Published online before print May 17, 2006
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
* Biochemisches Institut, Christian-Albrechts-Universität zu Kiel, Germany;
NovImmune SA, Geneva, Switzerland; and
Department of Medical Biochemistry and Immunology, The School of Medicine Cardiff University, Wales, United Kingdom
1Correspondence: Institut für Biochemie, Christian-Albrechts-Universität zu Kiel, Olshausenstr. 40, D-24098 Kiel, Germany. E-mail: rosejohn{at}biochem.uni-kiel.de
ABSTRACT
Cytokine receptors, which exist in membrane-bound and soluble forms, bind their ligands with comparable affinity. Although most soluble receptors are antagonists and compete with their membrane-associated counterparts for the ligands, certain soluble receptors are agonists. In these cases, complexes of ligand and soluble receptor bind on target cells to second receptor subunits and initiate intracellular signaling. The soluble receptors of the interleukin (IL)-6 family of cytokines (sIL-6R, sIL-11R, soluble ciliary neurotrophic factor receptor) are agonists capable of transmitting signals through interaction with the universal signal-transducing receptor for all IL-6 family cytokines, gp130. In vivo, the IL-6/sIL-6R complex stimulates several types of cells, which are unresponsive to IL-6 alone, as they do not express the membrane IL-6R. We have named this process trans-signaling. The generation of soluble cytokine receptors occurs via two distinct mechanisms—limited proteolysis and translation—from differentially spliced mRNA. We have demonstrated that a soluble form of the IL-6 family signaling receptor subunit gp130, which is generated by differential splicing, is the natural inhibitor of IL-6 trans-signaling responses. We have shown that in many chronic inflammatory diseases, including chronic inflammatory bowel disease, peritonitis, rheumatoid arthritis, asthma, as well as colon cancer, IL-6 trans-signaling is critically involved in the maintenance of a disease state, by promoting transition from acute to chronic inflammation. Moreover, in all these models, the course of the disease can be disrupted by specifically interfering with IL-6 trans-signaling using the soluble gp130 protein. The pathophysiological mechanisms by which the IL-6/sIL-6R complex regulates the inflammatory state are discussed.
Key Words: cytokine • cytokine receptor • gp130 • sgp130Fc fusion protein
This article has been cited by other articles:
 |
|
 |
|
  K Fosgerau, P Galle, T Hansen, A Albrechtsen, C d. L. Rieper, B K. Pedersen, L K. Larsen, A R. Thomsen, O Pedersen, M B. Hansen, et al. Interleukin-6 autoantibodies are involved in the pathogenesis of a subset of type 2 diabetes J. Endocrinol., March 1, 2010; 204(3): 265 - 273. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. W. Jones, R. M. McLoughlin, V. J. Hammond, C. R. Parker, J. D. Williams, R. Malhotra, J. Scheller, A. S. Williams, S. Rose-John, N. Topley, et al. 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., February 15, 2010; 184(4): 2130 - 2139. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Matsumoto, T. Hara, K. Mitsuyama, M. Yamamoto, O. Tsuruta, M. Sata, J. Scheller, S. Rose-John, S.-i. Kado, and T. Takada 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., February 1, 2010; 184(3): 1543 - 1551. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. H. Waetzig, A. Chalaris, P. Rosenstiel, J. Suthaus, C. Holland, N. Karl, L. Valles Uriarte, A. Till, J. Scheller, J. Grotzinger, et al. N-Linked Glycosylation Is Essential for the Stability but Not the Signaling Function of the Interleukin-6 Signal Transducer Glycoprotein 130 J. Biol. Chem., January 15, 2010; 285(3): 1781 - 1789. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-M. Dayer and E. Choy Therapeutic targets in rheumatoid arthritis: the interleukin-6 receptor Rheumatology, January 1, 2010; 49(1): 15 - 24. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Crabe, A. Guay-Giroux, A. J. Tormo, D. Duluc, R. Lissilaa, F. Guilhot, U. Mavoungou-Bigouagou, F. Lefouili, I. Cognet, W. Ferlin, et al. The IL-27 p28 Subunit Binds Cytokine-Like Factor 1 to Form a Cytokine Regulating NK and T Cell Activities Requiring IL-6R for Signaling J. Immunol., December 15, 2009; 183(12): 7692 - 7702. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Kim, I. C. Bagchi, and M. K. Bagchi Control of ovulation in mice by progesterone receptor-regulated gene networks Mol. Hum. Reprod., December 1, 2009; 15(12): 821 - 828. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. C. Sturgis, J. G. Cannon, D. A. Schreihofer, and M. W. Brands The role of aldosterone in mediating the dependence of angiotensin hypertension on IL-6 Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2009; 297(6): R1742 - R1748. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-Y. KAWASHIRI, A. KAWAKAMI, N. IWAMOTO, K. FUJIKAWA, T. ARAMAKI, M. TAMAI, K. ARIMA, M. KAMACHI, S. YAMASAKI, H. NAKAMURA, et al. Proinflammatory Cytokines Synergistically Enhance the Production of Chemokine Ligand 20 (CCL20) from Rheumatoid Fibroblast-like Synovial Cells in vitro and Serum CCL20 Is Reduced in vivo by Biologic Disease-modifying Antirheumatic Drugs J Rheumatol, November 1, 2009; 36(11): 2397 - 2402. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. K. Chatterjee, Y. Al-Abed, B. Sherry, and C. N. Metz Cholinergic agonists regulate JAK2/STAT3 signaling to suppress endothelial cell activation Am J Physiol Cell Physiol, November 1, 2009; 297(5): C1294 - C1306. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Andratsch, N. Mair, C. E. Constantin, N. Scherbakov, C. Benetti, S. Quarta, C. Vogl, C. A. Sailer, N. Uceyler, J. Brockhaus, et al. A Key Role for gp130 Expressed on Peripheral Sensory Nerves in Pathological Pain J. Neurosci., October 28, 2009; 29(43): 13473 - 13483. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Mack, R. S. BelAiba, T. Djordjevic, A. Gorlach, H. Hauner, and B. L. Bader Functional analyses reveal the greater potency of preadipocytes compared with adipocytes as endothelial cell activator under normoxia, hypoxia, and TNF{alpha} exposure Am J Physiol Endocrinol Metab, September 1, 2009; 297(3): E735 - E748. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Brahmachari and K. Pahan Suppression of Regulatory T Cells by IL-12p40 Homodimer via Nitric Oxide J. Immunol., August 1, 2009; 183(3): 2045 - 2058. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Chen, R. Das, R. Komorowski, A. Beres, M. J. Hessner, M. Mihara, and W. R. Drobyski Blockade of interleukin-6 signaling augments regulatory T-cell reconstitution and attenuates the severity of graft-versus-host disease Blood, July 23, 2009; 114(4): 891 - 900. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. A. Kaminski, A. Kozieradzka, T. Bonda, M. Banach, M. Kozuch, I. Wojtkowska, S. Dobrzycki, P. Kralisz, K. Nowak, P. Prokopczuk, et al. Percutaneous Coronary Interventions Affect Concentrations of Interleukin 6 and Its Soluble Receptors in Coronary Sinus Blood in Patients With Stable Angina Angiology, June 1, 2009; 60(3): 322 - 328. [Abstract] [PDF]
|
|
|
|
|
|
A. T. Dulay, C. S. Buhimschi, G. Zhao, E. A. Oliver, A. Mbele, S. Jing, and I. A. Buhimschi Soluble TLR2 Is Present in Human Amniotic Fluid and Modulates the Intraamniotic Inflammatory Response to Infection J. Immunol., June 1, 2009; 182(11): 7244 - 7253. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Cousin, D. Bracquart, A. Contrepas, P. Corvol, L. Muller, and G. Nguyen Soluble Form of the (Pro)Renin Receptor Generated by Intracellular Cleavage by Furin Is Secreted in Plasma Hypertension, June 1, 2009; 53(6): 1077 - 1082. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Chen, A. Frister, S. Wang, A. Ludwig, H. Behr, S. Pippig, B. Li, A. Simm, B. Hofmann, C. Pilowski, et al. Interaction of vascular smooth muscle cells and monocytes by soluble factors synergistically enhances IL-6 and MCP-1 production Am J Physiol Heart Circ Physiol, April 1, 2009; 296(4): H987 - H996. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. R. Mathers, B. M. Janelsins, J. P. Rubin, O. A. Tkacheva, W. J. Shufesky, S. C. Watkins, A. E. Morelli, and A. T. Larregina Differential Capability of Human Cutaneous Dendritic Cell Subsets to Initiate Th17 Responses J. Immunol., January 15, 2009; 182(2): 921 - 933. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Nowell, A. S. Williams, S. A. Carty, J. Scheller, A. J. Hayes, G. W. Jones, P. J. Richards, S. Slinn, M. Ernst, B. J. Jenkins, et al. Therapeutic Targeting of IL-6 Trans Signaling Counteracts STAT3 Control of Experimental Inflammatory Arthritis J. Immunol., January 1, 2009; 182(1): 613 - 622. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Islam, X. Gong, S. Rose-John, and K. Heese Interleukin-6 and Neural Stem Cells: More Than Gliogenesis Mol. Biol. Cell, January 1, 2009; 20(1): 188 - 199. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Nishimoto, K. Terao, T. Mima, H. Nakahara, N. Takagi, and T. Kakehi Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease Blood, November 15, 2008; 112(10): 3959 - 3964. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Tenhumberg, G. H. Waetzig, A. Chalaris, B. Rabe, D. Seegert, J. Scheller, S. Rose-John, and J. Grotzinger Structure-guided Optimization of the Interleukin-6 Trans-signaling Antagonist sgp130 J. Biol. Chem., October 3, 2008; 283(40): 27200 - 27207. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Simon, A. K. O. Denniston, P. J. Tomlins, G. R. Wallace, S. Rauz, M. Salmon, P. I. Murray, and S. J. Curnow Soluble gp130, an Antagonist of IL-6 Transsignaling, Is Elevated in Uveitis Aqueous Humor Invest. Ophthalmol. Vis. Sci., September 1, 2008; 49(9): 3988 - 3991. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. R. Velez, S. J. Fortunato, S. M. Williams, and R. Menon Interleukin-6 (IL-6) and receptor (IL6-R) gene haplotypes associate with amniotic fluid protein concentrations in preterm birth Hum. Mol. Genet., June 1, 2008; 17(11): 1619 - 1630. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. M. Briso, O. Dienz, and M. Rincon Cutting Edge: Soluble IL-6R Is Produced by IL-6R Ectodomain Shedding in Activated CD4 T Cells J. Immunol., June 1, 2008; 180(11): 7102 - 7106. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Rabe, A. Chalaris, U. May, G. H. Waetzig, D. Seegert, A. S. Williams, S. A. Jones, S. Rose-John, and J. Scheller Transgenic blockade of interleukin 6 transsignaling abrogates inflammation Blood, February 1, 2008; 111(3): 1021 - 1028. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. V. Popovic, R. Sandhoff, T. P. Sijmonsma, S. Kaden, R. Jennemann, E. Kiss, E. Tone, F. Autschbach, N. Platt, E. Malle, et al. Sulfated Glycosphingolipid as Mediator of Phagocytosis: SM4s Enhances Apoptotic Cell Clearance and Modulates Macrophage Activity J. Immunol., November 15, 2007; 179(10): 6770 - 6782. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Dominguez-Villar, A. Munoz-Suano, B. Anaya-Baz, S. Aguilar, J. P. Novalbos, J. A. Giron, M. Rodriguez-Iglesias, and F. Garcia-Cozar Hepatitis C virus core protein up-regulates anergy-related genes and a new set of genes, which affects T cell homeostasis J. Leukoc. Biol., November 1, 2007; 82(5): 1301 - 1310. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Pejcic-Karapetrovic, K. Gurnani, M. S. Russell, B. B. Finlay, S. Sad, and L. Krishnan Pregnancy Impairs the Innate Immune Resistance to Salmonella typhimurium Leading to Rapid Fatal Infection J. Immunol., November 1, 2007; 179(9): 6088 - 6096. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Dominitzki, M. C. Fantini, C. Neufert, A. Nikolaev, P. R. Galle, J. Scheller, G. Monteleone, S. Rose-John, M. F. Neurath, and C. Becker Cutting Edge: Trans-Signaling via the Soluble IL-6R Abrogates the Induction of FoxP3 in Naive CD4+CD25 T Cells J. Immunol., August 15, 2007; 179(4): 2041 - 2045. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Chattopadhyay, E. Tracy, P. Liang, O. Robledo, S. Rose-John, and H. Baumann Interleukin-31 and Oncostatin-M Mediate Distinct Signaling Reactions and Response Patterns in Lung Epithelial Cells J. Biol. Chem., February 2, 2007; 282(5): 3014 - 3026. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Shore Obesity and asthma: lessons from animal models J Appl Physiol, February 1, 2007; 102(2): 516 - 528. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Ammit, L. M. Moir, B. G. Oliver, J. M. Hughes, H. Alkhouri, Q. Ge, J. K. Burgess, J. L. Black, and M. Roth Effect of IL-6 trans-signaling on the pro-remodeling phenotype of airway smooth muscle Am J Physiol Lung Cell Mol Physiol, January 1, 2007; 292(1): L199 - L206. [Abstract] [Full Text] [PDF]
|
|
