Gene of the month: Interleukin 6 (IL-6)

Journal of Clinical Pathology

Volumn 67, Issue 11, 2014, Pages 932-937

  Ataie Kachoie, Parvin ^a   Pourgholami, Mohammad H ^a   Richardson, Des R ^b   Morris, David L ^a,c  

^a ST GEORGE HOSPITAL   (Australia)

^b UNIVERSITY OF SYDNEY   (Australia)

^c UNIVERSITY OF NEW SOUTH WALES   (Australia)

Author keywords

[No Author keywords available]

Indexed keywords

BE 8; CLAZAKIZUMAB; CORTICOSTEROID; INTERLEUKIN 6; INTERLEUKIN 6 ANTIBODY; INTERLEUKIN 6 RECEPTOR; NONSTEROID ANTIINFLAMMATORY AGENT; SILTUXIMAB; SIRUKUMAB; TETRACYCLINE DERIVATIVE; TOCILIZUMAB; UNCLASSIFIED DRUG; ANTIINFLAMMATORY AGENT; ANTINEOPLASTIC AGENT; AUTACOID; IL6 PROTEIN, HUMAN;

ARTICLE; AUTOIMMUNE DISEASE; GENE; GENE CONTROL; GENE STRUCTURE; HUMAN; INFLAMMATION; INTERLEUKIN 6 GENE; NEOPLASM; NONHUMAN; ANIMAL; ANTAGONISTS AND INHIBITORS; DRUG DESIGN; DRUG EFFECTS; GENETICS; IMMUNOLOGY; METABOLISM; NEOPLASMS; SIGNAL TRANSDUCTION;

ANIMALS; ANTI-INFLAMMATORY AGENTS; ANTINEOPLASTIC AGENTS; DRUG DESIGN; HUMANS; INFLAMMATION; INFLAMMATION MEDIATORS; INTERLEUKIN-6; NEOPLASMS; RECEPTORS, INTERLEUKIN-6; SIGNAL TRANSDUCTION;

EID: 84908488028     PISSN: 00219746     EISSN: 14724146     Source Type: Journal    
DOI: 10.1136/jclinpath-2014-202493     Document Type: Article

References (142)

1. Hirano T, Yasukawa K, Harada H, et al. Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature 1986;324:73-6.
2. Zilberstein A, Ruggieri R, Korn JH, et al. Structure and expression of cDNA and genes for human interferon-beta-2, a distinct species inducible by growth-stimulatory cytokines. EMBO J 1986;5:2529-37.
3. Simpson RJ, Hammacher A, Smith DK, et al. Interleukin-6: structure-function relationships. Protein Sci 1997;6:929-55.
4. Castell JV, Geiger T, Gross V, et al. Plasma clearance, organ distribution and target cells of interleukin-6/hepatocyte-stimulating factor in the rat. Eur J Biochem 1988;177:357-61.
5. Terasaka Y, Miyazaki D, Yakura K, et al. Induction of IL-6 in transcriptional networks in corneal epithelial cells after herpes simplex virus type 1 infection. Invest Ophthalmol Vis Sci 2010;51:2441-9.
6. Baccam M, Woo SY, Vinson C, et al. CD40-mediated transcriptional regulation of the IL-6 gene in B lymphocytes: involvement of NF-kappa B, AP-1, and C/EBP. J Immunol 2003;170:3099-108.
7. Ray A, Tatter SB, May LT, et al. Activation of the human "beta 2-interferon/hepatocyte-stimulating factor/interleukin 6" promoter by cytokines, viruses, and second messenger agonists. Proc Natl Acad Sci USA 1988;85:6701-5.
8. Isshiki H, Akira S, Tanabe O, et al. Constitutive and interleukin-1 (IL-1)-inducible factors interact with the IL-1-responsive element in the IL-6 gene. Mol Cell Biol 1990;10:2757-64.
9. Park JI, Lee MG, Cho K, et al. Transforming growth factor-beta1 activates interleukin-6 expression in prostate cancer cells through the synergistic collaboration of the Smad2, p38-NF-kappaB, JNK, and Ras signaling pathways. Oncogene 2003;22:4314-32.
10. Fishman D, Faulds G, Jeffery R, et al. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest 1998;102:1369-76.
11. Olomolaiye O, Wood NA, Bidwell JL. A novel NlaIII polymorphism in the human IL-6 promoter. Eur J Immunogenet 1998;25:267.
12. Bonafe M, Olivieri F, Cavallone L, et al. A gender-dependent genetic predisposition to produce high levels of IL-6 is detrimental for longevity. Eur J Immunol 2001;31:2357-61.
13. Licastro F, Grimaldi LM, Bonafe M, et al. Interleukin-6 gene alleles affect the risk of Alzheimer's disease and levels of the cytokine in blood and brain. Neurobiol Aging 2003;24:921-6.
14. Vozarova B, Fernandez-Real JM, Knowler WC, et al. The interleukin-6 (-174) G/C promoter polymorphism is associated with type-2 diabetes mellitus in Native Americans and Caucasians. Hum Genet 2003;112:409-13.
15. Chumaeva N, Hintsanen M, Pulkki-Raback L, et al. Interleukin-6 gene polymorphism, chronic stress and atherosclerosis: interleukin-6-174 G>C polymorphism, chronic stress and risk of early atherosclerosis in the Cardiovascular Risk in Young Finns Study. J Psychosom Res 2014;76:333-8.
16. Moura KF, Haidar M, Bonduki C, et al. Frequencies of interleukin-6, GST and progesterone receptor gene polymorphisms in postmenopausal women with low bone mineral density. Sao Paulo Med J 2014;132:36-40.
17. Humphries SE, Luong LA, Ogg MS, et al. The interleukin-6-174 G/C promoter polymorphism is associated with risk of coronary heart disease and systolic blood pressure in healthy men. Eur Heart J 2001;22:2243-52.
18. Biswas S, Ghoshal PK, Mandal N. Synergistic effect of anti and pro-inflammatory cytokine genes and their promoter polymorphism with ST-elevation of myocardial infarction. Gene 2014;544:145-51.
19. Tang S, Yuan Y, He Y, et al. Genetic polymorphism of interleukin-6 influences susceptibility to HBV-related hepatocellular carcinoma in a male Chinese Han population. Hum Immunol 2014;75:297-301.
20. Belluco C, Olivieri F, Bonafe M, et al. - 174 G>C polymorphism of interleukin 6 gene promoter affects interleukin 6 serum level in patients with colorectal cancer. Clin Cancer Res 2003;9:2173-6.
21. Mandal S, Abebe F, Chaudhary J. - 174 G/C polymorphism in the interleukin-6 promoter is differently associated with prostate cancer incidence depending on race. Genet Mol Res 2014;13:139-51.
22. Hefler LA, Grimm C, Ackermann S, et al. An interleukin-6 gene promoter polymorphism influences the biological phenotype of ovarian cancer. Cancer Res 2003;63:3066-8.
23. DeMichele A, Martin AM, Mick R, et al. Interleukin-6 -174G->C polymorphism is associated with improved outcome in high-risk breast cancer. Cancer Res 2003;63:8051-6.
24. Cozen W, Gill PS, Ingles SA, et al. IL-6 levels and genotype are associated with risk of young adult Hodgkin lymphoma. Blood 2004;103:3216-21.
25. Totaro F, Cimmino F, Pignataro P, et al. Impact of interleukin-6 -174 G>C gene promoter polymorphism on neuroblastoma. PLoS One 2013;8:e76810.
26. Ataie-Kachoie P, Pourgholami MH, Morris DL. Inhibition of the IL-6 signaling pathway: a strategy to combat chronic inflammatory diseases and cancer. Cytokine Growth Factor Rev 2013;24:163-73.
27. Kishimoto T. Interleukin-6: discovery of a pleiotropic cytokine. Arthritis Res Ther 2006;8(Suppl 2):S2.
28. Fielding CA, McLoughlin RM, McLeod L, et al. IL-6 regulates neutrophil trafficking during acute inflammation via STAT3. J Immunol 2008;181:2189-95.
29. Woodfin A, Voisin MB, Nourshargh S. Recent developments and complexities in neutrophil transmigration. Curr Opin Hematol 2010;17:9-17.
30. Neurath MF, Finotto S. IL-6 signaling in autoimmunity, chronic inflammation and inflammation-associated cancer. Cytokine Growth Factor Rev 2011;22:83-9.
31. Muraguchi A, Hirano T, Tang B, et al. The essential role of B cell stimulatory factor 2 (BSF-2/IL-6) for the terminal differentiation of B cells. J Exp Med 1988;167:332-44.
32. Heike T, Nakahata T. Ex vivo expansion of hematopoietic stem cells by cytokines. Biochim Biophys Acta 2002;1592:313-21.
33. Hassan HT, Drexler HG. Interleukins and colony stimulating factors in human myeloid leukemia cell lines. Leuk Lymphoma 1995;20:1-15.
34. Tartour E, Pere H, Maillere B, et al. Angiogenesis and immunity: a bidirectional link potentially relevant for the monitoring of antiangiogenic therapy and the development of novel therapeutic combination with immunotherapy. Cancer Metastasis Rev 2011;30:83-95.
35. Jones SA, Horiuchi S, Topley N, et al. The soluble interleukin 6 receptor: mechanisms of production and implications in disease. FASEB J 2001;15:43-58.
36. Smith AJ, Humphries SE. Cytokine and cytokine receptor gene polymorphisms and their functionality. Cytokine Growth Factor Rev 2009;20:43-59.
37. Moritz RL, Hall NE, Connolly LM, et al. Determination of the disulfide structure and N-glycosylation sites of the extracellular domain of the human signal transducer gp130. J Biol Chem 2001;276:8244-53.
38. Garbers C, Hermanns HM, Schaper F, et al. Plasticity and cross-talk of Interleukin 6-type cytokines. Cytokine Growth Factor Rev 2012;23:85-97.
39. Chalaris A, Garbers C, Rabe B, et al. The soluble Interleukin 6 receptor: generation and role in inflammation and cancer. Eur J Cell Biol 2011;90:484-94.
40. Rose-John S, Scheller J, Elson G, et al. Interleukin-6 biology is coordinated by membrane-bound and soluble receptors: role in inflammation and cancer. J Leukoc Biol 2006;80:227-36.
41. Heinrich PC, Behrmann I, Haan S, et al. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem J 2003;374(Pt 1):1-20.
42. Hennessy BT, Smith DL, Ram PT, et al. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov 2005;4:988-1004.
43. Chien CM, Lin KL, Su JC, et al. Naphtho[1,2-b]furan-4,5-dione induces apoptosis of oral squamous cell carcinoma: involvement of EGF receptor/PI3K/Akt signaling pathway. Eur J Pharmacol 2010;636:52-8.
44. Nakajima T, Kinoshita S, Sasagawa T, et al. Phosphorylation at threonine-235 by a ras-dependent mitogen-activated protein kinase cascade is essential for transcription factor NF-IL6. Proc Natl Acad Sci USA 1993;90:2207-11.
45. Tanaka T, Narazaki M, Kishimoto T. Therapeutic targeting of the interleukin-6 receptor. Annu Rev Pharmacol Toxicol 2012;52:199-219.
46. Cacquevel M, Lebeurrier N, Cheenne S, et al. Cytokines in neuroinflammation and Alzheimer's disease. Curr Drug Targets 2004;5:529-34.
47. Spirchez M, Samasca G, Iancu M, et al. Relation of interleukin-6, TNF-alpha and interleukin-1alpha with disease activity and severity in juvenile idiopathic arthritis patients. Clin Lab 2012;58:253-60.
48. Serada S, Fujimoto M, Mihara M, et al. IL-6 blockade inhibits the induction of myelin antigen-specific Th17 cells and Th1 cells in experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA 2008;105:9041-6.
49. Spooren A, Kolmus K, Laureys G, et al. Interleukin-6, a mental cytokine. Brain Res Rev 2011;67:157-83.
50. Hingorani AD, Casas JP. The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis. Lancet 2012;379:1214-24.
51. Rincon M, Anguita J, Nakamura T, et al. Interleukin (IL)-6 directs the differentiation of IL-4-producing CD4+ T cells. J Exp Med 1997;185:461-9.
52. Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006;441:235-8.
53. Hirahara K, Ghoreschi K, Laurence A, et al. Signal transduction pathways and transcriptional regulation in Th17 cell differentiation. Cytokine Growth Factor Rev 2010;21:425-34.
54. Hurst SM, Wilkinson TS, McLoughlin RM, et al. Il-6 and its soluble receptor orchestrate a temporal switch in the pattern of leukocyte recruitment seen during acute inflammation. Immunity 2001;14:705-14.
55. Kaplanski G, Marin V, Montero-Julian F, et al. IL-6: a regulator of the transition from neutrophil to monocyte recruitment during inflammation. Trends Immunol 2003;24:25-9.
56. Romano M, Sironi M, Toniatti C, et al. Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment. Immunity 1997;6:315-25.
57. Chen Q, Fisher DT, Clancy KA, et al. Fever-range thermal stress promotes lymphocyte trafficking across high endothelial venules via an interleukin 6 trans-signaling mechanism. Nat Immunol 2006;7:1299-308.
58. Chen Q, Wang WC, Bruce R, et al. Central role of IL-6 receptor signal-transducing chain gp130 in activation of L-selectin adhesion by fever-range thermal stress. Immunity 2004;20:59-70.
59. Chomarat P, Banchereau J, Davoust J, et al. IL-6 switches the differentiation of monocytes from dendritic cells to macrophages. Nat Immunol 2000;1:510-14.
60. Atreya R, Mudter J, Finotto S, et al. 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 2000;6:583-8.
61. Heikkila K, Ebrahim S, Lawlor DA. Systematic review of the association between circulating interleukin-6 (IL-6) and cancer. Eur J Cancer 2008;44:937-45.
62. Atsumi T, Singh R, Sabharwal L, et al. Inflammation amplifier, a new paradigm in cancer biology. Cancer Res 2014;74:8-14.
63. Suchi K, Fujiwara H, Okamura S, et al. Overexpression of Interleukin-6 suppresses cisplatin-induced cytotoxicity in esophageal squamous cell carcinoma cells. Anticancer Res 2011;31:67-75.
64. Nilsson MB, Langley RR, Fidler IJ. Interleukin-6, secreted by human ovarian carcinoma cells, is a potent proangiogenic cytokine. Cancer Res 2005;65:10794-800.
65. Sierra A. Metastases and their microenvironments: linking pathogenesis and therapy. Drug Resist Updat 2005;8:247-57.
66. Santer FR, Malinowska K, Culig Z, et al. Interleukin-6 trans-signalling differentially regulates proliferation, migration, adhesion and maspin expression in human prostate cancer cells. Endocr Relat Cancer 2010;17:241-53.
67. Nash MA, Ferrandina G, Gordinier M, et al. The role of cytokines in both the normal and malignant ovary. Endocr Relat Cancer 1999;6:93-107.
68. Guo Y, Xu F, Lu T, et al. Interleukin-6 signaling pathway in targeted therapy for cancer. Cancer Treat Rev 2012;38:904-10.
69. Weidle UH, Klostermann S, Eggle D, et al. Interleukin 6/interleukin 6 receptor interaction and its role as a therapeutic target for treatment of cachexia and cancer. Cancer Genomics Proteomics 2010;7:287-302.
70. van der Zee AG, de Cuyper EM, Limburg PC, et al. Higher levels of interleukin-6 in cystic fluids from patients with malignant versus benign ovarian tumors correlate with decreased hemoglobin levels and increased platelet counts. Cancer 1995;75:1004-9.
71. Grivennikov S, Karin M. Autocrine IL-6 signaling: a key event in tumorigenesis? Cancer Cell 2008;13:7-9.
72. Zhang X, Zhang J, Wei H, et al. STAT3-decoy oligodeoxynucleotide inhibits the growth of human lung cancer via down-regulating its target genes. Oncol Rep 2007;17:1377-82.
73. Darnell JE Jr. STATs and gene regulation. Science 1997;277:1630-5.
74. Wang XH, Liu BR, Qu B, et al. Silencing STAT3 may inhibit cell growth through regulating signaling pathway, telomerase, cell cycle, apoptosis and angiogenesis in hepatocellular carcinoma: potential uses for gene therapy. Neoplasma 2011;58:158-71.
75. Bollrath J, Phesse TJ, von Burstin VA, et al. gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis. Cancer Cell 2009;15:91-102.
76. Kiuchi N, Nakajima K, Ichiba M, et al. STAT3 is required for the gp130-mediated full activation of the c-myc gene. J Exp Med 1999;189:63-73.
77. Asgeirsson KS, Olafsdottir K, Jonasson JG, et al. The effects of IL-6 on cell adhesion and e-cadherin expression in breast cancer. Cytokine 1998;10:720-8.
78. Kujawski M, Kortylewski M, Lee H, et al. Stat3 mediates myeloid cell-dependent tumor angiogenesis in mice. J Clin Invest 2008;118:3367-77.
79. Vendramini-Costa DB, Carvalho JE. Molecular Link Mechanisms between Inflammation and Cancer. Curr Pharm Des 2012;18:3831-52.
80. Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell 2007;129:1261-74.
81. Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 2006;7:606-19.
82. Liu W, Zhou Y, Reske SN, et al. PTEN mutation: many birds with one stone in tumorigenesis. Anticancer Res 2008;28(6A):3613-19.
83. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell 2006;124:471-84.
84. Boye K, Grotterod I, Aasheim HC, et al. Activation of NF-kappaB by extracellular S100A4: analysis of signal transduction mechanisms and identification of target genes. Int J Cancer 2008;123:1301-10.
85. Yang XM, Wang YS, Zhang J, et al. Role of PI3K/Akt and MEK/ERK in mediating hypoxia-induced expression of HIF-1alpha and VEGF in laser-induced rat choroidal neovascularization. Invest Ophthalmol Vis Sci 2009;50:1873-9.
86. Shaul YD, Seger R. The MEK/ERK cascade: from signaling specificity to diverse functions. Biochim Biophys Acta 2007;1773:1213-26.
87. Lavoie JN, L'Allemain G, Brunet A, et al. Cyclin D1 expression is regulated positively by the p42/p44MAPK and negatively by the p38/HOGMAPK pathway. J Biol Chem 1996;271:20608-16.
88. Davis RJ. Transcriptional regulation by MAP kinases. Mol Reprod Dev 1995;42:459-67.
89. Kawada M, Yamagoe S, Murakami Y, et al. Induction of p27Kip1 degradation and anchorage independence by Ras through the MAP kinase signaling pathway. Oncogene 1997;15:629-37.
90. Steelman LS, Franklin RA, Abrams SL, et al. Roles of the Ras/Raf/MEK/ERK pathway in leukemia therapy. Leukemia 2011;25:1080-94.
91. Puchalski T, Prabhakar U, Jiao Q, et al. Pharmacokinetic and pharmacodynamic modeling of an anti-interleukin-6 chimeric monoclonal antibody (siltuximab) in patients with metastatic renal cell carcinoma. Clin Cancer Res 2010;16:1652-61.
92. Morgan G. Future drug developments in multiple myeloma: an overview of novel lenalidomide-based combination therapies. Blood Rev 2010;24(Suppl 1):S27-32.
93. Nonomura N, Nakayama M, Takayama H, et al. [Molecular-targeted therapy for prostate cancer]. Hinyokika Kiyo 2008;54:63-6.
94. Arai Y, Nonomura N, Nakai Y, et al. The growth-inhibitory effects of dexamethasone on renal cell carcinoma in vivo and in vitro. Cancer Invest 2008;26:35-40.
95. Liu Y, Liu A, Li H, et al. Celecoxib inhibits interleukin-6/interleukin-6 receptor-induced JAK2/STAT3 phosphorylation in human hepatocellular carcinoma cells. Cancer Prev Res (Phila) 2011;4:1296-305.
96. Nikitakis NG, Hamburger AW, Sauk JJ. The nonsteroidal anti-inflammatory drug sulindac causes down-regulation of signal transducer and activator of transcription 3 in human oral squamous cell carcinoma cells. Cancer Res 2002;62:1004-7.
97. Curiel-Lewandrowski C, Nijsten T, Gomez ML, et al. Long-term use of nonsteroidal anti-inflammatory drugs decreases the risk of cutaneous melanoma: results of a United States case-control study. J Invest Dermatol 2011;131:1460-8.
98. Slattery ML, Curtin K, Baumgartner R, et al. IL6, aspirin, nonsteroidal anti-inflammatory drugs, and breast cancer risk in women living in the southwestern United States. Cancer Epidemiol Biomarkers Prev 2007;16:747-55.
99. Berkel H, Holcombe RF, Middlebrooks M, et al. Nonsteroidal antiinflammatory drugs and colorectal cancer. Epidemiol Rev 1996;18:205-17.
100. Zerbini LF, Tamura RE, Correa RG, et al. Combinatorial effect of non-steroidal anti-inflammatory drugs and NF-kappaB inhibitors in ovarian cancer therapy. PLoS One 2011;6:e24285.
101. Mahmud SM, Franco EL, Aprikian AG. Use of nonsteroidal anti-inflammatory drugs and prostate cancer risk: a meta-analysis. Int J Cancer 2010;127:1680-91.
102. Oh SW, Myung SK, Park JY, et al. Aspirin use and risk for lung cancer: a meta-analysis. Ann Oncol 2011;22:2456-65.
103. Tian W, Zhao Y, Liu S, et al. Meta-analysis on the relationship between nonsteroidal anti-inflammatory drug use and gastric cancer. Eur J Cancer Prev 2010;19:288-98.
104. Abnet CC, Freedman ND, Kamangar F, et al. Non-steroidal anti-inflammatory drugs and risk of gastric and oesophageal adenocarcinomas: results from a cohort study and a meta-analysis. Br J Cancer 2009;100:551-7.
105. Tan XL, Reid Lombardo KM, Bamlet WR, et al. Aspirin, nonsteroidal anti-inflammatory drugs, acetaminophen, and pancreatic cancer risk: a clinic-based case-control study. Cancer Prev Res (Phila) 2011;4:1835-41.
106. Gu Y, Lee HM, Sorsa T, et al. Non-antibacterial tetracyclines modulate mediators of periodontitis and atherosclerotic cardiovascular disease: a mechanistic link between local and systemic inflammation. Pharmacol Res 2011;64:573-9.
107. Shieh JM, Huang TF, Hung CF, et al. Activation of c-Jun N-terminal kinase is essential for mitochondrial membrane potential change and apoptosis induced by doxycycline in melanoma cells. Br J Pharmacol 2010;160:1171-84.
108. Pourgholami MH, Mekkawy AH, Badar S, et al. Minocycline inhibits growth of epithelial ovarian cancer. Gynecol Oncol 2012;125:433-40.
109. Pourgholami MH, Ataie-Kachoie P, Badar S, et al. Minocycline inhibits malignant ascites of ovarian cancer through targeting multiple signaling pathways. Gynecol Oncol 2013;129:113-19.
110. Ataie-Kachoie P, Badar S, Morris DL, et al. Minocycline targets the NF-kappaB Nexus through suppression of TGF-beta1-TAK1-IkappaB signaling in ovarian cancer. Mol Cancer Res 2013;11:1279-91.
111. Dhanesuan N, Sharp JA, Blick T, et al. Doxycycline-inducible expression of SPARC/Osteonectin/BM40 in MDA-MB-231 human breast cancer cells results in growth inhibition. Breast Cancer Res Treat 2002;75:73-85.
112. Selzer MG, Zhu B, Block NL, et al. CMT-3, a chemically modified tetracycline, inhibits bony metastases and delays the development of paraplegia in a rat model of prostate cancer. Ann N Y Acad Sci 1999;878:678-82.
113. Bayliss TJ, Smith JT, Schuster M, et al. A humanized anti-IL-6 antibody (ALD518) in non-small cell lung cancer. Expert Opin Biol Ther 2011;11:1663-8.
114. Ara T, Declerck YA. Interleukin-6 in bone metastasis and cancer progression. Eur J Cancer 2010;46:1223-31.
115. Szepietowski JC, Nilganuwong S, Wozniacka A, et al. Phase I, randomized, double-blind, placebo-controlled, multiple intravenous, dose-ascending study of sirukumab in cutaneous or systemic lupus erythematosus. Arthritis Rheum 2013;65:2661-71.
116. Smolen JS, Weinblatt ME, Sheng S, et al. 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 2014;73:1616-25.
117. van Rhee F, Fayad L, Voorhees P, et al. Siltuximab, a novel anti-interleukin-6 monoclonal antibody, for Castleman's disease. J Clin Oncol 2010;28:3701-8.
118. Voorhees PM, Chen Q, Kuhn DJ, et al. Inhibition of interleukin-6 signaling with CNTO 328 enhances the activity of bortezomib in preclinical models of multiple myeloma. Clin Cancer Res 2007;13:6469-78.
119. Voorhees PM, Chen Q, Small GW, et al. Targeted inhibition of interleukin-6 with CNTO 328 sensitizes pre-clinical models of multiple myeloma to dexamethasone mediated cell death. Br J Haematol 2009;145:481-90.
120. Hunsucker SA, Magarotto V, Kuhn DJ, et al. Blockade of interleukin-6 signalling with siltuximab enhances melphalan cytotoxicity in preclinical models of multiple myeloma. Br J Haematol 2011;152:579-92.
121. Dorff TB, Goldman B, Pinski JK, et al. Clinical and correlative results of SWOG S0354: a phase II trial of CNTO328 (siltuximab), a monoclonal antibody against interleukin-6, in chemotherapy-pretreated patients with castration-resistant prostate cancer. Clin Cancer Res 2010;16:3028-34.
122. Karkera J, Steiner H, Li W, et al. The anti-interleukin-6 antibody siltuximab down-regulates genes implicated in tumorigenesis in prostate cancer patients from a phase I study. Prostate 2011;71:1455-65.
123. Fizazi K, De Bono JS, Flechon A, et al. 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 2012;48:85-93.
124. Coward J, Kulbe H, Chakravarty P, et al. Interleukin-6 as a therapeutic target in human ovarian cancer. Clin Cancer Res 2011;17:6083-96.
125. Weissglas M, Schamhart D, Lowik C, et al. Hypercalcemia and cosecretion of interleukin-6 and parathyroid hormone related peptide by a human renal cell carcinoma implanted into nude mice. J Urol 1995;153(3 Pt 1):854-7.
126. Song L, Rawal B, Nemeth JA, et al. JAK1 activates STAT3 activity in non-small-cell lung cancer cells and IL-6 neutralizing antibodies can suppress JAK1-STAT3 signaling. Mol Cancer Ther 2011;10:481-94.
127. Illei GG, Shirota Y, Yarboro CH, et al. Tocilizumab in systemic lupus erythematosus: data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study. Arthritis Rheum 2010;62:542-52.
128. Leffers HC, Ostergaard M, Glintborg B, et al. Efficacy of abatacept and tocilizumab in patients with rheumatoid arthritis treated in clinical practice: results from the nationwide Danish DANBIO registry. Ann Rheum Dis 2011;70:1216-22.
129. Burmester GR, Feist E, Kellner H, et al. Effectiveness and safety of the interleukin-6-receptor antagonist tocilizumab after 4 and 24 weeks in patients with active rheumatoid arthritis: the first phase IIIb real-life study (TAMARA). Ann Rheum Dis 2011;70:755-9.
130. Takeuchi T, Tanaka Y, Amano K, et al. Clinical, radiographic and functional effectiveness of tocilizumab for rheumatoid arthritis patients - REACTION 52-week study. Rheumatology (Oxford) 2011;50:1908-15.
131. Yokota S, Miyamae T, Imagawa T, et al. Therapeutic efficacy of humanized recombinant anti-interleukin-6 receptor antibody in children with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum 2005;52:818-25.
132. Yokota S, Imagawa T, Mori M, et al. Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial. Lancet 2008;371:998-1006.
133. Imagawa T, Yokota S, Mori M, et al. Safety and efficacy of tocilizumab, an anti-IL-6-receptor monoclonal antibody, in patients with polyarticular-course juvenile idiopathic arthritis. Mod Rheumatol 2012;22:109-15.
134. Nishimoto N, Nakahara H, Yoshio-Hoshino N, et al. Successful treatment of a patient with Takayasu arteritis using a humanized anti-interleukin-6 receptor antibody. Arthritis Rheum 2008;58:1197-200.
135. Seitz M, Reichenbach S, Bonel HM, et al. Rapid induction of remission in large vessel vasculitis by IL-6 blockade. A case series. Swiss Med Wkly 2011;141:w13156.
136. Shima Y, Kuwahara Y, Murota H, et al. The skin of patients with systemic sclerosis softened during the treatment with anti-IL-6 receptor antibody tocilizumab. Rheumatology (Oxford) 2010;49:2408-12.
137. Ito H, Takazoe M, Fukuda Y, et al. A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn's disease. Gastroenterology 2004;126:989-96; discussion 47.
138. Nishimoto N, Kanakura Y, Aozasa K, et al. Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease. Blood 2005;106:2627-32.
139. Shinriki S, Jono H, Ueda M, et al. Interleukin-6 signalling regulates vascular endothelial growth factor-C synthesis and lymphangiogenesis in human oral squamous cell carcinoma. J Pathol 2011;225:142-50.
140. Kudo M, Jono H, Shinriki S, et al. Antitumor effect of humanized anti-interleukin-6 receptor antibody (tocilizumab) on glioma cell proliferation. Laboratory investigation. J Neurosurg 2009;111:219-25.
141. Yoshio-Hoshino N, Adachi Y, Aoki C, et al. Establishment of a new interleukin-6 (IL-6) receptor inhibitor applicable to the gene therapy for IL-6-dependent tumor. Cancer Res 2007;67:871-5.
142. Adachi Y, Yoshio-Hoshino N, Aoki C, et al. VEGF targeting in mesotheliomas using an interleukin-6 signal inhibitor based on adenovirus gene delivery. Anticancer Res 2010;30:1947-52.