Genomes and Genes
cytokine receptor gp130
Summary: A cytokine receptor that contains extracellular FIBRONECTIN TYPE III DOMAINS which mediate its function through the formation of oligomeric complexes with itself, or with a variety of CYTOKINE RECEPTORS. It does not bind IL-6, but activates JANUS KINASES and STAT3 TRANSCRIPTION FACTOR.
- Tenhumberg S, Schuster B, Zhu L, Kovaleva M, Scheller J, Kallen K, et al. gp130 dimerization in the absence of ligand: preformed cytokine receptor complexes. Biochem Biophys Res Commun. 2006;346:649-57 pubmed..The present study clearly demonstrates the existence of preformed but inactive gp130/LIF-R hetero- and gp130/gp130 homo-dimers. The addition of ligand enhanced the respective dimer formation and was required for signal transduction. ..
- Ebihara N, Matsuda A, Nakamura S, Matsuda H, Murakami A. Role of the IL-6 classic- and trans-signaling pathways in corneal sterile inflammation and wound healing. Invest Ophthalmol Vis Sci. 2011;52:8549-57 pubmed publisher..To investigate the role of the IL-6 classic- and trans-signaling pathways in corneal sterile inflammation and wound healing...
- Andratsch M, Mair N, Constantin C, Scherbakov N, Benetti C, Quarta S, et al. A key role for gp130 expressed on peripheral sensory nerves in pathological pain. J Neurosci. 2009;29:13473-83 pubmed publisher..Our results uncover the significance of gp130 expressed in peripheral pain sensing neurons in the pathophysiology of major clinical pain disorders and suggest their use as novel pain relieving agents in inflammatory and tumor pain. ..
- Yajima T, Murofushi Y, Zhou H, Park S, Housman J, Zhong Z, et al. Absence of SOCS3 in the cardiomyocyte increases mortality in a gp130-dependent manner accompanied by contractile dysfunction and ventricular arrhythmias. Circulation. 2011;124:2690-701 pubmed publisher..Our results demonstrate an important role of SOCS3 regulation on cardiac gp130 signaling in the pathogenesis of contractile dysfunction and ventricular arrhythmias. ..
- Kirsch M, Trautmann N, Ernst M, Hofmann H. Involvement of gp130-associated cytokine signaling in Müller cell activation following optic nerve lesion. Glia. 2010;58:768-79 pubmed publisher..A potential role of CNTF was possibly masked by a compensatory increase in LIF signaling in the absence of CNTF. ..
- Fischer P, Hilfiker Kleiner D. Role of gp130-mediated signalling pathways in the heart and its impact on potential therapeutic aspects. Br J Pharmacol. 2008;153 Suppl 1:S414-27 pubmed publisher..Finally, we comment on tissue-specific diversity and challenges in targeted pharmacological interference with components of the gp130 receptor system. ..
- Skiniotis G, Lupardus P, Martick M, Walz T, Garcia K. Structural organization of a full-length gp130/LIF-R cytokine receptor transmembrane complex. Mol Cell. 2008;31:737-48 pubmed publisher..These studies also enumerate the organizing principles for assembly of the "tall" class of gp130 family cytokine receptor complexes including LIF, IL-27, IL-12, and others. ..
- Sander L, Obermeier F, Dierssen U, Kroy D, Singh A, Seidler U, et al. Gp130 signaling promotes development of acute experimental colitis by facilitating early neutrophil/macrophage recruitment and activation. J Immunol. 2008;181:3586-94 pubmed..We provide evidence that IL-6 cytokines acting via gp130 are required in the acute stages of intestinal inflammation by modulating the dynamics of innate immune cell recruitment and activation. ..
- Lee I, Kim J, Choi Y, Pillinger M, Kim S, Blaser M, et al. Helicobacter pylori CagA phosphorylation status determines the gp130-activated SHP2/ERK and JAK/STAT signal transduction pathways in gastric epithelial cells. J Biol Chem. 2010;285:16042-50 pubmed publisher..These findings indicate that the phosphorylation status of CagA affects the signal switch between the SHP2/ERK and JAK/STAT3 pathways through gp130, providing a novel mechanism to explain H. pylori signaling. ..
- Brenn D, Richter F, Schaible H. Sensitization of unmyelinated sensory fibers of the joint nerve to mechanical stimuli by interleukin-6 in the rat: an inflammatory mechanism of joint pain. Arthritis Rheum. 2007;56:351-9 pubmed..IL-6 has the potential to sensitize C fibers in the joint to mechanical stimulation. Thus, IL-6 contributes to mechanical hypersensitivity, most likely due to an action of IL-6 on nerve fibers themselves. ..
- Adam N, Rabe B, Suthaus J, Grötzinger J, Rose John S, Scheller J. Unraveling viral interleukin-6 binding to gp130 and activation of STAT-signaling pathways independently of the interleukin-6 receptor. J Virol. 2009;83:5117-26 pubmed publisher..These data indicate a novel activation mechanism of human IL-6 by the IL-6R that will be important for the construction of novel hyperactive cytokine variants. ..
- Bronte Tinkew D, Terebiznik M, Franco A, Ang M, Ahn D, Mimuro H, et al. Helicobacter pylori cytotoxin-associated gene A activates the signal transducer and activator of transcription 3 pathway in vitro and in vivo. Cancer Res. 2009;69:632-9 pubmed publisher..Collectively, these results indicate that H. pylori CagA activates the STAT3 signaling pathway in vitro and in vivo, providing a potential mechanism by which chronic H. pylori infection promotes the development of gastric cancer. ..
- Suthaus J, Adam N, Grötzinger J, Scheller J, Rose John S. Viral Interleukin-6: Structure, pathophysiology and strategies of neutralization. Eur J Cell Biol. 2011;90:495-504 pubmed publisher..Furthermore, mechanisms of activation of gp130 by hIL-6, vIL-6, and by forced dimerization will be discussed. ..
- Larousserie F, Charlot P, Bardel E, Froger J, Kastelein R, Devergne O. Differential effects of IL-27 on human B cell subsets. J Immunol. 2006;176:5890-7 pubmed..These data indicate that the B cell response to IL-27 is modulated during B cell differentiation and varies depending on the mode of B cell activation. ..
- Rabe B, Chalaris A, May U, Waetzig G, Seegert D, Williams A, et al. Transgenic blockade of interleukin 6 transsignaling abrogates inflammation. Blood. 2008;111:1021-8 pubmed..In these mice, inflammatory processes are blocked as in IL6(-/-) mice, strongly arguing for a major role of the soluble IL6R during inflammation in vivo. ..
- Jones S, Scheller J, Rose John S. Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J Clin Invest. 2011;121:3375-83 pubmed publisher..Attention will be given to the role of the soluble IL-6R, and we will provide a perspective into the clinical blockade of IL-6 activity in autoimmunity, inflammation, and cancer. ..
- Cronstein B. Interleukin-6--a key mediator of systemic and local symptoms in rheumatoid arthritis. Bull NYU Hosp Jt Dis. 2007;65 Suppl 1:S11-5 pubmed..Current evidence thus strongly supports the association between IL-6 and RA symptoms and suggests that IL-6 blockade will be a useful therapeutic strategy for patients with this disease. ..
- Sander L, Sackett S, Dierssen U, Beraza N, Linke R, Muller M, et al. Hepatic acute-phase proteins control innate immune responses during infection by promoting myeloid-derived suppressor cell function. J Exp Med. 2010;207:1453-64 pubmed publisher..Thus, gp130-dependent communication between the liver and MDSCs through APPs controls inflammatory responses during infection. ..
- Tenhumberg S, Waetzig G, Chalaris A, Rabe B, Seegert D, Scheller J, et al. Structure-guided optimization of the interleukin-6 trans-signaling antagonist sgp130. J Biol Chem. 2008;283:27200-7 pubmed publisher..Finally, we demonstrate the species specificity of these mutations in the optimal triple mutein (T102Y/Q113F/N114L) both in vitro and in a mouse model of acute inflammation. ..
- Ernst M, Najdovska M, Grail D, Lundgren May T, Buchert M, Tye H, et al. STAT3 and STAT1 mediate IL-11-dependent and inflammation-associated gastric tumorigenesis in gp130 receptor mutant mice. J Clin Invest. 2008;118:1727-38 pubmed publisher..Collectively, our data have identified IL-11 as a crucial cytokine promoting chronic gastric inflammation and associated tumorigenesis mediated by excessive activation of STAT3 and STAT1. ..
- Ogura H, Murakami M, Okuyama Y, Tsuruoka M, Kitabayashi C, Kanamoto M, et al. Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction. Immunity. 2008;29:628-36 pubmed publisher..Because this mechanism also enhanced experimental autoimmune encephalomyelitis (EAE) in wild-type mice, it may be a general etiologic process underlying other Th17 cell-mediated autoimmune diseases. ..
- Schuett H, Oestreich R, Waetzig G, Annema W, Luchtefeld M, Hillmer A, et al. Transsignaling of interleukin-6 crucially contributes to atherosclerosis in mice. Arterioscler Thromb Vasc Biol. 2012;32:281-90 pubmed publisher..These data clarify, for the first time, the critical involvement of, in particular, the transsignaling of IL-6 in CAD and warrant further investigation of sgp130Fc as a novel therapeutic for the treatment of CAD and related diseases. ..
- Nishihara M, Ogura H, Ueda N, Tsuruoka M, Kitabayashi C, Tsuji F, et al. IL-6-gp130-STAT3 in T cells directs the development of IL-17+ Th with a minimum effect on that of Treg in the steady state. Int Immunol. 2007;19:695-702 pubmed..Therefore, blockade of IL-6-gp130-STAT3 pathway in CD4+ T cells could be a good target for controlling unwanted Th17-mediated immune responses including autoimmune diseases. ..
- Rose John S, Waetzig G, Scheller J, Grötzinger J, Seegert D. The IL-6/sIL-6R complex as a novel target for therapeutic approaches. Expert Opin Ther Targets. 2007;11:613-24 pubmed..An optimised variant of the recently described fusion protein sgp30Fc is now heading towards its clinical evaluation. ..
- Judd L, Bredin K, Kalantzis A, Jenkins B, Ernst M, Giraud A. STAT3 activation regulates growth, inflammation, and vascularization in a mouse model of gastric tumorigenesis. Gastroenterology. 2006;131:1073-85 pubmed..Activation of STAT3 and the microbial environment are pivotal for gastric tumor initiation and development in the gp130(757F/F) mouse, thus supporting the notion that STAT3 activation may play a role in human gastric cancer development. ..
- Sims N, Walsh N. GP130 cytokines and bone remodelling in health and disease. BMB Rep. 2010;43:513-23 pubmed
- Ruwanpura S, McLeod L, Miller A, Jones J, Bozinovski S, Vlahos R, et al. Interleukin-6 promotes pulmonary emphysema associated with apoptosis in mice. Am J Respir Cell Mol Biol. 2011;45:720-30 pubmed publisher..We propose that the discrete targeting of IL-6 signaling may provide an effective therapeutic strategy against human lung disease. ..
- Fujio Y, Maeda M, Mohri T, Obana M, Iwakura T, Hayama A, et al. Glycoprotein 130 cytokine signal as a therapeutic target against cardiovascular diseases. J Pharmacol Sci. 2011;117:213-22 pubmed..Since IL-11 is used for patients with thrombocytopenia, we propose that IL-11 is a candidate cytokine clinically available for cardioprotection therapy. ..
- Fasnacht N, Muller W. Conditional gp130 deficient mouse mutants. Semin Cell Dev Biol. 2008;19:379-84 pubmed publisher..Here, we summarize the experimental results of the conditional gp130 mutants published so far. ..
- Rose John S, Scheller J, Elson G, Jones S. Interleukin-6 biology is coordinated by membrane-bound and soluble receptors: role in inflammation and cancer. J Leukoc Biol. 2006;80:227-36 pubmed..The pathophysiological mechanisms by which the IL-6/sIL-6R complex regulates the inflammatory state are discussed. ..
- Rose John S, Mitsuyama K, Matsumoto S, Thaiss W, Scheller J. Interleukin-6 trans-signaling and colonic cancer associated with inflammatory bowel disease. Curr Pharm Des. 2009;15:2095-103 pubmed
- Suthaus J, Stuhlmann Laeisz C, Tompkins V, Rosean T, Klapper W, Tosato G, et al. HHV-8-encoded viral IL-6 collaborates with mouse IL-6 in the development of multicentric Castleman disease in mice. Blood. 2012;119:5173-81 pubmed publisher..Our results in mice suggest that human IL-6 plays an important role in the pathogenesis of HHV-8-associated MCD. ..
- Richards P, Nowell M, Horiuchi S, McLoughlin R, Fielding C, Grau S, et al. Functional characterization of a soluble gp130 isoform and its therapeutic capacity in an experimental model of inflammatory arthritis. Arthritis Rheum. 2006;54:1662-72 pubmed..In this respect, our present results suggest that the soluble gp130 isoform gp130-RAPS may be useful in the treatment of chronic inflammatory arthritis. ..
- Silver J, Stumhofer J, Passos S, Ernst M, Hunter C. IL-6 mediates the susceptibility of glycoprotein 130 hypermorphs to Toxoplasma gondii. J Immunol. 2011;187:350-60 pubmed publisher..Collectively, these studies highlight that a failure to abbreviate IL-6-mediated gp130 signaling results in a profound anti-inflammatory signal that blocks the generation of protective immunity to T. gondii. ..
- Hendriks J, Slaets H, Carmans S, de Vries H, Dijkstra C, Stinissen P, et al. Leukemia inhibitory factor modulates production of inflammatory mediators and myelin phagocytosis by macrophages. J Neuroimmunol. 2008;204:52-7 pubmed publisher..Our findings demonstrate that LIF has anti-inflammatory properties and enhances myelin clearance, implicating that LIF may be an important factor in CNS inflammatory disease. ..
- Peterson A, Menheniott T, O Connor L, Walduck A, Fox J, Kawakami K, et al. Helicobacter pylori infection promotes methylation and silencing of trefoil factor 2, leading to gastric tumor development in mice and humans. Gastroenterology. 2010;139:2005-17 pubmed publisher..TFF2 negatively regulates preneoplastic progression and subsequent tumor development in the stomach, a role that is subverted by promoter methylation during H pylori infection. ..
- Plum W, Tschaharganeh D, Kroy D, Corsten E, Erschfeld S, Dierssen U, et al. Lack of glycoprotein 130/signal transducer and activator of transcription 3-mediated signaling in hepatocytes enhances chronic liver injury and fibrosis progression in a model of sclerosing cholangitis. Am J Pathol. 2010;176:2236-46 pubmed publisher..STAT3-dependent signaling pathways in hepatocytes protect from apoptosis and tissue injury, which subsequently reduce oval cell activation and prevent fibrosis progression. ..
- Howlett M, Menheniott T, Judd L, Giraud A. Cytokine signalling via gp130 in gastric cancer. Biochim Biophys Acta. 2009;1793:1623-33 pubmed publisher..The possibility of designing and utilising small molecule inhibitors of either IL-11 or STAT3 activation may be worthwhile in developing new cancer therapeutics. ..
- Finotto S, Eigenbrod T, Karwot R, Boross I, Doganci A, Ito H, et al. Local blockade of IL-6R signaling induces lung CD4+ T cell apoptosis in a murine model of asthma via regulatory T cells. Int Immunol. 2007;19:685-93 pubmed..Local targeting of IL-6R signaling could be a novel approach for inducing Th2 T cell death in allergic airways via regulatory T cells. ..
- Kanda N, Watanabe S. IL-12, IL-23, and IL-27 enhance human beta-defensin-2 production in human keratinocytes. Eur J Immunol. 2008;38:1287-96 pubmed publisher..STAT3 and STAT1 are involved in the effects of IL-12 and IL-27, respectively. Thus, IL-12, IL-23, and IL-27 may promote cutaneous antimicrobial defense and inflammation via hBD-2. ..
- Brazda V, Klusáková I, Svízenská I, Veselková Z, Dubovy P. Bilateral changes in IL-6 protein, but not in its receptor gp130, in rat dorsal root ganglia following sciatic nerve ligature. Cell Mol Neurobiol. 2009;29:1053-62 pubmed publisher..The data provide evidence for changes in IL-6 levels not only in the DRG associated with the damaged nerve but also in those unassociated with nerve injury during the experimental neuropathic pain model. ..
- White U, Stephens J. The gp130 receptor cytokine family: regulators of adipocyte development and function. Curr Pharm Des. 2011;17:340-6 pubmed..In addition, the modulation of gp130 cytokines in conditions of obesity, insulin resistance, and Type 2 diabetes will be presented. ..
- Kroy D, Beraza N, Tschaharganeh D, Sander L, Erschfeld S, Giebeler A, et al. Lack of interleukin-6/glycoprotein 130/signal transducers and activators of transcription-3 signaling in hepatocytes predisposes to liver steatosis and injury in mice. Hepatology. 2010;51:463-73 pubmed publisher..Thus, the presented model allows one to further dissect the role of IL-6/gp130-type signaling in hepatocytes during fatty liver degeneration to define new therapeutic targets in metabolic liver diseases. ..
- Howlett M, Giraud A, Lescesen H, Jackson C, Kalantzis A, van Driel I, et al. The interleukin-6 family cytokine interleukin-11 regulates homeostatic epithelial cell turnover and promotes gastric tumor development. Gastroenterology. 2009;136:967-77 pubmed publisher..Gastric cancer is the second most common cause of cancer-related mortality worldwide, mainly as a result of late-stage detection. Interleukin (IL)-11 is a multifunctional cytokine reported to be up-regulated in human gastric cancer...
- Shoji J, Kawaguchi A, Gotoh A, Inada N, Sawa M. Concentration of soluble interleukin-6 receptors in tears of allergic conjunctival disease patients. Jpn J Ophthalmol. 2007;51:332-337 pubmed publisher..53, P < 0.01). We concluded that IL-6/sIL-6R complex trans-signaling via gp130 is an exacerbating factor of ACD, and that the concentration of sIL-6R in tears is a useful clinical biomarker in patients with ACD. ..
- Sawa S, Kamimura D, Jin G, Morikawa H, Kamon H, Nishihara M, et al. Autoimmune arthritis associated with mutated interleukin (IL)-6 receptor gp130 is driven by STAT3/IL-7-dependent homeostatic proliferation of CD4+ T cells. J Exp Med. 2006;203:1459-70 pubmed
- Jenkins B, Grail D, Nheu T, Najdovska M, Wang B, Waring P, et al. Hyperactivation of Stat3 in gp130 mutant mice promotes gastric hyperproliferation and desensitizes TGF-beta signaling. Nat Med. 2005;11:845-52 pubmed
- Vlotides G, Zitzmann K, Stalla G, Auernhammer C. Novel neurotrophin-1/B cell-stimulating factor-3 (NNT-1/BSF-3)/cardiotrophin-like cytokine (CLC)--a novel gp130 cytokine with pleiotropic functions. Cytokine Growth Factor Rev. 2004;15:325-36 pubmed..Remark: After preparation of this manuscript, another novel gp130 cytokine named neuropoietin (NP) has been reported and shown to be a ligand of the CNTFR complex. ..
- Selander K, Li L, Watson L, Merrell M, Dahmen H, Heinrich P, et al. Inhibition of gp130 signaling in breast cancer blocks constitutive activation of Stat3 and inhibits in vivo malignancy. Cancer Res. 2004;64:6924-33 pubmedThe cytokine receptor gp130 is the common signaling subunit of receptors used by the interleukin (IL)-6 cytokine family. gp130 is widely expressed in breast cancer cell lines and primary tumors...