{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T02:42:31Z","timestamp":1792723351766,"version":"4.5.0"},"reference-count":172,"publisher":"Portland Press Ltd.","issue":"4","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2012,2,1]]},"abstract":"<jats:p>IL (interleukin)-6, which was originally identified as a B-cell differentiation factor, is a multifunctional cytokine that regulates the immune response, haemopoiesis, the acute phase response and inflammation. IL-6 is produced by various types of cell and influences various cell types, and has multiple biological activities through its unique receptor system. IL-6 exerts its biological activities through two molecules: IL-6R (IL-6 receptor) and gp130. When IL-6 binds to mIL-6R (membrane-bound form of IL-6R), homodimerization of gp130 is induced and a high-affinity functional receptor complex of IL-6, IL-6R and gp130 is formed. Interestingly, sIL-6R (soluble form of IL-6R) also binds with IL-6, and the IL-6\u2013sIL-6R complex can then form a complex with gp130. The homodimerization of receptor complex activates JAKs (Janus kinases) that then phosphorylate tyrosine residues in the cytoplasmic domain of gp130. The gp130-mediated JAK activation by IL-6 triggers two main signalling pathways: the gp130 Tyr759-derived SHP-2 (Src homology 2 domain-containing protein tyrosine phosphatase-2)\/ERK (extracellular-signal-regulated kinase) MAPK (mitogen-activated protein kinase) pathway and the gp130 YXXQ-mediated JAK\/STAT (signal transducer and activator of transcription) pathway. Increased IL-6 levels are observed in several human inflammatory diseases, such as rheumatoid arthritis, Castleman's disease and systemic juvenile idiopathic arthritis. IL-6 is also critically involved in experimentally induced autoimmune diseases. All clinical findings and animal models suggest that IL-6 plays a number of critical roles in the pathogenesis of autoimmune diseases. In the present review, we first summarize the IL-6\/IL-6R system and IL-6 signal transduction, and then go on to discuss the physiological and pathological roles of IL-6.<\/jats:p>","DOI":"10.1042\/cs20110340","type":"journal-article","created":{"date-parts":[[2011,10,14]],"date-time":"2011-10-14T08:19:10Z","timestamp":1318580350000},"page":"143-159","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":756,"title":["IL-6\/IL-6 receptor system and its role in physiological and pathological conditions"],"prefix":"10.1042","volume":"122","author":[{"given":"Masahiko","family":"Mihara","sequence":"first","affiliation":[{"name":"Fuji-Gotemba Research Laboratories, Product Research Department, Chugai Pharmaceutical Co. 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Ther."},{"key":"2021113010223213300_B6","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1016\/0092-8674(90)90411-7","article-title":"Molecular cloning and expression of an IL-6 signal transducer, gp130","volume":"63","author":"Hibi","year":"1990","journal-title":"Cell"},{"key":"2021113010223213300_B7","doi-asserted-by":"crossref","first-page":"3593","DOI":"10.1242\/jcs.113.20.3593","article-title":"The cytoplasmic domain of the interleukin-6 receptor gp80 mediates its basolateral sorting in polarized Madin\u2013Darby canine kidney cells","volume":"113","author":"Martens","year":"2000","journal-title":"J. Cell Sci."},{"key":"2021113010223213300_B8","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/S1074-7613(04)00003-2","article-title":"IL-6 trans-signaling: the heat is on","volume":"20","author":"Rose-John","year":"2004","journal-title":"Immunity"},{"key":"2021113010223213300_B9","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1182\/blood.V82.4.1120.1120","article-title":"Soluble forms of the interleukin-6 signal-transducing receptor component gp130 in human serum possessing a potential to inhibit signals through membrane-anchored gp130","volume":"82","author":"Narazaki","year":"1993","journal-title":"Blood"},{"key":"2021113010223213300_B10","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1046\/j.1432-1327.2001.01867.x","article-title":"Soluble gp130 is the natural inhibitor of soluble interleukin-6 receptor transsignaling responses","volume":"268","author":"Jostock","year":"2001","journal-title":"Eur. J. 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Immunol."},{"key":"2021113010223213300_B16","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1038\/ni1084","article-title":"Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice","volume":"5","author":"Dillon","year":"2004","journal-title":"Nat. Immunol."},{"key":"2021113010223213300_B17","doi-asserted-by":"crossref","first-page":"2225","DOI":"10.4049\/jimmunol.172.4.2225","article-title":"WSX-1 and glycoprotein 130 constitute a signal-transducing receptor for IL-27","volume":"172","author":"Pflanz","year":"2004","journal-title":"J. Immunol."},{"key":"2021113010223213300_B18","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1038\/nri2580","article-title":"New insights into the regulation of T cells by \u03b3c family cytokines","volume":"9","author":"Rochman","year":"2009","journal-title":"Nat. Rev. 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Chem."},{"key":"2021113010223213300_B21","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/S1359-6101(98)80005-1","article-title":"Signaling mechanisms through gp130: a model of the cytokine system","volume":"8","author":"Hirano","year":"1997","journal-title":"Cytokine Growth Factor Rev."},{"key":"2021113010223213300_B22","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1016\/S1357-2725(98)00067-3","article-title":"SOCS: suppressors of cytokine signalling","volume":"30","author":"Starr","year":"1998","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"2021113010223213300_B23","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.bbrc.2010.10.135","article-title":"High molecular weight hyaluronic acid inhibits IL-6-induced MMP production from human chondrocytes by up-regulating the ERK inhibitor, MKP-1","volume":"403","author":"Hashizume","year":"2010","journal-title":"Biochem. Biophys. Res. 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Pharm. Bull."},{"key":"2021113010223213300_B33","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1038\/368339a0","article-title":"Impaired immune and acute-phase responses in interleukin-6-deficient mice","volume":"368","author":"Kopf","year":"1994","journal-title":"Nature"},{"key":"2021113010223213300_B34","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/0049-0172(92)90001-T","article-title":"Amyloidosis. Semin","volume":"22","author":"Husby","year":"1992","journal-title":"Arthritis Rheum."},{"key":"2021113010223213300_B35","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1159\/000045265","article-title":"Crohn's disease with amyloid A amyloidosis and nephrotic syndrome","volume":"81","author":"Enriquez","year":"1999","journal-title":"Nephron"},{"key":"2021113010223213300_B36","doi-asserted-by":"crossref","first-page":"119","DOI":"10.3109\/13506129409148635","article-title":"Serum amyloid A (SAA): biochemistry, genetics and the pathogenesis of AA amyloidosis","volume":"1","author":"Husby","year":"1994","journal-title":"Amyloid"},{"key":"2021113010223213300_B37","first-page":"1132","article-title":"Anti-interleukin 6 receptor antibody inhibits murine AA-amyloidosis","volume":"31","author":"Mihara","year":"2004","journal-title":"J. Rheumatol."},{"key":"2021113010223213300_B38","doi-asserted-by":"crossref","first-page":"2997","DOI":"10.1002\/art.22118","article-title":"Successful use of a humanized anti-interleukin-6 receptor antibody, tocilizumab, to treat amyloid A amyloidosis complicating juvenile idiopathic arthritis","volume":"54","author":"Okuda","year":"2006","journal-title":"Arthritis Rheum."},{"key":"2021113010223213300_B39","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1136\/ard.2008.099267","article-title":"Rapid improvement of AA amyloidosis with humanised anti-interleukin 6 receptor antibody treatment","volume":"68","author":"Nishida","year":"2009","journal-title":"Ann. Rheum. Dis."},{"key":"2021113010223213300_B40","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1126\/science.274.5291.1379","article-title":"Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice","volume":"274","author":"Cressman","year":"1996","journal-title":"Science"},{"key":"2021113010223213300_B41","doi-asserted-by":"crossref","first-page":"1861","DOI":"10.1016\/S0024-3205(01)01264-4","article-title":"Elevated levels of vascular endothelial growth factor in the sera of patients with rheumatoid arthritis correlation with disease activity","volume":"69","author":"Sone","year":"2001","journal-title":"Life Sci."},{"key":"2021113010223213300_B42","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1002\/art.11143","article-title":"Anti-interleukin-6 receptor antibody therapy reduces vascular endothelial growth factor production in rheumatoid arthritis","volume":"48","author":"Nakahara","year":"2003","journal-title":"Arthritis Rheum."},{"key":"2021113010223213300_B43","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1007\/s00296-009-0885-8","article-title":"IL-6\/sIL-6R trans-signalling, but not TNF-\u03b1 induced angiogenesis in a HUVEC and synovial cell co-culture system","volume":"29","author":"Hashizume","year":"2009","journal-title":"Rheumatol. Int."},{"key":"2021113010223213300_B44","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1007\/s00256-010-1064-4","article-title":"Monitoring anti-interleukin 6 receptor antibody treatment for rheumatoid arthritis by quantitative magnetic resonance imaging of the hand and power Doppler ultrasonography of the finger","volume":"40","author":"Kamishima","year":"2011","journal-title":"Skeletal Radiol."},{"key":"2021113010223213300_B45","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1001\/archopht.120.3.338","article-title":"Prevention of experimental choroidal neovascularization with intravitreal anti-vascular endothelial growth factor antibody fragment","volume":"120","author":"Krzystolik","year":"2002","journal-title":"Arch. Ophthalmol."},{"key":"2021113010223213300_B46","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1056\/NEJMoa054481","article-title":"Ranibizumab for neovascular age-related macular degeneration","volume":"355","author":"Rosenfeld","year":"2006","journal-title":"N. Engl. J. Med."},{"key":"2021113010223213300_B47","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1001\/archopht.123.6.774","article-title":"Progression of age-related macular degeneration: prospective assessment of C-reactive protein, interleukin 6, and other cardiovascular biomarkers","volume":"123","author":"Seddon","year":"2005","journal-title":"Arch. Ophthalmol."},{"key":"2021113010223213300_B48","doi-asserted-by":"crossref","first-page":"2149","DOI":"10.2353\/ajpath.2007.061018","article-title":"Interleukin-6 receptor-mediated activation of signal transducer and activator of transcription-3 (STAT3) promotes choroidal neovascularization","volume":"170","author":"Izumi-Nagai","year":"2007","journal-title":"Am. J. Pathol."},{"key":"2021113010223213300_B49","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1182\/blood.V73.1.108.108","article-title":"In vivo hematologic effects of recombinant interleukin-6 on hematopoiesis and circulating numbers of RBCs and WBCs","volume":"73","author":"Ulich","year":"1989","journal-title":"Blood"},{"key":"2021113010223213300_B50","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1097\/MOH.0b013e3283333930","article-title":"Recent developments and complexities in neutrophil transmigration","volume":"17","author":"Woodfin","year":"2010","journal-title":"Curr. Opin. Hematol."},{"key":"2021113010223213300_B51","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/S1074-7613(00)80334-9","article-title":"Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment","volume":"6","author":"Romano","year":"1997","journal-title":"Immunity"},{"key":"2021113010223213300_B52","doi-asserted-by":"crossref","first-page":"2752","DOI":"10.1172\/JCI119821","article-title":"Retrograde inflammatory signaling from neutrophils to endothelial cells by soluble interleukin-6 receptor \u03b1","volume":"100","author":"Modur","year":"1997","journal-title":"J. Clin. Invest."},{"key":"2021113010223213300_B53","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1007\/s00296-009-0953-0","article-title":"Anti-inflammatory mechanism of tocilizumab, a humanized anti-IL-6R antibody: effect on the expression of chemokine and adhesion molecule","volume":"30","author":"Suzuki","year":"2010","journal-title":"Rheumatol. Int."},{"key":"2021113010223213300_B54","doi-asserted-by":"crossref","first-page":"2397","DOI":"10.3899\/jrheum.090132","article-title":"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","volume":"36","author":"Kawashiri","year":"2009","journal-title":"J. Rheumatol."},{"key":"2021113010223213300_B55","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1182\/blood-2007-07-102137","article-title":"Transgenic blockade of interleukin 6 transsignaling abrogates inflammation","volume":"111","author":"Rabe","year":"2008","journal-title":"Blood"},{"key":"2021113010223213300_B56","doi-asserted-by":"crossref","first-page":"1601","DOI":"10.4049\/jimmunol.167.3.1601","article-title":"Essential role of neutrophils in the initiation and progression of a murine model of rheumatoid arthritis","volume":"167","author":"Wipke","year":"2001","journal-title":"J. Immunol."},{"key":"2021113010223213300_B57","doi-asserted-by":"crossref","first-page":"1827","DOI":"10.1016\/S0002-9440(10)63542-0","article-title":"Collagen type\u00a0II-specific monoclonal antibody-induced arthritis in mice: description of the disease and the influence of age, sex, and genes","volume":"163","author":"Nandakumar","year":"2003","journal-title":"Am. J. Pathol."},{"key":"2021113010223213300_B58","doi-asserted-by":"crossref","first-page":"5193","DOI":"10.1182\/blood-2008-02-139535","article-title":"A key role for G-CSF-induced neutrophil production and trafficking during inflammatory arthritis","volume":"112","author":"Eyles","year":"2009","journal-title":"Blood"},{"key":"2021113010223213300_B59","doi-asserted-by":"crossref","first-page":"311","DOI":"10.3109\/10739689709146794","article-title":"Regulation of E-selectin, P-selectin, and intercellular adhesion molecule 1 expression in mouse cremaster muscle vasculature","volume":"4","author":"Jung","year":"1997","journal-title":"Microcirculation"},{"key":"2021113010223213300_B60","doi-asserted-by":"crossref","first-page":"H879","DOI":"10.1152\/ajpheart.00185.2002","article-title":"The effect of interleukin-6 on L-selectin levels on polymorphonuclear leukocytes","volume":"283","author":"Suwa","year":"2002","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"2021113010223213300_B61","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.cyto.2011.01.007","article-title":"IL-6 plays an essential role in neutrophilia under inflammation","volume":"54","author":"Hashizume","year":"2011","journal-title":"Cytokine"},{"key":"2021113010223213300_B62","first-page":"1426","article-title":"Toxicity, pharmacokinetics, and dose-finding study of repetitive treatment with the humanized anti-interleukin 6 receptor antibody MRA in rheumatoid arthritis. Phase I\/II clinical study","volume":"30","author":"Nishimoto","year":"2003","journal-title":"J. Rheumatol."},{"key":"2021113010223213300_B63","doi-asserted-by":"crossref","first-page":"2817","DOI":"10.1002\/art.22033","article-title":"Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate","volume":"54","author":"Maini","year":"2006","journal-title":"Arthritis Rheum."},{"key":"2021113010223213300_B64","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1084\/jem.167.2.332","article-title":"The essential role of B cell stimulatory factor 2 (BSF-2\/IL-6) for the terminal differentiation of B cells","volume":"167","author":"Muraguchi","year":"1988","journal-title":"J. Exp. Med."},{"key":"2021113010223213300_B65","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1084\/jem.20081571","article-title":"The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4+ T cells","volume":"206","author":"Dienz","year":"2009","journal-title":"J. Exp. Med."},{"key":"2021113010223213300_B66","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1073\/pnas.84.1.228","article-title":"Human B-cell differentiation factor defined by an anti-peptide antibody and its possible role in autoantibody production","volume":"84","author":"Hirano","year":"1987","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021113010223213300_B67","doi-asserted-by":"crossref","first-page":"7547","DOI":"10.1073\/pnas.86.19.7547","article-title":"IgG1 plasmacytosis in interleukin 6 transgenic mice","volume":"86","author":"Suematsu","year":"1989","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021113010223213300_B68","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1046\/j.1365-2249.1998.00612.x","article-title":"IL-6 receptor blockage inhibits the onset of autoimmune kidney disease in NZB\/W F1 mice","volume":"112","author":"Mihara","year":"1998","journal-title":"Clin. Exp. Immunol."},{"key":"2021113010223213300_B69","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1111\/j.1365-2249.1990.tb05485.x","article-title":"Immunologic abnormality in NZB\/W F1 mice. Thymus-independent expansion of B cells responding to interleukin-6","volume":"82","author":"Mihara","year":"1990","journal-title":"Clin. Exp. 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Rheumatol."},{"key":"2021113010223213300_B72","doi-asserted-by":"crossref","first-page":"2084","DOI":"10.1002\/art.21942","article-title":"Regulation of pre-B cell colony-enhancing factor by STAT-3-dependent interleukin-6 trans-signaling: implications in the pathogenesis of rheumatoid arthritis","volume":"54","author":"Nowell","year":"2006","journal-title":"Arthritis Rheum."},{"key":"2021113010223213300_B73","first-page":"1431","article-title":"Cloning and characterization of the cDNA encoding a novel human pre-B-cell colony-enhancing factor Mol","volume":"14","author":"Samal","year":"1994","journal-title":"Cell. Biol."},{"key":"2021113010223213300_B74","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1084\/jem.167.3.1253","article-title":"B cell stimulating factor 2\/interleukin 6 is a costimulant for human thymocytes and T lymphocytes","volume":"167","author":"Lotz","year":"1988","journal-title":"J. Exp. Med."},{"key":"2021113010223213300_B75","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/S0165-2478(02)00202-X","article-title":"Characterization of anti-mouse interleukin-6 receptor antibody","volume":"84","author":"Okazaki","year":"2002","journal-title":"Immunol. Lett."},{"key":"2021113010223213300_B76","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.ejphar.2010.02.026","article-title":"Anti-IL-6 receptor antibody suppressed T cell activation by inhibiting IL-2 production and inducing regulatory T cells","volume":"634","author":"Yoshida","year":"2010","journal-title":"Eur. J. Pharmacol."},{"key":"2021113010223213300_B77","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/S0161-5890(02)00210-9","article-title":"The two faces of IL-6 on Th1\/Th2 differentiation","volume":"39","author":"Diehl","year":"2002","journal-title":"Mol. 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Natl. Acad. Sci. U.S.A."},{"key":"2021113010223213300_B82","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1093\/rheumatology\/ken489","article-title":"Involvement of Th17 cells and the effect of anti-IL-6 therapy in autoimmune uveitis","volume":"48","author":"Yoshimura","year":"2009","journal-title":"Rheumatology"},{"key":"2021113010223213300_B83","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1002\/ibd.21384","article-title":"Comparative analysis of the effects of anti-IL-6 receptor mAb and anti-TNF mAb treatment on CD4+ T-cell responses in murine colitis","volume":"17","author":"Terabe","year":"2011","journal-title":"Inflamm. Bowel Dis."},{"key":"2021113010223213300_B84","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.molimm.2008.12.019","article-title":"Properties and origin of human Th17 cells","volume":"47","author":"Romagnani","year":"2009","journal-title":"Mol. 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Immunol."},{"key":"2021113010223213300_B87","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1002\/j.1460-2075.1994.tb06368.x","article-title":"Interleukin-6 deficient mice are protected from bone loss caused by estrogen depletion","volume":"13","author":"Poli","year":"1994","journal-title":"EMBO J."},{"key":"2021113010223213300_B88","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1359\/jbmr.1997.12.6.935","article-title":"The functional block of TNF but not of IL-6 prevents bone loss in ovariectomized mice","volume":"12","author":"Kimble","year":"1997","journal-title":"J. Bone Miner. Res."},{"key":"2021113010223213300_B89","doi-asserted-by":"crossref","first-page":"1926","DOI":"10.1002\/jbmr.5650111214","article-title":"Lack of evidence for an increase in interleukin-6 expression in adult murine bone, bone marrow, and marrow stromal cell cultures after ovariectomy","volume":"11","author":"Vargas","year":"1996","journal-title":"J. Bone Miner. Res."},{"key":"2021113010223213300_B90","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1002\/jbmr.5650110113","article-title":"Interleukin-6 and soluble interleukin-6 receptors in the synovial fluids from rheumatoid arthritis patients are responsible for osteoclast-like cell formation","volume":"11","author":"Kotake","year":"1996","journal-title":"J. Bone Miner. Res."},{"key":"2021113010223213300_B91","doi-asserted-by":"crossref","first-page":"19301","DOI":"10.1074\/jbc.274.27.19301","article-title":"STAT3 activation in stromal\/osteoblastic cells is required for induction of the receptor activator of NF-\u03baB ligand and stimulation of osteoclastogenesis by gp130-utilizing cytokines or interleukin-1 but not 1,25-dihydroxyvitamin D3 or parathyroid hormone","volume":"274","author":"O'Brien","year":"1999","journal-title":"J. Biol. Chem."},{"key":"2021113010223213300_B92","doi-asserted-by":"crossref","first-page":"11535","DOI":"10.1074\/jbc.M607999200","article-title":"Interleukin-6 directly inhibits osteoclast differentiation by suppressing receptor activator of NF-\u03baB signaling pathways","volume":"283","author":"Yoshitake","year":"2008","journal-title":"J. Biol. Chem."},{"key":"2021113010223213300_B93","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1111\/j.1365-2249.2010.04276.x","article-title":"Intercellular adhesion molecule-1 on synovial cells attenuated interleukin-6-induced inhibition of osteoclastogenesis induced by receptor activator for nuclear factor \u03baB ligand","volume":"163","author":"Suzuki","year":"2011","journal-title":"Clin. Exp. 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Dis."},{"key":"2021113010223213300_B113","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1136\/ard.2008.104844","article-title":"Overproduced interleukin 6 decreases blood lipid levels via upregulation of very-low-density lipoprotein receptor","volume":"69","author":"Hashizume","year":"2010","journal-title":"Ann. Rheum. Dis."},{"key":"2021113010223213300_B114","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1038\/oby.2004.51","article-title":"High local concentrations and effects on differentiation implicate interleukin-6 as a paracrine regulator","volume":"12","author":"Sopasakis","year":"2004","journal-title":"Obes. Res."},{"key":"2021113010223213300_B115","doi-asserted-by":"crossref","first-page":"5577","DOI":"10.1210\/jc.2004-0603","article-title":"Interleukin-6 regulates human adipose tissue lipid metabolism and leptin production in vitro","volume":"89","author":"Trujillo","year":"2004","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"2021113010223213300_B116","doi-asserted-by":"crossref","first-page":"E155","DOI":"10.1152\/ajpendo.00257.2004","article-title":"Acute IL-6 treatment increases fatty acid turnover in elderly humans in vivo and in tissue culture in vitro","volume":"288","author":"Petersen","year":"2005","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"2021113010223213300_B117","doi-asserted-by":"crossref","first-page":"3005","DOI":"10.1210\/jc.2002-021687","article-title":"Interleukin-6 stimulates lipolysis and fat oxidation in humans","volume":"88","author":"van Hall","year":"2003","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"2021113010223213300_B118","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1016\/S0022-2275(20)42003-6","article-title":"Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression","volume":"37","author":"Schoonjans","year":"1996","journal-title":"J. Lipid Res."},{"key":"2021113010223213300_B119","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/S0022-2275(20)31655-2","article-title":"Disturbances in the normal regulation of SREBP-sensitive genes in PPAR\u03b1-deficient mice","volume":"42","author":"Patel","year":"2001","journal-title":"J. Lipid Res."},{"key":"2021113010223213300_B120","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1172\/JCI0215593","article-title":"SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver","volume":"109","author":"Horton","year":"2002","journal-title":"J. Clin. Invest."},{"key":"2021113010223213300_B121","doi-asserted-by":"crossref","first-page":"30028","DOI":"10.1074\/jbc.274.42.30028","article-title":"Increased levels of nuclear SREBP-1c associated with fatty livers in two mouse models of diabetes mellitus","volume":"274","author":"Shimomura","year":"1999","journal-title":"J. Biol. Chem."},{"key":"2021113010223213300_B122","doi-asserted-by":"crossref","first-page":"325","DOI":"10.2492\/inflammregen.31.325","article-title":"IL-6 and lipid metabolism","volume":"31","author":"Hashizume","year":"2011","journal-title":"Inflammation Regener."},{"key":"2021113010223213300_B123","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.1002\/art.20303","article-title":"Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial","volume":"50","author":"Nishimoto","year":"2004","journal-title":"Arthritis Rheum."},{"key":"2021113010223213300_B124","first-page":"1997","article-title":"Infliximab but not methotrexate induces extra-high levels of VLDL-triglyceride in patients with rheumatoid arthritis","volume":"34","author":"Saiki","year":"2007","journal-title":"J. Rheumatol."},{"key":"2021113010223213300_B125","first-page":"2311","article-title":"Lipid profiles among US elderly with untreated rheumatoid arthritis: the Third National Health and Nutrition Examination Survey","volume":"32","author":"Choi","year":"2005","journal-title":"J. Rheumatol."},{"key":"2021113010223213300_B126","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/S0002-9343(02)01186-5","article-title":"Effects of antirheumatic therapy on serum lipid levels in patients with rheumatoid arthritis: a prospective study","volume":"113","author":"Park","year":"2002","journal-title":"Am. J. Med."},{"key":"2021113010223213300_B127","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1196\/annals.1351.039","article-title":"Effects of anti-TNF-\u03b1 treatment on lipid profile in patients with active rheumatoid arthritis","volume":"1069","author":"Seriolo","year":"2006","journal-title":"Ann. NY Acad. Sci."},{"key":"2021113010223213300_B128","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1007\/s00296-009-1303-y","article-title":"Effects of the anti-interleukin-6 receptor antibody, tocilizumab, on serum lipid levels in patients with rheumatoid arthritis","volume":"31","author":"Kawashiri","year":"2011","journal-title":"Rheumatol. Int."},{"key":"2021113010223213300_B129","first-page":"695","article-title":"Changes of cytokines and thyroid function in patients with recurrent breast cancer","volume":"17","author":"Yokoe","year":"1997","journal-title":"Anticancer Res."},{"key":"2021113010223213300_B130","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1097\/00000658-199803000-00012","article-title":"Marked elevation of serum interleukin-6 in patients with cholangiocarcinoma: validation of utility as a clinical marker","volume":"227","author":"Goydos","year":"1998","journal-title":"Ann. Surg."},{"key":"2021113010223213300_B131","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/S0022-5347(01)62092-5","article-title":"Elevated levels of circulating interleukin-6 and transforming growth factor-\u03b21 in patients with metastatic prostatic carcinoma","volume":"161","author":"Adler","year":"1999","journal-title":"J. Urol."},{"key":"2021113010223213300_B132","first-page":"523","article-title":"Soluble immunological parameters and early prognosis of renal cell cancer patients","volume":"20","author":"Kallio","year":"2001","journal-title":"J. Exp. Clin. 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Immunol."},{"key":"2021113010223213300_B136","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/S1359-6101(00)00021-6","article-title":"Interleukin-6 and prostate cancer progression","volume":"12","author":"Smith","year":"2001","journal-title":"Cytokine Growth Factor Rev."},{"key":"2021113010223213300_B137","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/0014-5793(89)80805-1","article-title":"Interleukin-6 (IL-6) functions as an in vitro autocrine growth factor in renal cell carcinomas","volume":"250","author":"Miki","year":"1989","journal-title":"FEBS Lett."},{"key":"2021113010223213300_B138","doi-asserted-by":"crossref","first-page":"2822","DOI":"10.1038\/sj.onc.1210097","article-title":"The antiapoptotic effect of IL-6 autocrine loop in a cellular model of advanced prostate cancer is mediated by Mcl-1","volume":"26","author":"Cavarretta","year":"2007","journal-title":"Oncogene"},{"key":"2021113010223213300_B139","first-page":"287","article-title":"Interleukin 6\/interleukin 6 receptor interaction and its role as a therapeutic target for treatment of cachexia and cancer","volume":"7","author":"Weidle","year":"2010","journal-title":"Cancer Genomics Proteomics"},{"key":"2021113010223213300_B140","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1016\/j.ejca.2010.02.026","article-title":"Interleukin-6 in bone metastasis and cancer progression","volume":"46","author":"Ara","year":"2010","journal-title":"Eur. J. 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Oncol."},{"key":"2021113010223213300_B148","doi-asserted-by":"crossref","first-page":"1193","DOI":"10.1007\/s11605-008-0505-z","article-title":"Cachexia worsens prognosis in patients with resectable pancreatic cancer","volume":"12","author":"Bachmann","year":"2008","journal-title":"J. Gastrointest. Surg."},{"key":"2021113010223213300_B149","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1097\/JES.0b013e3181f44f11","article-title":"Interleukin 6 as a key regulator of muscle mass during cachexia","volume":"38","author":"Carson","year":"2010","journal-title":"Exercise Sport Sci. Rev."},{"key":"2021113010223213300_B150","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1002\/ijc.2910610416","article-title":"Establishment and characterization of cachexia-inducing and -non-inducing clones of murine colon 26 carcinoma","volume":"61","author":"Fujimoto-Ouchi","year":"1995","journal-title":"Int. J. 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