Abstract
Since its discovery in 1986, originally as B cell stimulating factor 2, the knowledge on IL-6 for immune homeostasis and its pathophysiological implications has rapidly increased. It is now clear that IL-6, alone or in combination with other cytokines, is an architect for shaping and generating immune responses which exerts profound activities on the induction of acute-phase reactions, the differentiation of B lymphocytes, the modulation of T cell apoptosis, the activation of T helper cells and the balance between regulatory T cells and Th17 cells. In parallel to the identification of these physiologic functions, IL-6 has emerged as a critical mediator for perpetuating chronic inflammation and autoimmunity and is increasingly recognized as a key cytokine for linking chronic inflammation to cancer development. In this review, we begin by briefly summarizing the molecular events of IL-6 regulation and signaling and then describe the role of IL-6 in orchestrating innate and adaptive immune responses and its immunopathological relevance for chronic inflammatory diseases. We further outline how IL-6 links chronic inflammation and cancer development and finally provide an outlook on novel therapeutic strategies targeting IL-6 signaling for the treatment of chronic inflammatory diseases and cancer.
Similar content being viewed by others
References
Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F (2007) Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol 8:942–949. doi:10.1038/ni1496
Adler HL, McCurdy MA, Kattan MW, Timme TL, Scardino PT, Thompson TC (1999) Elevated levels of circulating interleukin-6 and transforming growth factor-beta1 in patients with metastatic prostatic carcinoma. J Urol 161:182–187
Alonzi T et al (1998) Interleukin 6 is required for the development of collagen-induced arthritis. J Exp Med 187:461–468
Angevin E et al (2014) A phase I/II, multiple-dose, dose-escalation study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with advanced solid tumors. Clin Cancer Res 20:2192–2204. doi:10.1158/1078-0432.ccr-13-2200
Arvidson NG, Gudbjornsson B, Elfman L, Ryden AC, Totterman TH, Hallgren R (1994) Circadian rhythm of serum interleukin-6 in rheumatoid arthritis. Ann Rheum Dis 53:521–524
Atreya R et al (2000) Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in crohn disease and experimental colitis in vivo. Nat Med 6:583–588. doi:10.1038/75068
Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357:539–545. doi:10.1016/S0140-6736(00)04046-0
Banks RE et al (1995) The acute phase protein response in patients receiving subcutaneous IL-6. Clin Exp Immunol 102:217–223
Baxter EJ et al (2005) Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 365:1054–1061. doi:10.1016/s0140-6736(05)71142-9
Bayliss TJ, Smith JT, Schuster M, Dragnev KH, Rigas JR (2011) A humanized anti-IL-6 antibody (ALD518) in non-small cell lung cancer. Expert Opin Biol Ther 11:1663–1668. doi:10.1517/14712598.2011.627850
Becker C et al (2004) TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling. Immunity 21:491–501. doi:10.1016/j.immuni.2004.07.020
Bendell JC et al (2014) Phase 1, open-label, dose-escalation, and pharmacokinetic study of STAT3 inhibitor OPB-31121 in subjects with advanced solid tumors. Cancer Chemother Pharmacol 74:125–130. doi:10.1007/s00280-014-2480-2
Bettelli E et al (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441:235–238. doi:10.1038/nature04753
Bollrath J et al (2009) gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis. Cancer Cell 15:91–102. doi:10.1016/j.ccr.2009.01.002
Bournazou E, Bromberg J (2013) Targeting the tumor microenvironment: JAK-STAT3 signaling. JAKSTAT 2(2):e23828. doi:10.4161/jkst.23828
Brown KA et al (2002) Lamina propria and circulating interleukin-6 in newly diagnosed pediatric inflammatory bowel disease patients. Am J Gastroenterol 97:2603–2608. doi:10.1111/j.1572-0241.2002.06030.x
Calabrese LH, Rose-John S (2014) IL-6 biology: implications for clinical targeting in rheumatic disease. Nat Rev Rheumatol 10:720–727. doi:10.1038/nrrheum.2014.127
Chen W et al (2003) Conversion of peripheral CD4 + CD25—naive T cells to CD4 + CD25 + regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 198:1875–1886. doi:10.1084/jem.20030152
Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867. doi:10.1038/nature01322
Cronstein BN (2007) Interleukin-6–a key mediator of systemic and local symptoms in rheumatoid arthritis. Bull NYU Hosp Jt Dis 65(Suppl 1):S11–S15
Dasgupta B, Corkill M, Kirkham B, Gibson T, Panayi G (1992) Serial estimation of interleukin 6 as a measure of systemic disease in rheumatoid arthritis. J Rheumatol 19:22–25
Desgeorges A et al (1997) Concentrations and origins of soluble interleukin 6 receptor-alpha in serum and synovial fluid. J Rheumatol 24:1510–1516
Dienz O et al (2009) The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4 + T cells. J Exp Med 206:69–78. doi:10.1084/jem.20081571
Dixon AE, Raymond DM, Suratt BT, Bourassa LM, Irvin CG (2008) Lower airway disease in asthmatics with and without rhinitis. Lung 186:361–368. doi:10.1007/s00408-008-9119-1
Doganci A et al (2005) The IL-6R alpha chain controls lung CD4 + CD25 + Treg development and function during allergic airway inflammation in vivo. J Clin Invest 115:313–325. doi:10.1172/jci22433
Dominitzki S et al (2007) Cutting edge: trans-signaling via the soluble IL-6R abrogates the induction of FoxP3 in naive CD4 + CD25 T cells. J Immunol 179:2041–2045
Fantini MC, Becker C, Monteleone G, Pallone F, Galle PR, Neurath MF (2004) Cutting edge: TGF-beta induces a regulatory phenotype in CD4 + CD25—T cells through Foxp3 induction and down-regulation of Smad7. J Immunol 172:5149–5153
Ferreira MA et al (2011) Identification of IL6R and chromosome 11q13.5 as risk loci for asthma. Lancet 378:1006–1014. doi:10.1016/s0140-6736(11)60874-x
Finotto S et al (2007) Local blockade of IL-6R signaling induces lung CD4 + T cell apoptosis in a murine model of asthma via regulatory T cells. Int Immunol 19:685–693. doi:10.1093/intimm/dxm037
Fizazi K et al (2012) Randomised phase II study of siltuximab (CNTO 328), an anti-IL-6 monoclonal antibody, in combination with mitoxantrone/prednisone versus mitoxantrone/prednisone alone in metastatic castration-resistant prostate cancer. Eur J Cancer 48:85–93. doi:10.1016/j.ejca.2011.10.014
Fujimoto M et al (2011) The influence of excessive IL-6 production in vivo on the development and function of Foxp3 + regulatory T cells. J Immunol 186:32–40. doi:10.4049/jimmunol.0903314
Fujimoto M et al (2008) Interleukin-6 blockade suppresses autoimmune arthritis in mice by the inhibition of inflammatory Th17 responses. Arthritis Rheum 58:3710–3719. doi:10.1002/art.24126
Gabay C et al (2013) Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial. Lancet 381:1541–1550. doi:10.1016/s0140-6736(13)60250-0
Galicia JC, Tai H, Komatsu Y, Shimada Y, Akazawa K, Yoshie H (2004) Polymorphisms in the IL-6 receptor (IL-6R) gene: strong evidence that serum levels of soluble IL-6R are genetically influenced. Genes Immun 5:513–516. doi:10.1038/sj.gene.6364120
Genovese MC et al (2014) Efficacy and safety of olokizumab in patients with rheumatoid arthritis with an inadequate response to TNF inhibitor therapy: outcomes of a randomised phase IIb study. Ann Rheum Dis 73:1607–1615. doi:10.1136/annrheumdis-2013-204760
Goydos JS, Brumfield AM, Frezza E, Booth A, Lotze MT, Carty SE (1998) Marked elevation of serum interleukin-6 in patients with cholangiocarcinoma: validation of utility as a clinical marker. Ann Surg 227:398–404
Grivennikov S et al (2009) IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 15:103–113. doi:10.1016/j.ccr.2009.01.001
Guerne PA, Zuraw BL, Vaughan JH, Carson DA, Lotz M (1989) Synovium as a source of interleukin 6 in vitro. Contribution to local and systemic manifestations of arthritis. J Clin Invest 83:585–592. doi:10.1172/jci113921
Hausding M et al (2011) Induction of tolerogenic lung CD4 + T cells by local treatment with a pSTAT-3 and pSTAT-5 inhibitor ameliorated experimental allergic asthma. Int Immunol 23:1–15. doi:10.1093/intimm/dxq451
Hawkins GA et al (2012) The IL6R variation Asp (358) Ala is a potential modifier of lung function in subjects with asthma. J Allergy Clin Immunol 130(510–515):e511. doi:10.1016/j.jaci.2012.03.018
Hayakawa F, Sugimoto K, Harada Y, Hashimoto N, Ohi N, Kurahashi S, Naoe T (2013) A novel STAT inhibitor, OPB-31121, has a significant antitumor effect on leukemia with STAT-addictive oncokinases. Blood Cancer J 3:e166. doi:10.1038/bcj.2013.63
He B et al (2003) SOCS-3 is frequently silenced by hypermethylation and suppresses cell growth in human lung cancer. Proc Natl Acad Sci USA 100:14133–14138. doi:10.1073/pnas.2232790100
Hirano T et al (1987) Human B-cell differentiation factor defined by an anti-peptide antibody and its possible role in autoantibody production. Proc Natl Acad Sci USA 84:228–231
Hirano T et al (1986) Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature 324:73–76. doi:10.1038/324073a0
Holt I, Cooper RG, Hopkins SJ (1991) Relationships between local inflammation, interleukin-6 concentration and the acute phase protein response in arthritis patients. Eur J Clin Invest 21:479–484
Holtkamp W, Stollberg T, Reis HE (1995) Serum interleukin-6 is related to disease activity but not disease specificity in inflammatory bowel disease. J Clin Gastroenterol 20:123–126
Houssiau FA, Devogelaer JP, Van Damme J, de Deuxchaisnes CN, Van Snick J (1988) Interleukin-6 in synovial fluid and serum of patients with rheumatoid arthritis and other inflammatory arthritides. Arthritis Rheum 31:784–788
Hudes G et al (2013) A phase 1 study of a chimeric monoclonal antibody against interleukin-6, siltuximab, combined with docetaxel in patients with metastatic castration-resistant prostate cancer. Invest New Drugs 31:669–676. doi:10.1007/s10637-012-9857-z
Huizinga TW et al (2014) Sarilumab, a fully human monoclonal antibody against IL-6Ralpha in patients with rheumatoid arthritis and an inadequate response to methotrexate: efficacy and safety results from the randomised SARIL-RA-mobility part A trial. Ann Rheum Dis 73:1626–1634. doi:10.1136/annrheumdis-2013-204405
Hurst SM et al (2001) Il-6 and its soluble receptor orchestrate a temporal switch in the pattern of leukocyte recruitment seen during acute inflammation. Immunity 14:705–714
Hyams JS, Fitzgerald JE, Treem WR, Wyzga N, Kreutzer DL (1993) Relationship of functional and antigenic interleukin 6 to disease activity in inflammatory bowel disease. Gastroenterology 104:1285–1292
Iwanami K et al (2008) Crucial role of the interleukin-6/interleukin-17 cytokine axis in the induction of arthritis by glucose-6-phosphate isomerase. Arthritis Rheum 58:754–763. doi:10.1002/art.23222
James C et al (2005) A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 434:1144–1148. doi:10.1038/nature03546
Jones SA, Horiuchi S, Topley N, Yamamoto N, Fuller GM (2001) The soluble interleukin 6 receptor: mechanisms of production and implications in disease. FASEB J 15:43–58. doi:10.1096/fj.99-1003rev
Jones SA, Scheller J, Rose-John S (2011) Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J Clin Investig 121:3375–3383. doi:10.1172/JCI57158
Kai Y et al (2005) Colitis in mice lacking the common cytokine receptor gamma chain is mediated by IL-6-producing CD4 + T cells. Gastroenterology 128:922–934
Kallio JP, Tammela TL, Marttinen AT, Kellokumpu-Lehtinen PL (2001) Soluble immunological parameters and early prognosis of renal cell cancer patients. J Exp Clin Cancer Res 20:523–528
Kim MJ et al (2013) OPB-31121, a novel small molecular inhibitor, disrupts the JAK2/STAT3 pathway and exhibits an antitumor activity in gastric cancer cells. Cancer Lett 335:145–152. doi:10.1016/j.canlet.2013.02.010
Kimura A, Kishimoto T (2010) IL-6: regulator of Treg/Th17 balance. Eur J Immunol 40:1830–1835. doi:10.1002/eji.201040391
Kimura A, Kishimoto T (2011) Th17 cells in inflammation. Int Immunopharmacol 11:319–322. doi:10.1016/j.intimp.2010.10.004
Kishimoto T, Akira S, Taga T (1992) Interleukin-6 and its receptor: a paradigm for cytokines. Science 258:593–597
Kitamura K, Nakamoto Y, Kaneko S, Mukaida N (2004) Pivotal roles of interleukin-6 in transmural inflammation in murine T cell transfer colitis. J Leukoc Biol 76:1111–1117. doi:10.1189/jlb.0604328
Kopf M et al (1994) Impaired immune and acute-phase responses in interleukin-6-deficient mice. Nature 368:339–342. doi:10.1038/368339a0
Kotake S et al (1996) Interleukin-6 and soluble interleukin-6 receptors in the synovial fluids from rheumatoid arthritis patients are responsible for osteoclast-like cell formation. J Bone Miner Res 11:88–95. doi:10.1002/jbmr.5650110113
Kralovics R et al (2005) A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 352:1779–1790. doi:10.1056/NEJMoa051113
Levine RL et al (2005) Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 7:387–397. doi:10.1016/j.ccr.2005.03.023
Li Y et al (2010) Disease-related expression of the IL6/STAT3/SOCS3 signalling pathway in ulcerative colitis and ulcerative colitis-related carcinogenesis. Gut 59:227–235. doi:10.1136/gut.2009.184176
Lissilaa R et al (2010) Although IL-6 trans-signaling is sufficient to drive local immune responses, classical IL-6 signaling is obligate for the induction of T cell-mediated autoimmunity. J Immunol 185:5512–5521. doi:10.4049/jimmunol.1002015
Liu H, Rohowsky-Kochan C (2008) Regulation of IL-17 in human CCR6 + effector memory T cells. J Immunol 180:7948–7957
Louis E, Belaiche J, van Kemseke C, Franchimont D, de Groote D, Gueenen V, Mary JY (1997) A high serum concentration of interleukin-6 is predictive of relapse in quiescent Crohn’s disease. Eur J Gastroenterol Hepatol 9:939–944
Madhok R, Crilly A, Watson J, Capell HA (1993) Serum interleukin 6 levels in rheumatoid arthritis: correlations with clinical and laboratory indices of disease activity. Ann Rheum Dis 52:232–234
Maini RN et al (2006) 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. Arthritis Rheum 54:2817–2829. doi:10.1002/art.22033
Mangan PR et al (2006) Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 441:231–234. doi:10.1038/nature04754
Manicourt DH, Triki R, Fukuda K, Devogelaer JP, Nagant de Deuxchaisnes C, Thonar EJ (1993) Levels of circulating tumor necrosis factor alpha and interleukin-6 in patients with rheumatoid arthritis. Relationship to serum levels of hyaluronan and antigenic keratan sulfate. Arthritis Rheum 36:490–499
Marini M, Vittori E, Hollemborg J, Mattoli S (1992) Expression of the potent inflammatory cytokines, granulocyte-macrophage-colony-stimulating factor and interleukin-6 and interleukin-8, in bronchial epithelial cells of patients with asthma. J Allergy Clin Immunol 89:1001–1009
Mascarenhas J, Hoffman R (2012) Ruxolitinib: the first FDA approved therapy for the treatment of myelofibrosis. Clin Cancer Res 18:3008–3014. doi:10.1158/1078-0432.CCR-11-3145
Matsumoto S et al (2010) 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 184:1543–1551. doi:10.4049/jimmunol.0801217
Mattoli S, Colotta F, Fincato G, Mezzetti M, Mantovani A, Patalano F, Fasoli A (1991) Time course of IL1 and IL6 synthesis and release in human bronchial epithelial cell cultures exposed to toluene diisocyanate. J Cell Physiol 149:260–268. doi:10.1002/jcp.1041490212
Mattoli S, Miante S, Calabro F, Mezzetti M, Fasoli A, Allegra L (1990) Bronchial epithelial cells exposed to isocyanates potentiate activation and proliferation of T-cells. Am J Physiol 259:L320–L327
Mease P et al (2012) A phase II, double-blind, randomised, placebo-controlled study of BMS945429 (ALD518) in patients with rheumatoid arthritis with an inadequate response to methotrexate. Ann Rheum Dis 71:1183–1189. doi:10.1136/annrheumdis-2011-200704
Melzer D et al (2008) A genome-wide association study identifies protein quantitative trait loci (pQTLs). PLoS Genet 4:e1000072. doi:10.1371/journal.pgen.1000072
Mendoza CE, Rosado MF, Bernal L (2001) The role of interleukin-6 in cases of cardiac myxoma. Clinical features, immunologic abnormalities, and a possible role in recurrence. Tex Heart Inst J 28:3–7
Mezzetti M, Soloperto M, Fasoli A, Mattoli S (1991) Human bronchial epithelial cells modulate CD3 and mitogen-induced DNA synthesis in T cells but function poorly as antigen-presenting cells compared to pulmonary macrophages. J Allergy Clin Immunol 87:930–938
Mihara M, Moriya Y, Kishimoto T, Ohsugi Y (1995) Interleukin-6 (IL-6) induces the proliferation of synovial fibroblastic cells in the presence of soluble IL-6 receptor. Br J Rheumatol 34:321–325
Mihara M, Takagi N, Takeda Y, Ohsugi Y (1998) IL-6 receptor blockage inhibits the onset of autoimmune kidney disease in NZB/W F1 mice. Clin Exp Immunol 112:397–402
Mitsuyama K, Sata M, Rose-John S (2006) Interleukin-6 trans-signaling in inflammatory bowel disease. Cytokine Growth Factor Rev 17:451–461. doi:10.1016/j.cytogfr.2006.09.003
Mitsuyama K et al (1995) Soluble interleukin-6 receptors in inflammatory bowel disease: relation to circulating interleukin-6. Gut 36:45–49
Morjaria JB, Babu KS, Vijayanand P, Chauhan AJ, Davies DE, Holgate ST (2011) Sputum IL-6 concentrations in severe asthma and its relationship with FEV1. Thorax 66:537. doi:10.1136/thx.2010.136523
Mudter J et al (2008) The transcription factor IFN regulatory factor-4 controls experimental colitis in mice via T cell-derived IL-6. J Clin Investig 118:2415–2426. doi:10.1172/JCI33227
Muraguchi A, Hirano T, Tang B, Matsuda T, Horii Y, Nakajima K, Kishimoto T (1988) The essential role of B cell stimulatory factor 2 (BSF-2/IL-6) for the terminal differentiation of B cells. J Exp Med 167:332–344
Naugler WE, Karin M (2008) The wolf in sheep’s clothing: the role of interleukin-6 in immunity, inflammation and cancer. Trends Mol Med 14:109–119. doi:10.1016/j.molmed.2007.12.007
Neurath MF, Finotto S (2011) IL-6 signaling in autoimmunity, chronic inflammation and inflammation-associated cancer. Cytokine Growth Factor Rev 22:83–89. doi:10.1016/j.cytogfr.2011.02.003
Neveu WA et al (2010) Elevation of IL-6 in the allergic asthmatic airway is independent of inflammation but associates with loss of central airway function. Respir Res 11:28. doi:10.1186/1465-9921-11-28
Nishimoto N et al (2014) Drug free REmission/low disease activity after cessation of tocilizumab (actemra) monotherapy (dream) study. Mod Rheumatol 24:17–25. doi:10.3109/14397595.2013.854079
Nishimoto N et al (2005) Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease. Blood 106:2627–2632. doi:10.1182/blood-2004-12-4602
Nishimoto N, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, Azuma J (2009) Long-term safety and efficacy of tocilizumab, an anti-IL-6 receptor monoclonal antibody, in monotherapy, in patients with rheumatoid arthritis (the stream study): evidence of safety and efficacy in a 5-year extension study. Ann Rheum Dis 68:1580–1584. doi:10.1136/ard.2008.092866
Nishimoto N et al (2000) Improvement in Castleman’s disease by humanized anti-interleukin-6 receptor antibody therapy. Blood 95:56–61
Nishimoto N et al (2004) Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum 50:1761–1769. doi:10.1002/art.20303
Niwa Y et al (2005) Methylation silencing of SOCS-3 promotes cell growth and migration by enhancing JAK/STAT and FAK signalings in human hepatocellular carcinoma. Oncogene 24:6406–6417. doi:10.1038/sj.onc.1208788
Nowell MA et al (2003) Soluble IL-6 receptor governs IL-6 activity in experimental arthritis: blockade of arthritis severity by soluble glycoprotein 130. J Immunol 171:3202–3209
Orlowski RZ et al (2014) A phase II, randomized, double-blind, placebo-controlled study of siltuximab (Anti-IL-6 mAb) and bortezomib versus bortezomib alone in patients with relapsed or refractory multiple myeloma. Am J Hematol 90(1):42–49. doi:10.1002/ajh.23868
Palmqvist P, Persson E, Conaway HH, Lerner UH (2002) IL-6, leukemia inhibitory factor, and oncostatin M stimulate bone resorption and regulate the expression of receptor activator of NF-kappa B ligand, osteoprotegerin, and receptor activator of NF-kappa B in mouse calvariae. J Immunol 169:3353–3362
Pinede L, Duhaut P, Loire R (2001) Clinical presentation of left atrial cardiac myxoma. A series of 112 consecutive cases. Medicine (Baltimore) 80:159–172
Qiu Z, Fujimura M, Kurashima K, Nakao S, Mukaida N (2004) Enhanced airway inflammation and decreased subepithelial fibrosis in interleukin 6-deficient mice following chronic exposure to aerosolized antigen. Clin Exp Allergy 34:1321–1328. doi:10.1111/j.1365-2222.2004.02013.x
Rafiq S et al (2007) A common variant of the interleukin 6 receptor (IL-6r) gene increases IL-6r and IL-6 levels, without other inflammatory effects. Genes Immun 8:552–559. doi:10.1038/sj.gene.6364414
Reich D et al (2007) Admixture mapping of an allele affecting interleukin 6 soluble receptor and interleukin 6 levels. Am J Hum Genet 80:716–726. doi:10.1086/513206
Reinisch W et al (1999) Clinical relevance of serum interleukin-6 in Crohn’s disease: single point measurements, therapy monitoring, and prediction of clinical relapse. Am j gastroenterol 94:2156–2164. doi:10.1111/j.1572-0241.1999.01288.x
Rigby RJ, Simmons JG, Greenhalgh CJ, Alexander WS, Lund PK (2007) Suppressor of cytokine signaling 3 (SOCS3) limits damage-induced crypt hyper-proliferation and inflammation-associated tumorigenesis in the colon. Oncogene 26:4833–4841. doi:10.1038/sj.onc.1210286
Rincon M, Anguita J, Nakamura T, Fikrig E, Flavell RA (1997) Interleukin (IL)-6 directs the differentiation of IL-4-producing CD4 + T cells. J Exp Med 185:461–469
Romagnani S, Maggi E, Liotta F, Cosmi L, Annunziato F (2009) Properties and origin of human Th17 cells. Mol Immunol 47:3–7. doi:10.1016/j.molimm.2008.12.019
Rosser EC et al (2014) Regulatory B cells are induced by gut microbiota-driven interleukin-1beta and interleukin-6 production. Nat Med 20:1334–1339. doi:10.1038/nm.3680
San-Miguel J et al (2014) Phase 2 randomized study of bortezomib-melphalan-prednisone with or without siltuximab (anti-IL-6) in multiple myeloma. Blood 123:4136–4142. doi:10.1182/blood-2013-12-546374
Sasai M et al (1999) Delayed onset and reduced severity of collagen-induced arthritis in interleukin-6-deficient mice. Arthritis Rheum 42:1635–1643. doi:10.1002/1529-0131(199908)42:8<1635:aid-anr11>3.0.co;2-q
Sen M et al (2014) Systemic administration of a cyclic signal transducer and activator of transcription 3 (STAT3) decoy oligonucleotide inhibits tumor growth without inducing toxicological effects. Mol Med 20:46–56. doi:10.2119/molmed.2013.00104
Sen M et al (2012) First-in-human trial of a STAT3 decoy oligonucleotide in head and neck tumors: implications for cancer therapy. Cancer Discov 2:694–705. doi:10.1158/2159-8290.cd-12-0191
Shaw S et al (2014) Discovery and characterization of olokizumab: a humanized antibody targeting interleukin-6 and neutralizing gp130-signaling. MAbs 6:774–782. doi:10.4161/mabs.28612
Sieper J et al (2014) Sarilumab for the treatment of ankylosing spondylitis: results of a phase II, randomised, double-blind, placebo-controlled study (ALIGN). Ann Rheum Dis. doi:10.1136/annrheumdis-2013-204963
Smolen JS, Weinblatt ME, Sheng S, Zhuang Y, Hsu B (2014) Sirukumab, a human anti-interleukin-6 monoclonal antibody: a randomised, 2-part (proof-of-concept and dose-finding), phase II study in patients with active rheumatoid arthritis despite methotrexate therapy. Ann Rheum Dis 73:1616–1625. doi:10.1136/annrheumdis-2013-205137
Soresi M et al (2006) Interleukin-6 and its soluble receptor in patients with liver cirrhosis and hepatocellular carcinoma. World J Gastroenterol 12:2563–2568
Stadnyk AW (1994) Cytokine production by epithelial cells. FASEB J 8:1041–1047
Straub RH, Muller-Ladner U, Lichtinger T, Scholmerich J, Menninger H, Lang B (1997) Decrease of interleukin 6 during the first 12 months is a prognostic marker for clinical outcome during 36 months treatment with disease-modifying anti-rheumatic drugs. Br J Rheumatol 36:1298–1303
Suematsu S et al (1989) IgG1 plasmacytosis in interleukin 6 transgenic mice. Proc Natl Acad Sci USA 86:7547–7551
Suzuki M, Hashizume M, Yoshida H, Mihara M (2010) Anti-inflammatory mechanism of tocilizumab, a humanized anti-IL-6R antibody: effect on the expression of chemokine and adhesion molecule. Rheumatol Int 30:309–315. doi:10.1007/s00296-009-0953-0
Swaak AJ, van Rooyen A, Nieuwenhuis E, Aarden LA (1988) Interleukin-6 (IL-6) in synovial fluid and serum of patients with rheumatic diseases. Scand J Rheumatol 17:469–474
Szepietowski JC et al (2013) Phase I, randomized, double-blind, placebo-controlled, multiple intravenous, dose-ascending study of sirukumab in cutaneous or systemic lupus erythematosus. Arthritis Rheum 65:2661–2671. doi:10.1002/art.38091
Takagi N et al (1998) Blockage of interleukin-6 receptor ameliorates joint disease in murine collagen-induced arthritis. Arthritis Rheum 41:2117–2121. doi:10.1002/1529-0131(199812)41:12<2117:aid-art6>3.0.co;2-p
Tanaka T, Narazaki M, Kishimoto T (2012) Therapeutic targeting of the interleukin-6 receptor. Annu Rev Pharmacol Toxicol 52:199–219. doi:10.1146/annurev-pharmtox-010611-134715
Tanaka T, Narazaki M, Kishimoto T (2014a) IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol 6:a016295. doi:10.1101/cshperspect.a016295
Tanaka T, Narazaki M, Ogata A, Kishimoto T (2014b) A new era for the treatment of inflammatory autoimmune diseases by interleukin-6 blockade strategy. Semin Immunol 26:88–96. doi:10.1016/j.smim.2014.01.009
Tanaka T, Ogata A, Narazaki M (2010) Tocilizumab for the treatment of rheumatoid arthritis. Expert Rev Clin Immunol 6:843–854. doi:10.1586/eci.10.70
Tanaka Y, Martin Mola E (2014) IL-6 targeting compared to TNF targeting in rheumatoid arthritis: studies of olokizumab, sarilumab and sirukumab. Ann Rheum Dis 73:1595–1597. doi:10.1136/annrheumdis-2013-205002
Tangkijvanich P, Thong-ngam D, Theamboonlers A, Hanvivatvong O, Kullavanijaya P, Poovorawan Y (2004) Diagnostic role of serum interleukin 6 and CA 19-9 in patients with cholangiocarcinoma. Hepatogastroenterology 51:15–19
Taniguchi K, Karin M (2014) IL-6 and related cytokines as the critical lynchpins between inflammation and cancer. Semin Immunol 26:54–74. doi:10.1016/j.smim.2014.01.001
Teague TK, Marrack P, Kappler JW, Vella AT (1997) IL-6 rescues resting mouse T cells from apoptosis. J Immunol 158:5791–5796
Terabe F et al (2011) Comparative analysis of the effects of anti-IL-6 receptor mAb and anti-TNF mAb treatment on CD4 + T-cell responses in murine colitis. Inflamm Bowel Dis 17:491–502. doi:10.1002/ibd.21384
Thanarajasingam U, Niewold TB (2014) Sirukumab : a novel therapy for lupus nephritis? Expert Opin Investig Drugs 23:1449–1455. doi:10.1517/13543784.2014.950837
Tillie-Leblond I et al (1999) Balance between proinflammatory cytokines and their inhibitors in bronchial lavage from patients with status asthmaticus. Am J Respir Crit Care Med 159:487–494. doi:10.1164/ajrccm.159.2.9805115
Umehara Y, Kudo M, Nakaoka R, Kawasaki T, Shiomi M (2006) Serum proinflammatory cytokines and adhesion molecules in ulcerative colitis. Hepatogastroenterology 53:879–882
Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B (2006) TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24:179–189. doi:10.1016/j.immuni.2006.01.001
Virchow JC, Jr., Kroegel C, Walker C, Matthys H (1996) Inflammatory determinants of asthma severity: mediator and cellular changes in bronchoalveolar lavage fluid of patients with severe asthma. J Allergy Clin Immunol 98:S27–33; discussion S33–40
Voorhees PM et al (2013) A phase 2 multicentre study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with relapsed or refractory multiple myeloma. Br J Haematol 161:357–366. doi:10.1111/bjh.12266
Wakasa-Morimoto C et al (2008) Arthritis and pneumonitis produced by the same T cell clones from mice with spontaneous autoimmune arthritis. Int Immunol 20:1331–1342. doi:10.1093/intimm/dxn091
Waldner MJ, Neurath MF (2014) Master regulator of intestinal disease: IL-6 in chronic inflammation and cancer development. Semin Immunol 26:75–79. doi:10.1016/j.smim.2013.12.003
Waldner MJ et al (2010) VEGF receptor signaling links inflammation and tumorigenesis in colitis-associated cancer. J Exp Med 207:2855–2868. doi:10.1084/jem.20100438
Wang J, Homer RJ, Chen Q, Elias JA (2000) Endogenous and exogenous IL-6 inhibit aeroallergen-induced Th2 inflammation. J Immunol 165:4051–4061
Weigmann B et al (2008) The transcription factor NFATc2 controls IL-6-dependent T cell activation in experimental colitis. J Exp Med 205:2099–2110. doi:10.1084/jem.20072484
Woo P et al (2005) Open label phase II trial of single, ascending doses of MRA in caucasian children with severe systemic juvenile idiopathic arthritis: proof of principle of the efficacy of IL-6 receptor blockade in this type of arthritis and demonstration of prolonged clinical improvement. Arthritis Res Ther 7:R1281–R1288. doi:10.1186/ar1826
Xing Z, Gauldie J, Cox G, Baumann H, Jordana M, Lei XF, Achong MK (1998) IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses. J Clin Invest 101:311–320. doi:10.1172/jci1368
Xu S, Neamati N (2013) gp130: a promising drug target for cancer therapy. Expert Opin Ther Targets 17:1303–1328. doi:10.1517/14728222.2013.830105
Yamamoto K, Rose-John S (2012) Therapeutic blockade of interleukin-6 in chronic inflammatory disease. Clin Pharmacol Ther 91:574–576. doi:10.1038/clpt.2012.11
Yamamoto M, Yoshizaki K, Kishimoto T, Ito H (2000) IL-6 is required for the development of Th1 cell-mediated murine colitis. J Immunol 164:4878–4882
Yokoe T et al (1997) Changes of cytokines and thyroid function in patients with recurrent breast cancer. Anticancer Res 17:695–699
Yokota S et al (2008) Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial. Lancet 371:998–1006. doi:10.1016/S0140-6736(08)60454-7
Yokota S et al (2005) Therapeutic efficacy of humanized recombinant anti-interleukin-6 receptor antibody in children with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum 52:818–825. doi:10.1002/art.20944
Yokoyama A et al (1995) Circulating interleukin-6 levels in patients with bronchial asthma. Am J Respir Crit Care Med 151:1354–1358. doi:10.1164/ajrccm.151.5.7735584
Yokoyama A, Kohno N, Sakai K, Kondo K, Hirasawa Y, Hiwada K (1997) Circulating levels of soluble interleukin-6 receptor in patients with bronchial asthma. Am J Respir Crit Care Med 156:1688–1691. doi:10.1164/ajrccm.156.5.9610070
Yoshida H, Hashizume M, Suzuki M, Mihara M (2010) Anti-IL-6 receptor antibody suppressed T cell activation by inhibiting IL-2 production and inducing regulatory T cells. Eur J Pharmacol 634:178–183. doi:10.1016/j.ejphar.2010.02.026
Yoshimura T et al (2009) Involvement of Th17 cells and the effect of anti-IL-6 therapy in autoimmune uveitis. Rheumatology (Oxford) 48:347–354. doi:10.1093/rheumatology/ken489
Yue C et al (2010) The effects of adalimumab and methotrexate treatment on peripheral Th17 cells and IL-17/IL-6 secretion in rheumatoid arthritis patients. Rheumatol Int 30:1553–1557. doi:10.1007/s00296-009-1179-x
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Rath, T., Billmeier, U., Waldner, M.J. et al. From physiology to disease and targeted therapy: interleukin-6 in inflammation and inflammation-associated carcinogenesis. Arch Toxicol 89, 541–554 (2015). https://doi.org/10.1007/s00204-015-1461-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00204-015-1461-5