The IL-6 feed-forward loop: A driver of tumorigenesis

Sansone, 2012, Targeting the interleukin-6/Jak/stat pathway in human malignancies, Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 30, 1005, 10.1200/JCO.2010.31.8907 Kasama, 2013, Serum macrophage migration inhibitory factor levels are correlated with response to tocilizumab therapy in patients with rheumatoid arthritis, Rheumatology International Shimamoto, 2013, Serum interleukin 6 before and after therapy with tocilizumab is a principal biomarker in patients with rheumatoid arthritis, Journal of Rheumatology, 40, 1074, 10.3899/jrheum.121389 Woo, 2013, IL-6 polymorphisms: a useful genetic tool for inflammation research?, Journal of Clinical Investigation, 123, 1413, 10.1172/JCI67221 Kim, 2009, Immuno-modulatory gene polymorphisms and outcome in breast and ovarian cancer, Immunological Investigations, 38, 324, 10.1080/08820130902910567 Gao, 2007, Mutations in the EGFR kinase domain mediate STAT3 activation via IL-6 production in human lung adenocarcinomas, Journal of Clinical Investigation, 117, 3846, 10.1172/JCI31871 Schafer, 2007, IL-6 involvement in epithelial cancers, Journal of Clinical Investigation, 117, 3660, 10.1172/JCI34237 Hartman, 2011, HER2 overexpression elicits a proinflammatory IL-6 autocrine signaling loop that is critical for tumorigenesis, Cancer Research, 71, 4380, 10.1158/0008-5472.CAN-11-0308 Langkamp-Henken, 2006, Nutritional formula improved immune profiles of seniors living in nursing homes, Journal of the American Geriatrics Society, 54, 1861, 10.1111/j.1532-5415.2006.00982.x Leslie, 2010, Differential interleukin-6/Stat3 signaling as a function of cellular context mediates Ras-induced transformation, Breast Cancer Research: BCR, 12, R80, 10.1186/bcr2725 Ancrile, 2007, Oncogenic Ras-induced secretion of IL6 is required for tumorigenesis, Genes & Development, 21, 1714, 10.1101/gad.1549407 Chou, 2005, Up-regulation of interleukin-6 in human ovarian cancer cell via a Gi/PI3K-Akt/NF-kappaB pathway by lysophosphatidic acid, an ovarian cancer-activating factor, Carcinogenesis, 26, 45, 10.1093/carcin/bgh301 Dagia, 2010, A preferential p110alpha/gamma PI3K inhibitor attenuates experimental inflammation by suppressing the production of proinflammatory mediators in a NF-kappaB-dependent manner, American Journal of Physiology Cell Physiology, 298, C929, 10.1152/ajpcell.00461.2009 Tapia-Abellan, 2013, Role of MAP kinases and PI3K-Akt on the cytokine inflammatory profile of peritoneal macrophages from the ascites of cirrhotic patients, Liver International: Official Journal of the International Association for the Study of the Liver, 33, 552, 10.1111/liv.12072 Garbers, 2013, An interleukin-6 receptor-dependent molecular switch mediates signal transduction of the IL-27 cytokine subunit p28 (IL-30) via a gp130 protein receptor homodimer, Journal of Biological Chemistry, 288, 4346, 10.1074/jbc.M112.432955 Gross, 1993, Regulation of interleukin-6 (IL-6) expression: evidence for a tissue-specific role of protein kinase C, Journal of Clinical Immunology, 13, 310, 10.1007/BF00920239 Karin, 2009, NF-kappaB as a critical link between inflammation and cancer, Cold Spring Harbor Perspectives in Biology, 1, a000141, 10.1101/cshperspect.a000141 Spooren, 2010, Cooperation of NFkappaB and CREB to induce synergistic IL-6 expression in astrocytes, Cellular Signalling, 22, 871, 10.1016/j.cellsig.2010.01.018 Gerlo, 2008, Transcriptional regulation of autocrine IL-6 expression in multiple myeloma cells, Cellular Signalling, 20, 1489, 10.1016/j.cellsig.2008.04.004 Matsusaka, 1993, Transcription factors NF-IL6 and NF-kappa B synergistically activate transcription of the inflammatory cytokines, interleukin 6 and interleukin 8, Proceedings of the National Academy of Sciences of the United States of America, 90, 10193, 10.1073/pnas.90.21.10193 Kishimoto, 2005, Interleukin-6: from basic science to medicine – 40 years in immunology, Annual Review of Immunology, 23, 1, 10.1146/annurev.immunol.23.021704.115806 Grivennikov, 2008, Autocrine IL-6 signaling: a key event in tumorigenesis?, Cancer Cell, 13, 7, 10.1016/j.ccr.2007.12.020 Sansone, 2007, IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland, Journal of Clinical Investigation, 117, 3988, 10.1172/JCI32533 Chang, 2013, The IL-6/JAK/Stat3 feed-forward loop drives tumorigenesis and metastasis, Neoplasia, 15, 848, 10.1593/neo.13706 Yang, 2007, Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFkappaB, Genes & Development, 21, 1396, 10.1101/gad.1553707 Wang, 2013, STAT3 activation in response to IL-6 is prolonged by the binding of IL-6 receptor to EGF receptor, Proceedings of the National Academy of Sciences of the United States of America, 110, 16975, 10.1073/pnas.1315862110 Dry, 2010, Transcriptional pathway signatures predict MEK addiction and response to selumetinib (AZD6244), Cancer Research, 70, 2264, 10.1158/0008-5472.CAN-09-1577 Bid, 2013, Development, characterization, and reversal of acquired resistance to the MEK1 inhibitor selumetinib (AZD6244) in an in vivo model of childhood astrocytoma, Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 10.1158/1078-0432.CCR-13-0842 Vultur, 2013, MEK inhibition affects STAT3 signaling and invasion in human melanoma cell lines, Oncogene, 10.1038/onc.2013.131 Krasilnikov, 2003, ERK and PI3K negatively regulate STAT-transcriptional activities in human melanoma cells: implications towards sensitization to apoptosis, Oncogene, 22, 4092, 10.1038/sj.onc.1206598 Lodge, 2005, Increased gp130 signaling in combination with inhibition of the MEK/ERK pathway facilitates embryonic stem cell isolation from normally refractory murine CBA blastocysts, Cloning and Stem Cells, 7, 2, 10.1089/clo.2005.7.2 Radtke, 2010, Cross-regulation of cytokine signalling: pro-inflammatory cytokines restrict IL-6 signalling through receptor internalisation and degradation, Journal of Cell Science, 123, 947, 10.1242/jcs.065326 Dittrich, 1996, A di-leucine motif and an upstream serine in the interleukin-6 (IL-6) signal transducer gp130 mediate ligand-induced endocytosis and down-regulation of the IL-6 receptor, Journal of Biological Chemistry, 271, 5487, 10.1074/jbc.271.10.5487 Dittrich, 1994, Identification of a region within the cytoplasmic domain of the interleukin-6 (IL-6) signal transducer gp130 important for ligand-induced endocytosis of the IL-6 receptor, Journal of Biological Chemistry, 269, 19014, 10.1016/S0021-9258(17)32267-6 Schmidt-Arras, 2013, Oncogenic deletion mutants of gp130 signal from intracellular compartments, Journal of Cell Science, 10.1242/jcs.130294 Schutt, 2013, gp130 activation is regulated by D2-D3 interdomain connectivity, Biochemical Journal, 450, 487, 10.1042/BJ20121660 Rebouissou, 2009, Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours, Nature, 457, 200, 10.1038/nature07475 Babon, 2012, The biology and mechanism of action of suppressor of cytokine signaling 3, Growth Factors, 30, 207, 10.3109/08977194.2012.687375 Balko, 2014, Molecular profiling of the residual disease of triple-negative breast cancers after neoadjuvant chemotherapy identifies actionable therapeutic targets, Cancer Discovery, 10.1158/2159-8290.CD-13-0286 Fidler, 2003, The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited, Nature Reviews Cancer, 3, 453, 10.1038/nrc1098 Reynaud, 2011, IL-6 controls leukemic multipotent progenitor cell fate and contributes to chronic myelogenous leukemia development, Cancer Cell, 20, 661, 10.1016/j.ccr.2011.10.012 Huang, 2013, Mesenchymal stem cells promote growth and angiogenesis of tumors in mice, Oncogene, 32, 4343, 10.1038/onc.2012.458 Hugo, 2012, Contribution of fibroblast and mast cell (afferent) and tumor (efferent) IL-6 effects within the tumor microenvironment, Cancer Microenvironment: Official Journal of the International Cancer Microenvironment Society, 10.1007/s12307-012-0098-7 Tsai, 2011, Mesenchymal stem cells promote formation of colorectal tumors in mice, Gastroenterology, 141, 1046, 10.1053/j.gastro.2011.05.045 Fierro, 2004, Marrow-derived mesenchymal stem cells: role in epithelial tumor cell determination, Clinical & Experimental Metastasis, 21, 313, 10.1023/B:CLIN.0000046130.79363.33 Sethi, 2011, Tumor-derived JAGGED1 promotes osteolytic bone metastasis of breast cancer by engaging notch signaling in bone cells, Cancer Cell, 19, 192, 10.1016/j.ccr.2010.12.022 Chalmin, 2010, Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells, Journal of Clinical Investigation, 120, 457 Liu, 2010, Contribution of MyD88 to the tumor exosome-mediated induction of myeloid derived suppressor cells, American Journal of Pathology, 176, 2490, 10.2353/ajpath.2010.090777 Bretz, 2013, Body fluid exosomes promote secretion of inflammatory cytokines in monocytic cells via TLR signaling, Journal of Biological Chemistry, 10.1074/jbc.M113.512806 Peinado, 2011, The secreted factors responsible for pre-metastatic niche formation: old sayings and new thoughts, Seminars in Cancer Biology, 21, 139, 10.1016/j.semcancer.2011.01.002 Kuilman, 2008, Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network, Cell, 133, 1019, 10.1016/j.cell.2008.03.039 Lee, 2007, Interleukin-6 undergoes transition from growth inhibitor associated with neuroendocrine differentiation to stimulator accompanied by androgen receptor activation during LNCaP prostate cancer cell progression, Prostate, 67, 764, 10.1002/pros.20553 Chen, 1991, IL-6 receptors and sensitivity to growth inhibition by IL-6 in clones of human breast carcinoma cells, Journal of Biological Regulators and Homeostatic Agents, 5, 125 Kortylewski, 1999, Interleukin-6 and oncostatin M-induced growth inhibition of human A375 melanoma cells is STAT-dependent and involves upregulation of the cyclin-dependent kinase inhibitor p27/Kip1, Oncogene, 18, 3742, 10.1038/sj.onc.1202708 Badache, 2001, Interleukin 6 inhibits proliferation and, in cooperation with an epidermal growth factor receptor autocrine loop, increases migration of T47D breast cancer cells, Cancer Research, 61, 383 Culig, 2012, Interleukin-6: a multifunctional targetable cytokine in human prostate cancer, Molecular and Cellular Endocrinology, 360, 52, 10.1016/j.mce.2011.05.033 D’Anello, 2010, Epigenetic control of the basal-like gene expression profile via Interleukin-6 in breast cancer cells, Molecular Cancer, 9, 300, 10.1186/1476-4598-9-300 Schroeder, 2013, Loss of androgen receptor expression promotes a stem-like cell phenotype in prostate cancer through STAT3 signaling, Cancer Research Lee, 2012, Acetylated STAT3 is crucial for methylation of tumor-suppressor gene promoters and inhibition by resveratrol results in demethylation, Proceedings of the National Academy of Sciences of the United States of America, 109, 7765, 10.1073/pnas.1205132109 Studebaker, 2008, Fibroblasts isolated from common sites of breast cancer metastasis enhance cancer cell growth rates and invasiveness in an interleukin-6-dependent manner, Cancer Research, 68, 9087, 10.1158/0008-5472.CAN-08-0400 Dethlefsen, 2013, The role of intratumoral and systemic IL-6 in breast cancer, Breast Cancer Research and Treatment, 138, 657, 10.1007/s10549-013-2488-z He, 2013, Identification of liver cancer progenitors whose malignant progression depends on autocrine IL-6 signaling, Cell, 155, 384, 10.1016/j.cell.2013.09.031 Iliopoulos, 2011, Inducible formation of breast cancer stem cells and their dynamic equilibrium with non-stem cancer cells via IL6 secretion, Proceedings of the National Academy of Sciences of the United States of America, 108, 1397, 10.1073/pnas.1018898108 Korkaya, 2012, Activation of an IL6 inflammatory loop mediates trastuzumab resistance in HER2+ breast cancer by expanding the cancer stem cell population, Molecular Cell, 47, 570, 10.1016/j.molcel.2012.06.014 Wang, 2013, Autocrine production of interleukin-6 confers ovarian cancer cells resistance to tamoxifen via ER isoforms and SRC-1, Molecular and Cellular Endocrinology, 382, 791, 10.1016/j.mce.2013.10.029 Quante, 2011, Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth, Cancer Cell, 19, 257, 10.1016/j.ccr.2011.01.020 Yi, 2012, Blockade of interleukin-6 receptor suppresses the proliferation of H460 lung cancer stem cells, International Journal of Oncology, 41, 310 Marotta, 2011, The JAK2/STAT3 signaling pathway is required for growth of CD44(+)CD24(−) stem cell-like breast cancer cells in human tumors, Journal of Clinical Investigation, 121, 2723, 10.1172/JCI44745 Douglas, 1997, Expression and function of members of the cytokine receptor superfamily on breast cancer cells, Oncogene, 14, 661, 10.1038/sj.onc.1200882 Tamm, 1994, E-cadherin distribution in interleukin 6-induced cell-cell separation of ductal breast carcinoma cells, Proceedings of the National Academy of Sciences of the United States of America, 91, 4338, 10.1073/pnas.91.10.4338 Tamm, 1994, Cell-adhesion-disrupting action of interleukin 6 in human ductal breast carcinoma cells, Proceedings of the National Academy of Sciences of the United States of America, 91, 3329, 10.1073/pnas.91.8.3329 Kim, 2009, Tumor self-seeding by circulating cancer cells, Cell, 139, 1315, 10.1016/j.cell.2009.11.025 Bao, 2012, Hypoxia-induced aggressiveness of pancreatic cancer cells is due to increased expression of VEGF, IL-6 and miR-21, which can be attenuated by CDF treatment, PLoS ONE, 7, e50165, 10.1371/journal.pone.0050165 Bao, 2012, Hypoxia induced aggressiveness of prostate cancer cells is linked with deregulated expression of VEGF, IL-6 and miRNAs that are attenuated by CDF, PLoS ONE, 7, e43726, 10.1371/journal.pone.0043726 Matsui, 1999, Induction of interleukin (IL)-6 by hypoxia is mediated by nuclear factor (NF)-kappa B and NF-IL6 in cardiac myocytes, Cardiovascular Research, 42, 104, 10.1016/S0008-6363(98)00285-5 Qu, 2013, Generation of prostate tumor-initiating cells is associated with elevation of reactive oxygen species and IL-6/STAT3 signaling, Cancer Research, 73, 7090, 10.1158/0008-5472.CAN-13-1560 Catalano, 2013, Tumor and its microenvironment: a synergistic interplay, Seminars in Cancer Biology, 23, 522, 10.1016/j.semcancer.2013.08.007 Oh, 2013, A mutual activation loop between breast cancer cells and myeloid-derived suppressor cells facilitates spontaneous metastasis through IL-6 trans-signaling in a murine model, Breast Cancer Research: BCR, 15, R79, 10.1186/bcr3473 Lee, 2010, STAT3-induced S1PR1 expression is crucial for persistent STAT3 activation in tumors, Nature Medicine, 16, 1421, 10.1038/nm.2250 Man, 2007, On the development of models in mice of advanced visceral metastatic disease for anti-cancer drug testing, Cancer Metastasis Reviews, 26, 737, 10.1007/s10555-007-9087-6 Karnoub, 2007, Mesenchymal stem cells within tumour stroma promote breast cancer metastasis, Nature, 449, 557, 10.1038/nature06188 Pardoll, 2012, The blockade of immune checkpoints in cancer immunotherapy, Nature Reviews Cancer, 12, 252, 10.1038/nrc3239 Menetrier-Caux, 1998, Inhibition of the differentiation of dendritic cells from CD34(+) progenitors by tumor cells: role of interleukin-6 and macrophage colony-stimulating factor, Blood, 92, 4778, 10.1182/blood.V92.12.4778 Chomarat, 2000, IL-6 switches the differentiation of monocytes from dendritic cells to macrophages, Nature Immunology, 1, 510, 10.1038/82763 Roca, 2009, CCL2 and interleukin-6 promote survival of human CD11b+ peripheral blood mononuclear cells and induce M2-type macrophage polarization, Journal of Biological Chemistry, 284, 34342, 10.1074/jbc.M109.042671 Wang, 2009, IL-17 can promote tumor growth through an IL-6-Stat3 signaling pathway, Journal of Experimental Medicine, 206, 1457, 10.1084/jem.20090207 Sumida, 2012, Anti-IL-6 receptor mAb eliminates myeloid-derived suppressor cells and inhibits tumor growth by enhancing T-cell responses, European Journal of Immunology, 42, 2060, 10.1002/eji.201142335 Gabrilovich, 2009, Myeloid-derived suppressor cells as regulators of the immune system, Nature Reviews Immunology, 9, 162, 10.1038/nri2506 Kujawski, 2008, Stat3 mediates myeloid cell-dependent tumor angiogenesis in mice, Journal of Clinical Investigation, 118, 3367, 10.1172/JCI35213 Smith, 2012, IDO is a nodal pathogenic driver of lung cancer and metastasis development, Cancer Discovery, 2, 722, 10.1158/2159-8290.CD-12-0014 Monu, 2012, Myeloid-derived suppressor cells and anti-tumor T cells: a complex relationship, Immunological Investigations, 41, 595, 10.3109/08820139.2012.673191 Deng, 2012, S1PR1-STAT3 signaling is crucial for myeloid cell colonization at future metastatic sites, Cancer Cell, 21, 642, 10.1016/j.ccr.2012.03.039 Grivennikov, 2009, IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer, Cancer Cell, 15, 103, 10.1016/j.ccr.2009.01.001 Zhang, 2013, Interleukin-6 is required for pancreatic cancer progression by promoting MAPK signaling activation and oxidative stress resistance, Cancer Research, 73, 6359, 10.1158/0008-5472.CAN-13-1558-T Sung, 2013, Loss of let-7 microRNA upregulates IL-6 in bone marrow-derived mesenchymal stem cells triggering a reactive stromal response to prostate cancer, PLoS ONE, 8, e71637, 10.1371/journal.pone.0071637 Gentile, 2013, Perspectives in the treatment of multiple myeloma, Expert Opinion on Biological Therapy, 13, S1, 10.1517/14712598.2013.799132 Kurzrock, 2013, A phase I, open-label study of siltuximab, an anti-IL-6 monoclonal antibody, in patients with B-cell non-Hodgkin lymphoma, multiple myeloma, or Castleman disease, Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 19, 3659, 10.1158/1078-0432.CCR-12-3349 Voorhees, 2013, A phase 2 multicentre study of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with relapsed or refractory multiple myeloma, British Journal of Haematology, 161, 357, 10.1111/bjh.12266 Hudes, 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, Investigational New Drugs, 31, 669, 10.1007/s10637-012-9857-z Moreau, 2012, The future of therapy for relapsed/refractory multiple myeloma: emerging agents and novel treatment strategies, Seminars in Hematology, 49, S33, 10.1053/j.seminhematol.2012.05.004 Fizazi, 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, European Journal of Cancer, 48, 85, 10.1016/j.ejca.2011.10.014 Coward, 2011, Interleukin-6 as a therapeutic target in human ovarian cancer, Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 17, 6083, 10.1158/1078-0432.CCR-11-0945 Hunsucker, 2011, Blockade of interleukin-6 signalling with siltuximab enhances melphalan cytotoxicity in preclinical models of multiple myeloma, British Journal of Haematology, 152, 579, 10.1111/j.1365-2141.2010.08533.x Rossi, 2010, A phase I/II study of siltuximab (CNTO 328), an anti-interleukin-6 monoclonal antibody, in metastatic renal cell cancer, British Journal of Cancer, 103, 1154, 10.1038/sj.bjc.6605872 Guo, 2010, Effects of siltuximab on the IL-6-induced signaling pathway in ovarian cancer, Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 16, 5759, 10.1158/1078-0432.CCR-10-1095 van Rhee, 2010, Siltuximab, a novel anti-interleukin-6 monoclonal antibody, for Castleman's disease, Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 28, 3701, 10.1200/JCO.2009.27.2377 Li, 2005, CNTO-328 (Centocor), Current Opinion on Investigational Drugs, 6, 639 Nagaraj, 2010, Anti-inflammatory triterpenoid blocks immune suppressive function of MDSCs and improves immune response in cancer, Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 16, 1812, 10.1158/1078-0432.CCR-09-3272 Annels, 2013, The effects of gemcitabine and capecitabine combination chemotherapy and of low-dose adjuvant GM-CSF on the levels of myeloid-derived suppressor cells in patients with advanced pancreatic cancer, Cancer Immunology, Immunotherapy: CII Sawant, 2013, Enhancement of antitumor immunity in lung cancer by targeting myeloid-derived suppressor cell pathways, Cancer Research, 73, 6609, 10.1158/0008-5472.CAN-13-0987 Mundy-Bosse, 2011, Myeloid-derived suppressor cell inhibition of the IFN response in tumor-bearing mice, Cancer Research, 71, 5101, 10.1158/0008-5472.CAN-10-2670 Le, 2009, Gemcitabine directly inhibits myeloid derived suppressor cells in BALB/c mice bearing 4T1 mammary carcinoma and augments expansion of T cells from tumor-bearing mice, International Immunopharmacology, 9, 900, 10.1016/j.intimp.2009.03.015 Sinha, 2007, Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response, Journal of Immunology, 179, 977, 10.4049/jimmunol.179.2.977 Vincent, 2010, 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity, Cancer Research, 70, 3052, 10.1158/0008-5472.CAN-09-3690 Song, 2011, JAK1 activates STAT3 activity in non-small-cell lung cancer cells and IL-6 neutralizing antibodies can suppress JAK1-STAT3 signaling, Molecular Cancer Therapeutics, 10, 481, 10.1158/1535-7163.MCT-10-0502 Korkaya, 2011, Regulation of cancer stem cells by cytokine networks: attacking cancer's inflammatory roots, Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 17, 6125, 10.1158/1078-0432.CCR-10-2743 Stamell, 2013, The abscopal effect associated with a systemic anti-melanoma immune response, International Journal of Radiation Oncology, Biology, Physics, 85, 293, 10.1016/j.ijrobp.2012.03.017 Chari, 2013, Complete remission achieved with single agent CNTO 328, an anti-IL-6 monoclonal antibody, in relapsed and refractory myeloma, Clinical Lymphoma, Myeloma & Leukemia, 13, 333, 10.1016/j.clml.2012.12.010 Wallenius, 2002, Interleukin-6-deficient mice develop mature-onset obesity, Nature Medicine, 8, 75, 10.1038/nm0102-75 Kojima, 2013, Monitoring C-reactive protein levels to predict favourable clinical outcomes from tocilizumab treatment in patients with rheumatoid arthritis, Modern Rheumatology/The Japan Rheumatism Association, 23, 977, 10.3109/s10165-012-0782-y Bay-Jensen, 2013, Effect of tocilizumab combined with methotrexate on circulating biomarkers of synovium, cartilage, and bone in the LITHE study, Seminars in Arthritis and Rheumatism Bhagwat, 2013, Sensitivity and resistance of JAK2 inhibitors to myeloproliferative neoplasms, International Journal of Hematology, 97, 695, 10.1007/s12185-013-1353-5 Blanchard, 2001, Antioxidants inhibit cytokine production and suppress NF-kappaB activation in CAPAN-1 and CAPAN-2 cell lines, Digestive Diseases and Sciences, 46, 2768, 10.1023/A:1012795900871