Skip to main content
SpringerLink
Log in

The Role of Interleukin (IL)-6/IL-6 Receptor Axis in Cancer

  • Chapter
  • First Online:
Cytokine and Chemokine Networks in Cancer

  • 241 Accesses

Abstract

As a pleiotropic cytokine, interleukin (IL)-6 plays a key role in mediating the host’s immune defense. Multiple cell types are involved in IL-6 production, including macrophages, dendritic cells, fibroblasts, mast cells, vascular endothelial cells, monocytes, dendritic cells, T cells, B cells, etc. Furthermore, stromal cells, immune cells that infiltrate tumors, and cancer cells present in the tumor microenvironment are also in charge of producing IL-6. Although the blood levels of IL-6 are barely noticeable at physiological levels (1–5 pg/ml), they have been observed to increase by more than 100,000 times during an immediate inflammatory reaction. Elevated intensities of IL-6 have been identified in almost all human cancers. Overexpression of IL-6 in the tumor microenvironment stimulates carcinogenesis by controlling all the pathways that lead to cancer. There are two categories of interleukin-6 receptors: the first one comprises the cell membrane-bound receptor of IL-6 (IL-6R). Upon binding with IL-6R, IL-6 forms a complex with glycoprotein 130 (gp130) (a signal transducer), and, thus, the classical signaling pathway that exhibits anti-inflammatory activity gets activated. The second category comprises a soluble derivative of the interleukin-6 receptor, i.e., soluble IL-6R (sIL-6R). Upon IL-6 binding to sIL-6R, a membrane-associated signal transducer (gp130) complex is formed and trans-signaling gets activated. Signaling pathways, for instance, Ras/Raf/mitogen-activated protein kinase (MAPK), Janus kinase/signal transducer and activator of transcription (JAK/STAT), phosphatidylinositol-3 kinase (PI3K), or Src/yes-associated protein (Src/YAP), exhibit inflammatory activity, as a result of which they get activated. Almost all human malignancies are related to higher IL-6 levels in the blood. In this chapter we have summarized the function of interleukin-6 and its associated signaling pathways that promote cancer progression via various processes such as angiogenesis and increased expression of antiapoptotic genes known to promote cancer. Moreover, we have discussed the potential agents targeting IL-6R/IL-6/JAK/STAT3 that restores the anti-tumor activity by inhibiting IL-6/JAK/STAT3 axis.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Altundag O et al (2004) Interleukin-6 and C-reactive protein in metastatic renal cell carcinoma. J Clin Oncol 23(5):1044–1044

    Article  Google Scholar 

  • 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 phase I/II study of anti-IL-6 in solid tumors. Clin Cancer Res 20(8):2192–2204

    Article  CAS  PubMed  Google Scholar 

  • Angstwurm MW et al (1997) Cyclic plasma IL-6 levels during normal menstrual cycle. Cytokine 9(5):370–374

    Article  CAS  PubMed  Google Scholar 

  • Arihiro K et al (2000) Cytokines facilitate chemotactic motility of breast carcinoma cells. Breast Cancer 7(3):221–230

    Article  CAS  PubMed  Google Scholar 

  • Bachelot T et al (2003) Prognostic value of serum levels of interleukin 6 and of serum and plasma levels of vascular endothelial growth factor in hormone-refractory metastatic breast cancer patients. Br J Cancer 88(11):1721–1726

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baran P et al (2018) The balance of interleukin (IL)-6, IL-6· soluble IL-6 receptor (sIL-6R), and IL-6· sIL-6R· sgp130 complexes allows simultaneous classic and trans-signaling. J Biol Chem 293(18):6762–6775

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Becker C et al (2005) IL-6 signaling promotes tumor growth in colorectal cancer. Cell Cycle 4(2):220–223

    Article  Google Scholar 

  • Blackburn P et al (2006) Postprandial variations of plasma inflammatory markers in abdominally obese men. Obesity 14(10):1747–1754

    Article  CAS  PubMed  Google Scholar 

  • Boulanger MJ et al (2003) Hexameric structure and assembly of the interleukin-6/IL-6 α-receptor/gp130 complex. Science 300(5628):2101–2104

    Article  CAS  PubMed  Google Scholar 

  • Bozcuk H et al (2004) Tumour necrosis factor-alpha, interleukin-6, and fasting serum insulin correlate with clinical outcome in metastatic breast cancer patients treated with chemotherapy. Cytokine 27(2–3):58–65

    Article  CAS  PubMed  Google Scholar 

  • Brakenhoff J et al (1990) Structure-function analysis of human IL-6. Epitope mapping of neutralizing monoclonal antibodies with amino-and carboxyl-terminal deletion mutants. J Immunol 145(2):561–568

    Article  CAS  PubMed  Google Scholar 

  • Brakenhoff JP et al (1994) Development of a human interleukin-6 receptor antagonist. J Biol Chem 269(1):86–93

    Article  CAS  PubMed  Google Scholar 

  • Brocker C et al (2010) Evolutionary divergence and functions of the human interleukin (IL) gene family. Hum Genomics 5(1):1–26

    Article  Google Scholar 

  • Brooks C et al (2007) Bak regulates mitochondrial morphology and pathology during apoptosis by interacting with mitofusins. Proc Natl Acad Sci 104(28):11649–11654

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Buchert M et al (2016) Targeting JAK kinase in solid tumors: emerging opportunities and challenges. Oncogene 35(8):939–951

    Article  CAS  PubMed  Google Scholar 

  • Chang CH et al (2013a) Circulating interleukin-6 level is a prognostic marker for survival in advanced nonsmall cell lung cancer patients treated with chemotherapy. Int J Cancer 132(9):1977–1985

    Article  CAS  PubMed  Google Scholar 

  • Chang Q et al (2013b) The IL-6/JAK/Stat3 feed-forward loop drives tumorigenesis and metastasis. Neoplasia 15(7):848–IN845

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen M-F et al (2013) IL-6 expression regulates tumorigenicity and correlates with prognosis in bladder cancer. PLoS One 8(4):e61901

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chiu JJ et al (1996) Interleukin 6 acts as a paracrine growth factor in human mammary carcinoma cell lines. Clin Cancer Res 2(1):215–221

    CAS  PubMed  Google Scholar 

  • Chung YC, Chang YF (2003) Serum interleukin-6 levels reflect the disease status of colorectal cancer. J Surg Oncol 83(4):222–226

    Article  PubMed  Google Scholar 

  • Colotta F et al (2009) Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis 30(7):1073–1081

    Article  CAS  PubMed  Google Scholar 

  • Conze D et al (2001) Autocrine production of interleukin 6 causes multidrug resistance in breast cancer cells. Cancer Res 61(24):8851–8858

    CAS  PubMed  Google Scholar 

  • Corvinus FM et al (2005) Persistent STAT3 activation in colon cancer is associated with enhanced cell proliferation and tumor growth. Neoplasia 7(6):545–555

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Culig Z, Puhr M (2012) Interleukin-6: a multifunctional targetable cytokine in human prostate cancer. Mol Cell Endocrinol 360(1–2):52–58

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • D’Auria L et al (1997) Cytokines in the sera of patients with pemphigus vulgaris: interleukin-6 and tumour necrosis factor-alpha levels are significantly increased as compared to healthy subjects and correlate with disease activity. Eur Cytokine Netw 8(4):383–387

    PubMed  Google Scholar 

  • Danforth DN Jr, Sgagias MK (1993) Interleukin-1α and interleukin-6 act additively to inhibit growth of MCF-7 breast cancer cells in vitro. Cancer Res 53(7):1538–1545

    CAS  PubMed  Google Scholar 

  • Dethlefsen C et al (2013) The role of intratumoral and systemic IL-6 in breast cancer. Breast Cancer Res Treat 138(3):657–664

    Article  CAS  PubMed  Google Scholar 

  • Devaraj S et al (2005) Hyperglycemia induces monocytic release of interleukin-6 via induction of protein kinase C-α and-β. Diabetes 54(1):85–91

    Article  CAS  PubMed  Google Scholar 

  • Ehlers M et al (1994) Identification of two novel regions of human IL-6 responsible for receptor binding and signal transduction. J Immunol 153(4):1744–1753

    Article  CAS  PubMed  Google Scholar 

  • Ferrao R, Lupardus PJ (2017) The Janus kinase (JAK) FERM and SH2 domains: bringing specificity to JAK–receptor interactions. Front Endocrinol 8:71

    Article  Google Scholar 

  • Finkel KA et al (2016) IL-6 inhibition with MEDI5117 decreases the fraction of head and neck cancer stem cells and prevents tumor recurrence. Neoplasia 18(5):273–281

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fisher DT et al (2014) The two faces of IL-6 in the tumor microenvironment. Semin Immunol 26(1):38–47

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Frank SJ et al (1995) Regions of the JAK2 tyrosine kinase required for coupling to the growth hormone receptor. J Biol Chem 270(24):14776–14785

    Article  CAS  PubMed  Google Scholar 

  • Gandhi NA et al (2016) Targeting key proximal drivers of type 2 inflammation in disease. Nat Rev Drug Discov 15(1):35–50

    Article  CAS  PubMed  Google Scholar 

  • Gauldie J et al (1987) Interferon beta 2/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells. Proc Natl Acad Sci 84(20):7251–7255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Giacinti C, Giordano A (2006) RB and cell cycle progression. Oncogene 25(38):5220–5227

    Article  CAS  PubMed  Google Scholar 

  • Gislén A et al (2003) Superior underwater vision in a human population of sea gypsies. Curr Biol 13(10):833–836

    Article  PubMed  Google Scholar 

  • Gritsko T et al (2006) Persistent activation of stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells. Clin Cancer Res 12(1):11–19

    Article  CAS  PubMed  Google Scholar 

  • Groblewska M et al (2008) Serum interleukin 6 (IL-6) and C-reactive protein (CRP) levels in colorectal adenoma and cancer patients. Clin Chem Lab Med 46(10):1423–1428

    Article  CAS  PubMed  Google Scholar 

  • Grötzinger J et al (1999) IL-6 type cytokine receptor complexes: hexamer, tetramer or both? Biol Chem 380(7–8):803–813

    PubMed  Google Scholar 

  • Hagemann T et al (2007) Ovarian cancer cell–derived migration inhibitory factor enhances tumor growth, progression, and angiogenesis. Mol Cancer Ther 6(7):1993–2002

    Article  CAS  PubMed  Google Scholar 

  • Haverty AA et al (1997) Interleukin-6 upregulates GP96 expression in breast cancer. J Surg Res 69(1):145–149

    Article  CAS  PubMed  Google Scholar 

  • Heink S et al (2017) Trans-presentation of IL-6 by dendritic cells is required for the priming of pathogenic TH17 cells. Nat Immunol 18(1):74–85

    Article  CAS  PubMed  Google Scholar 

  • Helbig G et al (2003) NF-kappaB promotes breast cancer cell migration and metastasis by inducing the expression of the chemokine receptor CXCR4. J Biol Chem 278(24):21631–21638

    Article  CAS  PubMed  Google Scholar 

  • Hibi M et al (1990) Molecular cloning and expression of an IL-6 signal transducer, gp130. Cell 63(6):1149–1157

    Article  CAS  PubMed  Google Scholar 

  • Hideshima T et al (2001) The role of tumor necrosis factor α in the pathophysiology of human multiple myeloma: therapeutic applications. Oncogene 20(33):4519–4527

    Article  CAS  PubMed  Google Scholar 

  • Hirano T (2014) Revisiting the 1986 molecular cloning of interleukin 6. Front Immunol 5:456

    Article  PubMed  PubMed Central  Google Scholar 

  • Hirano T et al (1986) Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature 324(6092):73–76

    Article  CAS  PubMed  Google Scholar 

  • 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 84(1):228–231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hirano T et al (1988) Excessive production of interleukin 6/B cell stimulatory factor-2 in rheumatoid arthritis. Eur J Immunol 18(11):1797–1802

    Article  CAS  PubMed  Google Scholar 

  • Hirano T et al (2000) Roles of STAT3 in mediating the cell growth, differentiation and survival signals relayed through the IL-6 family of cytokine receptors. Oncogene 19(21):2548–2556

    Article  CAS  PubMed  Google Scholar 

  • Hodge DR et al (2005) The role of IL-6 and STAT3 in inflammation and cancer. Eur J Cancer 41(16):2502–2512

    Article  CAS  PubMed  Google Scholar 

  • Howard M et al (1982) Identification of a T cell-derived b cell growth factor distinct from interleukin 2. J Exp Med 155(3):914–923

    Article  CAS  PubMed  Google Scholar 

  • Ji C et al (2011) IL-6 induces lipolysis and mitochondrial dysfunction, but does not affect insulin-mediated glucose transport in 3T3-L1 adipocytes. J Bioenerg Biomembr 43(4):367–375

    Article  CAS  PubMed  Google Scholar 

  • Johnson DE et al (2018) Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat Rev Clin Oncol 15(4):234–248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jostock T et al (2001) Soluble gp130 is the natural inhibitor of soluble interleukin-6 receptor transsignaling responses. Eur J Biochem 268(1):160–167

    Article  CAS  PubMed  Google Scholar 

  • Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119(6):1420–1428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kishimoto T et al (1978) Induction of IgG production in human B lymphoblastoid cell lines with normal human T cells. Nature 271(5647):756–758

    Article  CAS  PubMed  Google Scholar 

  • Klein B et al (1989) Paracrine rather than autocrine regulation of myeloma-cell growth and differentiation by interleukin-6. Blood 73(2):517–526

    Article  CAS  PubMed  Google Scholar 

  • Klein B et al (1991) Murine anti-interleukin-6 monoclonal antibody therapy for a patient with plasma cell leukemia. Blood 78(5):1198–1204

    Article  CAS  PubMed  Google Scholar 

  • Komoda H et al (1998) Interleukin-6 levels in colorectal cancer tissues. World J Surg 22(8):895–898

    Article  CAS  PubMed  Google Scholar 

  • Krishnamoorthy N, Paglia M, Ray A, Ray P (2007) A critical role for IL-6 secretion by dendritic cells promoting Th2 and limiting Th1 response (95.24). J Immunol 178(1_Supplement):S181–S181

    Article  Google Scholar 

  • Kujawski M et al (2008) Stat3 mediates myeloid cell–dependent tumor angiogenesis in mice. J Clin Invest 118(10):3367–3377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kumari N et al (2016) Role of interleukin-6 in cancer progression and therapeutic resistance. Tumor Biol 37(9):11553–11572

    Article  CAS  Google Scholar 

  • Lai KS et al (1995) A kinase-deficient splice variant of the human JAK3 is expressed in hematopoietic and epithelial cancer cells (∗). J Biol Chem 270(42):25028–25036

    Article  CAS  PubMed  Google Scholar 

  • Landskron G et al (2014) Chronic inflammation and cytokines in the tumor microenvironment. J Immunol Res 2014:149185

    Article  PubMed  PubMed Central  Google Scholar 

  • Lederle W et al (2011) IL-6 promotes malignant growth of skin SCCs by regulating a network of autocrine and paracrine cytokines. Int J Cancer 128(12):2803–2814

    Article  CAS  PubMed  Google Scholar 

  • Liu X et al (2016) The biology behind interleukin-6 targeted interventions. Curr Opin Rheumatol 28(2):152–160

    Article  CAS  PubMed  Google Scholar 

  • Lust JA et al (1992) Isolation of an mRNA encoding a soluble form of the human interleukin-6 receptor. Cytokine 4(2):96–100

    Article  CAS  PubMed  Google Scholar 

  • Macciò A, Madeddu C (2013) The role of interleukin-6 in the evolution of ovarian cancer: clinical and prognostic implications—a review. J Mol Med 91(12):1355–1368

    Article  PubMed  Google Scholar 

  • Macciò A et al (1998) High serum levels of soluble IL-2 receptor, cytokines, and C reactive protein correlate with impairment of T cell response in patients with advanced epithelial ovarian cancer. Gynecol Oncol 69(3):248–252

    Article  PubMed  Google Scholar 

  • Mehraj U et al (2021a) Tumor microenvironment promotes breast cancer chemoresistance. Cancer Chemother Pharmacol 87(2):147–158

    Article  PubMed  Google Scholar 

  • Mehraj U et al (2021b) The tumor microenvironment as driver of stemness and therapeutic resistance in breast cancer: new challenges and therapeutic opportunities. Cell Oncol 44:1209–1229

    Article  Google Scholar 

  • Mehraj U et al (2021c) Prognostic significance and targeting tumor-associated macrophages in cancer: new insights and future perspectives. Breast Cancer 28(3):539–555

    Article  PubMed  Google Scholar 

  • Mir MA (2015a) Introduction to costimulation and costimulatory molecules. In: Mir MA (ed) Developing costimulatory molecules for immunotherapy of diseases. Academic Press, London, pp 1–43

    Google Scholar 

  • Mir MA (2015b) Costimulation in lymphomas and cancers. In: Mir MA (ed) Developing costimulatory molecules for immunotherapy of diseases. Academic Press, London, pp 185–254

    Chapter  Google Scholar 

  • Mir MA (2015c) T-cell costimulation and its applications in diseases. In: Mir MA (ed) Developing costimulatory molecules for immunotherapy of diseases. Academic Press, London, pp 255–292

    Chapter  Google Scholar 

  • Mir MA, Mehraj U (2019) Double-crosser of the immune system: macrophages in tumor progression and metastasis. Curr Immunol Rev 15(2):172–184

    Article  CAS  Google Scholar 

  • Mir MA, Qayoom H, Mehraj U, Nisar S, Bhat B, Wani NA (2020) Targeting different pathways using novel combination therapy in triple negative breast cancer. Curr Cancer Drug Targets 20(8):586–602. https://doi.org/10.2174/1570163817666200518081955. PMID: 32418525

    Article  CAS  PubMed  Google Scholar 

  • Mir MA et al (2022a) The tumor microenvironment. In: Mir MA (ed) Role of tumor microenvironment in breast cancer and targeted therapies. Academic Press, London, pp 31–58

    Chapter  Google Scholar 

  • Mir MA et al (2022b) Role of cancer-associated fibroblasts in tumor microenvironment. In: Mir MA (ed) Role of tumor microenvironment in breast cancer and targeted therapies. Academic Press, London, pp 59–86

    Chapter  Google Scholar 

  • Mir MA et al (2022c) Targeting biologically specific molecules in triple negative breast cancer (TNBC). In: Mir MA (ed) Combinational therapy in triple negative breast cancer. Academic Press, London, pp 177–200

    Chapter  Google Scholar 

  • Mir WR, Bhat BA, Kumar A, Dhiman R, Alkhanani M, Almilaibary A, Dar MY, Ganie SA, Mir MA (2023) Network pharmacology combined with molecular docking and in vitro verification reveals the therapeutic potential of Delphinium roylei munz constituents on breast carcinoma. Front Pharmacol 14:1135898. https://doi.org/10.3389/fphar.2023.1135898. PMID:37724182; PMCID: PMC10505441

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mitchem JB et al (2013) Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic ResponsesMacrophages regulate tumor-initiating cells. Cancer Res 73(3):1128–1141

    Article  CAS  PubMed  Google Scholar 

  • Miura T et al (2015) Characterization of patients with advanced pancreatic cancer and high serum interleukin-6 levels. Pancreas 44(5):756–763

    Article  CAS  PubMed  Google Scholar 

  • Mülberg J et al (1993) The soluble interleukin-6 receptor is generated by shedding. Eur J Immunol 23(2):473–480

    Article  Google Scholar 

  • Nagasaki T et al (2014) Interleukin-6 released by colon cancer-associated fibroblasts is critical for tumour angiogenesis: anti-interleukin-6 receptor antibody suppressed angiogenesis and inhibited tumour–stroma interaction. Br J Cancer 110(2):469–478

    Article  CAS  PubMed  Google Scholar 

  • Nakajima T et al (1993) Phosphorylation at threonine-235 by a ras-dependent mitogen-activated protein kinase cascade is essential for transcription factor NF-IL6. Proc Natl Acad Sci 90(6):2207–2211

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Narazaki M et al (1993) Soluble forms of the interleukin-6 signal-transducing receptor component gp130 in human serum possessing a potential to inhibit signals through membrane-anchored gp130. Blood 82(4):1120–1126

    Article  CAS  PubMed  Google Scholar 

  • Narbutt J et al (2008) Serum concentration of interleukin-6 is increased both in active and remission stages of pemphigus vulgaris. Mediators Inflamm 2008:875394

    Article  PubMed  PubMed Central  Google Scholar 

  • Naugler WE et al (2007) Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317(5834):121–124

    Article  CAS  PubMed  Google Scholar 

  • Nevins JR (2001) The Rb/E2F pathway and cancer. Hum Mol Genet 10(7):699–703

    Article  CAS  PubMed  Google Scholar 

  • Nilsson MB et al (2005) Interleukin-6, secreted by human ovarian carcinoma cells, is a potent proangiogenic cytokine. Cancer Res 65(23):10794–10800

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nishimura R et al (2000) An analysis of serum interleukin-6 levels to predict benefits of medroxyprogesterone acetate in advanced or recurrent breast cancer. Oncology 59(2):166–173

    Article  CAS  PubMed  Google Scholar 

  • Niu G et al (2005) Role of Stat3 in regulating p53 expression and function. Mol Cell Biol 25(17):7432–7440

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nolen BM et al (2008) Serum biomarker profiles and response to neoadjuvant chemotherapy for locally advanced breast cancer. Breast Cancer Res 10(3):1–9

    Article  Google Scholar 

  • Nowak M et al (2010) Proinflammatory and immunosuppressive serum, ascites and cyst fluid cytokines in patients with early and advanced ovarian cancer and benign ovarian tumors. Neuroendocrinol Lett 31(3):375–383

    CAS  PubMed  Google Scholar 

  • Nozawa H et al (2006) Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis. Proc Natl Acad Sci 103(33):12493–12498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oh K et al (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 Res 15(5):1–16

    Article  Google Scholar 

  • Paladugu RR et al (1985) Bronchopulmonary Kulchitzky cell carcinomas. A new classification scheme for typical and atypical carcinoids. Cancer 55(6):1303–1311

    Article  CAS  PubMed  Google Scholar 

  • Paonessa G et al (1995) Two distinct and independent sites on IL-6 trigger gp 130 dimer formation and signalling. EMBO J 14(9):1942–1951

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Peyser ND et al (2016) Frequent promoter hypermethylation of PTPRT increases STAT3 activation and sensitivity to STAT3 inhibition in head and neck cancer. Oncogene 35(9):1163–1169

    Article  CAS  PubMed  Google Scholar 

  • Puthier D et al (1999) Mcl-1 and Bcl-xL are co-regulated by IL-6 in human myeloma cells. Br J Haematol 107(2):392–395

    Article  CAS  PubMed  Google Scholar 

  • Qayoom H et al (2021) An insight into the cancer stem cell survival pathways involved in chemoresistance in triple-negative breast cancer. Future Oncol 17(31):4185–4206

    Article  CAS  PubMed  Google Scholar 

  • Qayoom H, Sofi S, Mir MA (2023) Targeting tumor microenvironment using tumor-infiltrating lymphocytes as therapeutics against tumorigenesis. Immunol Res. https://doi.org/10.1007/s12026-023-09376-2. Epub ahead of print. PMID: 37004645

  • Qayoom H, Mehraj U, Sofi S, Aisha S, Almilaibary A, Alkhanani M, Mir MA (2022) Expression patterns and therapeutic implications of CDK4 across multiple carcinomas: a molecular docking and MD simulation study. Med Oncol 39(10):158. https://doi.org/10.1007/s12032-022-01779-9. PMID: 35870089

    Article  CAS  PubMed  Google Scholar 

  • Qayoom H, Alkhanani M, Almilaibary A, Alsagaby SA, Mir MA (2023a) Mechanistic elucidation of Juglanthraquinone C targeting breast cancer: a network pharmacology-based investigation. Saudi. J Biol Sci 30(7):103705. https://doi.org/10.1016/j.sjbs.2023.103705. Epub 2023 Jun 15. PMID: 37425621; PMCID: PMC10329161

    Article  CAS  Google Scholar 

  • Qayoom H, Alkhanani M, Almilaibary A, Alsagaby SA, Mir MA (2023b) A network pharmacology-based investigation of brugine reveals its multi-target molecular mechanism against breast cancer. Med Oncol 40(7):202. https://doi.org/10.1007/s12032-023-02067-w. PMID: 37308611

    Article  CAS  PubMed  Google Scholar 

  • Rabinovich A et al (2007) Regulation of ovarian carcinoma SKOV-3 cell proliferation and secretion of MMPs by autocrine IL-6. Anticancer Res 27(1A):267–272

    CAS  PubMed  Google Scholar 

  • Rane SG, Reddy EP (1994) JAK3: a novel JAK kinase associated with terminal differentiation of hematopoietic cells. Oncogene 9(8):2415–2423

    CAS  PubMed  Google Scholar 

  • Reihmane D, Dela F (2014) Interleukin-6: possible biological roles during exercise. Eur J Sport Sci 14(3):242–250

    Article  PubMed  Google Scholar 

  • Ricciardi M et al (2015) Epithelial-to-mesenchymal transition (EMT) induced by inflammatory priming elicits mesenchymal stromal cell-like immune-modulatory properties in cancer cells. Br J Cancer 112(6):1067–1075

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Riethmueller S et al (2017) Proteolytic origin of the soluble human IL-6R in vivo and a decisive role of N-glycosylation. PLoS Biol 15(1):e2000080

    Article  PubMed  PubMed Central  Google Scholar 

  • Rohleder N et al (2012) Role of interleukin-6 in stress, sleep, and fatigue. Ann N Y Acad Sci 1261(1):88–96

    Article  CAS  PubMed  Google Scholar 

  • Rose-John S et al (2015) “Family Reunion”–a structured view on the composition of the receptor complexes of interleukin-6-type and interleukin-12-type cytokines. Cytokine Growth Factor Rev 5(26):471–474

    Article  Google Scholar 

  • Sakamoto K et al (1994) Elevation of circulating interleukin 6 after surgery: factors influencing the serum level. Cytokine 6(2):181–186

    Article  CAS  PubMed  Google Scholar 

  • Salgado R et al (2003) Circulating interleukin-6 predicts survival in patients with metastatic breast cancer. Int J Cancer 103(5):642–646

    Article  CAS  PubMed  Google Scholar 

  • Savino R et al (1994a) Rational design of a receptor super-antagonist of human interleukin-6. EMBO J 13(24):5863–5870

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Savino R et al (1994b) Generation of interleukin-6 receptor antagonists by molecular-modeling guided mutagenesis of residues important for gp130 activation. EMBO J 13(6):1357–1367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schafer ZT, Brugge JS (2007) IL-6 involvement in epithelial cancers. J Clin Invest 117(12):3660–3663

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Scheller J et al (2011) The pro-and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta 1813(5):878–888

    Article  CAS  PubMed  Google Scholar 

  • Seif F et al (2017) The role of JAK-STAT signaling pathway and its regulators in the fate of T helper cells. Cell Commun Signal 15(1):1–13

    Article  Google Scholar 

  • Shabo Y et al (1988) The myeloid blood cell differentiation-inducing protein MGI-2A is interleukin-6. Blood 72(6):2070–2073

    Article  CAS  PubMed  Google Scholar 

  • Simpson RJ et al (1997) Interleukin-6: structure-function relationships. Protein Sci 6(5):929–955

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sofi S, Mehraj U, Qayoom H, Aisha S, Almilaibary A, Alkhanani M, Mir MA (2022) Targeting cyclin-dependent kinase 1 (CDK1) in cancer: molecular docking and dynamic simulations of potential CDK1 inhibitors. Med Oncol 39(9):133. https://doi.org/10.1007/s12032-022-01748-2. PMID: 35723742; PMCID: PMC9207877

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sofi S, Jan N, Qayoom H, Alkhanani M, Almilaibary A, Ahmad MM (2023) Elucidation of interleukin-19 as a therapeutic target for breast cancer by computational analysis and experimental validation. Saudi J Biol Sci 30(9):103774. https://doi.org/10.1016/j.sjbs.2023.103774. Epub 2023 Aug 11. PMID: 37675062; PMCID: PMC10477739

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sprang SR, Bazan JF (1993) Cytokine structural taxonomy and mechanisms of receptor engagement. Curr Opin Struct Biol 3(6):815–827

    Article  CAS  Google Scholar 

  • Taga T, Kishimoto T (1997) Gp130 and the interleukin-6 family of cytokines. Annu Rev Immunol 15:797

    Article  CAS  PubMed  Google Scholar 

  • Taga T et al (1989) Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130. Cell 58(3):573–581

    Article  CAS  PubMed  Google Scholar 

  • Takahashi T, Shirasaw T (1994) Molecular cloning of rat JAK3, a novel member of the JAK family of protein tyrosine kinases. FEBS Lett 342(2):124–128

    Article  CAS  PubMed  Google Scholar 

  • Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 140(6):805–820

    Article  CAS  PubMed  Google Scholar 

  • Tanaka T et al (2014) IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol 6(10):a016295

    Article  PubMed  PubMed Central  Google Scholar 

  • Taniguchi K et al (2015) A gp130–Src–YAP module links inflammation to epithelial regeneration. Nature 519(7541):57–62

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Taniguchi K et al (2017) YAP–IL-6ST autoregulatory loop activated on APC loss controls colonic tumorigenesis. Proc Natl Acad Sci 114(7):1643–1648

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tartaglia M et al (2003) Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia. Nat Genet 34(2):148–150

    Article  CAS  PubMed  Google Scholar 

  • Tawara K et al (2011) Clinical significance of interleukin (IL)-6 in cancer metastasis to bone: potential of anti-IL-6 therapies. Cancer Manag Res 3:177

    CAS  PubMed  PubMed Central  Google Scholar 

  • Urashima M et al (1996) Interleukin-6 promotes multiple myeloma cell growth via phosphorylation of retinoblastoma protein. Blood 88(6):2219–2227

    Article  CAS  PubMed  Google Scholar 

  • Vaillant AAJ, Qurie A (2021) Interleukin. In: StatPearls. StatPearls Publishing, St. Petersburg, FL

    Google Scholar 

  • Van Rhee F et al (2010) Siltuximab, a novel anti–interleukin-6 monoclonal antibody, for Castleman’s disease. J Clin Oncol 28(23):3701–3708

    Article  PubMed  Google Scholar 

  • Van Rhee F et al (2014) Siltuximab for multicentric Castleman’s disease: a randomised, double-blind, placebo-controlled trial. Lancet Oncol 15(9):966–974

    Article  PubMed  Google Scholar 

  • Velazquez L et al (1995) Distinct domains of the protein tyrosine kinase tyk2 required for binding of interferon-α/β and for signal transduction. J Biol Chem 270(7):3327–3334

    Article  CAS  PubMed  Google Scholar 

  • Verbsky JW et al (1996) Expression of Janus kinase 3 in human endothelial and other non-lymphoid and non-myeloid cells. J Biol Chem 271(24):13976–13980

    Article  CAS  PubMed  Google Scholar 

  • Waldner MJ et al (2012) Interleukin-6-a key regulator of colorectal cancer development. Int J Biol Sci 8(9):1248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Waxman AB, Kolliputi N (2009) IL-6 protects against hyperoxia-induced mitochondrial damage via Bcl-2–induced Bak interactions with mitofusions. Am J Respir Cell Mol Biol 41(4):385–396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wei Q et al (2015) Estrogen suppresses hepatocellular carcinoma cells through ERβ-mediated upregulation of the NLRP3 inflammasome. Lab Investig 95(7):804–816

    Article  CAS  PubMed  Google Scholar 

  • Wunderlich FT et al (2010) Interleukin-6 signaling in liver-parenchymal cells suppresses hepatic inflammation and improves systemic insulin action. Cell Metab 12(3):237–249

    Article  CAS  PubMed  Google Scholar 

  • Yamasaki K et al (1988) Cloning and expression of the human interleukin-6 (BSF-2/IFNβ 2) receptor. Science 241(4867):825–828

    Article  CAS  PubMed  Google Scholar 

  • Yanaihara N et al (2016) Antitumor effects of interleukin-6 (IL-6)/interleukin-6 receptor (IL-6R) signaling pathway inhibition in clear cell carcinoma of the ovary. Mol Carcinog 55(5):832–841

    Article  CAS  PubMed  Google Scholar 

  • Yawata H et al (1993) Structure-function analysis of human IL-6 receptor: dissociation of amino acid residues required for IL-6-binding and for IL-6 signal transduction through gp130. EMBO J 12(4):1705–1712

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yokoe T, Morishita Y (2000) Trends of IL-6 and IL-8 levels in patients with recurrent breast cancer: preliminary report. Breast Cancer 7(3):187–190

    Article  CAS  PubMed  Google Scholar 

  • Zeng J et al (2017) Clinicopathological significance of overexpression of interleukin-6 in colorectal cancer. World J Gastroenterol 23(10):1780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang X et al (2007) Identification of STAT3 as a substrate of receptor protein tyrosine phosphatase T. Proc Natl Acad Sci 104(10):4060–4064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao W et al (2008) p38α stabilizes Interleukin-6 mRNA via multiple AU-richElements. J Biol Chem 283(4):1778–1785

    Article  CAS  PubMed  Google Scholar 

  • Zilberstein A et al (1986) Structure and expression of cDNA and genes for human interferon-beta-2, a distinct species inducible by growth-stimulatory cytokines. EMBO J 5(10):2529–2537

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar, Jammu and Kashmir, India

    Manzoor Ahmad Mir, Masrat Bashir & Nusrat Jan

Authors
  1. Manzoor Ahmad Mir
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masrat Bashir
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nusrat Jan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Manzoor Ahmad Mir .

Editor information

Editors and Affiliations

  1. Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar, Jammu and Kashmir, India

    Manzoor Ahmad Mir

Rights and permissions

Reprints and permissions

Copyright information

© 2023 The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Mir, M.A., Bashir, M., Jan, N. (2023). The Role of Interleukin (IL)-6/IL-6 Receptor Axis in Cancer . In: Mir, M.A. (eds) Cytokine and Chemokine Networks in Cancer. Springer, Singapore. https://doi.org/10.1007/978-981-99-4657-0_5

Download citation

Publish with us

Policies and ethics

Search

Navigation