete for the ligands with their membrane counterparts, some soluble receptors are agonists. In this case, the complex of ligand and soluble receptor binds on target cells to a second receptor subunit and initiates signal transduction. Soluble receptors of the IL-6 family of cytokines are agonists. In vivo, the IL-6/soluble IL-6R complex stimulates several types of target cells not stimulated by IL-6 alone, since they do not express the membrane bound IL-6R. This process has been named transsignaling. We have shown that in several chronic inflammatory diseases like chronic inflammatory bowl disease, peritonitis and rheumatoid arthritis, transsignaling via the soluble IL-6R complexed to IL-6 is a crucial point in the transition from the acute to the chronic state of the disease. The mechanism by which the IL-6/ soluble IL-6R complex regulates the inflammatory state is discussed.
Physical description
  • Department of Biochemistry, Christian-Albrechts-Universität zu Kiel, Olshausenstr. 40, D-24098 Kiel, Germany
  • Aasland D, Oppmann B, Grötzinger J, Rose-John S, Kallen K-J. (2002) The upper cytokine binding module and the Ig-like domain of the Leukaemia Inhibitory Factor (LIF) Receptor are sufficient for a functional LIFR complex. J Mol Biol.; 315: 637-46.
  • Aasland D, Schuster B, Grötzinger J, Rose-John S, Kallen K-J. (2003) Analysis of the leukemia inhibitory factor receptor functional domains by chimeric receptors and cytokines. Biochemistry.; 42: 5244-52.
  • Althoff K, Reddy P, Peschon J, Voltz N, Rose-John S, Mullberg J. (2000) Contribution of the amino acid sequence at the cleavage site to the cleavage pattern of transmembrane proteins. Eur J Biochem.; 267: 2624-31.
  • Althoff K, Müllberg J, Aasland D, Voltz N, Kallen K-J, Grötzinger J, Rose-John S. (2001) Recognition sequences and structural elements contribute to shedding susceptibility of membrane proteins. Biochem J.; 353: 663-72.
  • Aoki Y, Jaffe ES, Chang Y, Jones K, Teruya-Feldstein J, Moore PS, Tosato G. (1999) Angiogenesis and hematopoiesis induced by Kaposi's sarcoma-associated herpesvirus-encoded interleukin-6. Blood.; 93: 4034-43.
  • 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. (2000) Blockade of IL-6 transsignaling abrogates established experimental colitis in mice by suppression of the antiapoptotic resistance of lamina propria T cells. Nature Med.; 6: 583-8.
  • Audet J, Miller CL, Rose-John S, Piret JM, Eaves CJ. (2001) Distinct role of gp130 activation in promoting self-renewal divisions by mitogenically stimulated murine hematopoietic cells. Proc Natl Acad Sci U.S.A.; 98: 1757-62.
  • Brunello AG, Weissenberger J, Kappeler A, Franke S, Peters M, Rose-John S, Weis J. (2000) Astrocytic alterations in interleukin-6/soluble interleukin-6 receptor a double-transgenic mice. Am J Pathol.; 157: 1485-93.
  • Burger R, Neipel F, Fleckenstein B, Savino R, Ciliberto G, Kalden JR, Gramatzki M. (1998) Human herpesvirus type 8 interleukin-6 homologue is functionally active on human myeloma cells. Blood.; 91: 1858-63.
  • Chow DC, He XL, Snow AL, Rose-John S, Garcia KC. (2001) Structure of an extracellular gp130-cytokine receptor signalling complex. Science.; 291: 2150-5.
  • De Vos AM, Ultsch M, Kossiakoff AA. (1992) Human growth hormone and extracellular domain of its receptor: crystall structure the complex. Science.; 255: 306-12.
  • Fischer M, Goldschmitt J, Peschel C, Kallen KJ, Brakenhoff JPJ, Wollmer A, Grötzinger J, Rose-John S. (1997) A designer cytokine with high activity on human hematopoietic progenitor cells. Nat Biotechnol.; 15: 142-5.
  • Hacker C, Kirsch RD, Ju XS, Hieronymus T, Gust TC, Kuhl C, Jorgas T, Kurz SM, Rose-John S, Yokota Y, Zenke M. (2003) Transcriptional profiling identifies Id2 function in dendritic cell development. Nat Immunol.; 4: 380-6.
  • Hoischen SH, Vollmer P, März P, Özbek S, Götze K, Jostock T, Geib T, Müllberg J, Mechtersheimer S, Fischer M, Grötzinger J, Galle PR, Rose-John S. (2000) Human Herpesvirus 8 interleukin-6 homologue triggers gp130 on neuronal and hematopoietic cells. Eur J Biochem.; 267: 3604-12.
  • Hundhausen C, Misztela D, Berkhout TA, Broadway N, Saftig P, Hartmann D, Fahrenholz F, Postina R, Matthews V, Kallen K-J, Rose-John S, Ludwig A. (2003) The disintegrin-like metalloproteinase ADAM 10 is involved in constitutive cleavage of CX3CL1 (fractalkine) and regulates CX3CL1-mediated cell-cell adhesion. Blood.; 102: 1186-95.
  • Hurst SM, Wilkinson TS, Mcloughlin RM, Jones S, Horiuchi S, Yamamoto N, Rose-John S, Fuller GM, Topley N, Jones SA. (2001) Control of leukocyte infiltration during inflammation: IL-6 and its soluble receptor orchestrate a temporal switch in the pattern of leukocyte recruitment. Immunity.; 14: 705-14.
  • Jones S, Rose-John S. (2002) The role of soluble receptors in cytokine biology: The agonistic properties of the sIL-6R/IL-6 complex. Biochim Biophys Acta.; 1592: 251-64.
  • Jostock T, Müllberg J, Özbek S, Atreya R, Blinn G, Voltz N, Fischer M, Neurath MF, Rose-John S. (2001) Soluble gp130 is the natural inhibitor of soluble IL-6R transsignaling responses. Eur J Biochem.; 268: 160-7.
  • Kallen K-J, Grötzinger J, Lelièvre E, Vollmer P, Aasland D, Renné C, Müllberg J, Meyer Zum Büschenfelde K-H, Gascan H, Rose-John S. (1999) Receptor recognition sites of cytokines are organized as exchangeable moduls: transfer of the LIFR binding site from CNTF to IL-6. J Biol Chem.; 274: 11859-67.
  • Kallen K-J, Grötzinger J, Rose-John S. (2000) New perspectives in the design of cytokines and growth factors. Trends Biotechnol.; 18: 455-61.
  • Klouche M, Bhakdi S, Hemmes M, Rose-John S. (1999) 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.; 163: 4583-9.
  • Klouche M, Brockmeyer N, Knabbe C, Rose-John S. (2002) Human herpesvirus 8 derived viral interleukin-6 induces PTX3 expression in Kaposi's sarcoma cells. AIDS.; 16: F9-18.
  • Lust JA, Donovan KA, Kline MP, Greipp PR, Kyle RA, Maihle NJ. (1992) Isolation of an mRNA encoding a soluble form of the human interleukin-6 receptor. Cytokine.; 4: 96-100.
  • Mackiewicz A, Schooltink H, Heinrich PC, Rose-John S. (1992) Complex of soluble human IL-6-receptor/IL-6 up-regulates expression of acute-phase proteins. J Immunol.; 149: 2021-7.
  • März P, Cheng J-C, Gadient RA, Patterson P, Stoyan T, Otten U, Rose-John S. (1998) Sympathetic neurons can produce and respond to interleukin-6. Proc Natl Acad Sci U S A.; 95: 3251-6.
  • März P, Otten U, Rose-John S. (1999) Neuronal activities of IL-6 type cytokines often depend on soluble cytokine receptors. Eur J Neurosci.; 11: 2995-3004.
  • Matthews V, Schuster B, Schutze S, Bussmeyer I, Ludwig A, Hundhausen C, Sadowski T, Saftig P, Hartmann D, Kallen K-J, Rose-John S. (2003) Cellular cholesterol depletion triggers shedding of the human interleukin-6 receptor by ADAM10 and ADAM17 (TACE). J Biol Chem.; in press.
  • Molden J, Chang Y, You Y, Moore PS, Goldsmith MA. (1997) A Kaposi's sarcoma-associated herpesvirus-encoded cytokine homolog (vIL-6) activates signaling through the shared gp130 receptor subunit. J Biol Chem.; 272: 19625-31.
  • Moore PS, Boshoff C, Weiss RA, Chang Y. (1996) Molecular mimicry of human cytokine and cytokine response pathway genes by KSHV. Science.; 274: 1739-44.
  • Mosley B, De Imus C, Friend D, Boiani N, Thoma B, Park LS, Cosman D. (1996) Dual oncostatin M (OSM) receptors. Cloning and characterization of an alternative signaling subunit conferring OSM-specific receptor activation. J Biol Chem.; 271: 32635-43.
  • Müllberg J, Althoff K, Jostock T, Rose-John S. (2000a) The importance of shedding of membrane proteins for cytokine biology. Eur Cytokine Netw.; 11: 27-38.
  • Müllberg J, Geib T, Jostock T, Hoischen SH, Vollmer P, Voltz N, Heinz D, Galle PR, Klouche M, Rose-John S. (2000b) IL-6-receptor independent stimulation of human gp130 by viral IL-6. J Immunol.; 164: 4672-7.
  • Neipel F, Albrecht JC, Ensser A, Huang YQ, Li JJ, Friedman Kien AE, Fleckenstein B. (1997) Human herpesvirus 8 encodes a homolog of interleukin-6. J Virol.; 71: 839-42.
  • Pennica D, Arce V, Swanson TA, Vejsada R, Pollock RA, Armanini M, Dudley K, Phillips HS, Rosenthal A, Kato AC, Henderson CE. (1996) Cardiotrophin-1, a cytokine present in embryonic muscle, supports long-term survival of spinal motoneurons. Neuron.; 17: 63-74.
  • Peters M, Jacobs S, Ehlers M, Vollmer P, Müllberg J, Wolf E, Brem G, Meyer Zum Büschenfelde KH, Rose-John S. (1996) The function of the soluble interleukin 6 (IL-6) receptor in vivo: sensitization of human soluble IL-6 receptor transgenic mice towards IL-6 and prolongation of the plasma half-life of IL-6. J Exp Med.; 183: 1399-406.
  • Peters M, Müller A, Rose-John S. (1998) Interleukin-6 and soluble interleukin-6 receptor: direct stimulation of gp130 and hematopoiesis. Blood.; 92: 3495-504.
  • Peters M, Schirmacher P, Goldschmitt J, Odenthal M, Peschel C, Dienes HP, Fattori E, Ciliberto G, Meyer Zum Büschenfelde KH, Rose-John S. (1997) Extramedullary expansion of hematopoietic progenitor cells in IL-6/sIL-6R double transgenic mice. J Exp Med.; 185: 755-66.
  • Pflanz S, Tacken I, Grötzinger J, Jacques Y, Dahmen H, Heinrich PC, Muller-Newen G. (1999) A fusion protein of interleukin-11 and soluble interleukin-11 receptor acts as a superagonist on cells expressing gp130. FEBS Lett.; 450: 117-22.
  • Renné C, Kallen K-J, Müllberg J, Jostock T, Grötzinger J, Rose-John S. (1998) A new type of cytokine receptor antagonist directly targeting gp130. J Biol Chem.; 273: 27213-9.
  • 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. (1997) Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment. Immunity.; 6: 315-25.
  • Rose-John S. (2001) Coordination of interleukin-6 biology by membrane bound and soluble receptors. Adv Exp Med Biol.; 495: 145-51.
  • Rose-John S. (2002) gp130 stimulation and the maintenance of stem cells. Trends Biotechnol.; 20: 417-9.
  • Rose-John S, Heinrich PC. (1994) Soluble receptors for cytokines and growth factors: generation and biological function. Biochem J.; 300: 281-90.
  • Schuster B, Kovaleva M, Sun Y, Regenhard P, Matthews V, Grötzinger J, Rose-John S, Kallen K-J. (2003) Signalling of human ciliary neurotrophic factor C (CNTF) revisited: the interleukin-6 receptor can serve as an α-receptor for ciliary neurotrophic factor (CNTF). J Biol Chem.; 278: 9528-35.
  • Sun Y, März P, Otten U, Ge J, Rose-John S. (2002) The Effect of gp130 stimulation on glutamate-induced excitotoxicity in primary hippocampal neurons. Biochem Biophys Res Commun.; 295: 532-9.
  • Taga T, Hibi M, Hirata Y, Yamasaki K, Yasukawa K, Matsuda T, Hirano T, Kishimoto T. (1989) Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130. Cell.; 58: 573-81.
  • Taga T, Kishimoto T. (1997) gp130 and the interleukin-6 family of cytokines. Annu Rev Immunol.; 15: 797-819.
  • Tamura T, Udagawa N, Takahashi N, Miyaura C, Tanaka S, Yamada Y, Koishihara Y, Ohsugi Y, Kumaki K, Taga T, Kishimoto T, Suda T. (1993) Soluble interleukin-6 receptor triggers osteoclast formation by interleukin 6. Proc Natl Acad Sci U S A.; 90: 11924-8.
Document Type
Publication order reference
YADDA identifier
JavaScript is turned off in your web browser. Turn it on to take full advantage of this site, then refresh the page.