Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer

Abstract

The IL-6 family of cytokines consists of IL-6, IL-11, IL-27, IL-31, oncostatin M (OSM), leukaemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), cardiotrophin 1 (CT-1) and cardiotrophin-like cytokine factor 1 (CLCF1). Membership of this cytokine family is defined by usage of common β-receptor signalling subunits, which activate various intracellular signalling pathways. Each IL-6 family member elicits responses essential to the physiological control of immune homeostasis, haematopoiesis, inflammation, development and metabolism. Accordingly, distortion of these cytokine activities often promotes chronic disease and cancer; the pathological importance of this is exemplified by the successful treatment of certain autoimmune conditions with drugs that target the IL-6 pathway. Here, we discuss the emerging roles for IL-6 family members in infection, chronic inflammation, autoimmunity and cancer and review therapeutic strategies designed to manipulate these cytokines in disease.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Cytokine receptor usage by the IL-6 family of cytokines.
Fig. 2: The intrinsic and extrinsic properties of IL-6 family cytokines in cancer.
Fig. 3: The IL-6 cytokine family as therapeutic targets.

Similar content being viewed by others

References

  1. Dinarello, C. Historical insights into cytokines. Eur. J. Immunol. 37, S34–S45 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Garbers, C. et al. Plasticity and cross-talk of interleukin 6-type cytokines. Cytokine Growth Factor Rev. 23, 85–97 (2012).

    CAS  PubMed  Google Scholar 

  3. Choy, E. H., Kavanaugh, A. F. & Jones, S. A. The problem of choice: current biologic agents and future prospects in RA. Nat. Rev. Rheumatol. 9, 154–163 (2013).

    CAS  PubMed  Google Scholar 

  4. Ernst, M. & Putoczki, T. L. Targeting IL-11 signaling in colon cancer. Oncotarget 4, 1860–1861 (2013).

    PubMed  PubMed Central  Google Scholar 

  5. Hunter, C. A. & Jones, S. A. IL-6 as a keystone cytokine in health and disease. Nat. Immunol. 16, 448–457 (2015).

    CAS  PubMed  Google Scholar 

  6. Johnson, D. E., O’Keefe, R. A. & Grandis, J. R. Targeting the IL-6/JAK/STAT3 signalling axis in cancer. Nat. Rev. Clin. Oncol. 15, 234–248 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. McInnes, I. B. & Schett, G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat. Rev. Immunol. 7, 429–442 (2007).

    CAS  PubMed  Google Scholar 

  8. Schett, G., Elewaut, D., McInnes, I. B., Dayer, J. M. & Neurath, M. F. How cytokine networks fuel inflammation: toward a cytokine-based disease taxonomy. Nat. Med. 19, 822–824 (2013). References 7 and 8 discuss the context-dependent nature of inflammation and the importance of understanding these processes in determining the appropriate course of biological drug therapy.

    CAS  PubMed  Google Scholar 

  9. Villarino, A. V., Kanno, Y. & O’Shea, J. J. Mechanisms and consequences of Jak-STAT signaling in the immune system. Nat. Immunol. 18, 374–384 (2017).This is an excellent review on the mechanisms of JAK–STAT signalling and an introduction to new methodologies relevant to the study of these processes.

    CAS  PubMed  Google Scholar 

  10. Nishimoto, N. et al. Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease. Blood 106, 2627–2632 (2005).

    CAS  PubMed  Google Scholar 

  11. Villiger, P. M. et al. Tocilizumab for induction and maintenance of remission in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet 387, 1921–1927 (2016).

    CAS  PubMed  Google Scholar 

  12. Nishimoto, N. et al. Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum. 50, 1761–1769 (2004).

    CAS  PubMed  Google Scholar 

  13. Bordon, Y. Immunometabolism: IL-6, the resistance fighter. Nat. Rev. Immunol. 14, 282–283 (2014). This is an excellent commentary on the importance of IL-6 in metabolism and immune homeostasis.

    CAS  PubMed  Google Scholar 

  14. Kishimoto, T. Interleukin-6: discovery of a pleiotropic cytokine. Arthritis Res. Ther. 8, S2 (2006).

    PubMed  PubMed Central  Google Scholar 

  15. Rose-John, S. Interleukin-6 family cytokines. Cold Spring Harb. Perspect. Biol. 10, a028415 (2018).

    PubMed  PubMed Central  Google Scholar 

  16. Heinrich, P. C. et al. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem. J. 374, 1–20 (2003). This article provides a comprehensive overview of the signal transduction mechanisms employed by the IL-6 cytokine family.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Garbers, C. & Rose-John, S. Dissecting interleukin-6 classic- and trans-signaling in inflammation and cancer. Methods Mol. Biol. 1725, 127–140 (2018).

    CAS  PubMed  Google Scholar 

  18. Ferretti, E., Corcione, A. & Pistoia, V. The IL-31/IL-31 receptor axis: general features and role in tumor microenvironment. J. Leukoc. Biol. 102, 711–717 (2017).

    CAS  PubMed  Google Scholar 

  19. Hermanns, H. Oncostatin M and interleukin-31: cytokines, receptors, signal transduction and physiology. Cytokine Growth Factor Rev. 26, 545–558 (2015).

    CAS  PubMed  Google Scholar 

  20. Jones, L. L. & Vignali, D. A. A. Molecular interactions within the IL-6/IL-12 cytokine/receptor superfamily. Immunol. Res. 51, 5–14 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Brocker, C., Thompson, D., Matsumoto, A., Nebert, D. W. & Vasiliou, V. Evolutionary divergence and functions of the human interleukin (IL) gene family. Hum. Genom. 5, 30–55 (2010).

    CAS  Google Scholar 

  22. Huising, M. O., Kruiswijk, C. P. & Flik, G. Phylogeny and evolution of class-I helical cytokines. J. Endocrinol. 189, 1–25 (2006).

    CAS  PubMed  Google Scholar 

  23. Hunter, C. A. New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions. Nat. Rev. Immunol. 5, 521–531 (2005).

    CAS  PubMed  Google Scholar 

  24. Wang, X. et al. Interleukin (IL)-39 [IL-23p19/Epstein-Barr virus-induced 3 (Ebi3)] induces differentiation/expansion of neutrophils in lupus-prone mice. Clin. Exp. Immunol. 186, 144–156 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Ning-Wei, Z. Interleukin (IL)-35 is raising our expectations. Rev. Med. Chil. 138, 758–766 (2010).

    PubMed  Google Scholar 

  26. Collison, L. W. et al. The composition and signaling of the IL-35 receptor are unconventional. Nat. Immunol. 13, 290–299 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Stumhofer, J. S. et al. A role for IL-27p28 as an antagonist of gp130-mediated signaling. Nat. Immunol. 11, 1119–1126 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Yoshida, K. et al. Targeted disruption of gp130, a common signal transducer for the interleukin 6 family of cytokines, leads to myocardial and hematological disorders. Proc. Natl Acad. Sci. USA 93, 407–411 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Heinrich, P. C., Behrmann, I., Müller-Newen, G., Schaper, F. & Graeve, L. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem. J. 334, 297–314 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Kopf, M. et al. Impaired immune and acute-phase responses in interleukin-6-deficient mice. Nature 368, 339–342 (1994).This is the original description of the Il6 −/− mouse.

    CAS  PubMed  Google Scholar 

  31. Escary, J. L., Perreau, J., Dumenil, D., Ezine, S. & Brulet, P. Leukaemia inhibitory factor is necessary for maintenance of haematopoietic stem cells and thymocyte stimulation. Nature 363, 361–364 (1993).

    CAS  PubMed  Google Scholar 

  32. Schuster, B. et al. Signaling of human ciliary neurotrophic factor (CNTF) revisited. The interleukin-6 receptor can serve as an alpha-receptor for CTNF. J. Biol. Chem. 278, 9528–9535 (2003).

    CAS  PubMed  Google Scholar 

  33. Nicolaou, A. et al. The ADAM17 metalloproteinase maintains arterial elasticity. Thromb. Haemost. 118, 210–213 (2018).

    PubMed  Google Scholar 

  34. Prystaz, K. et al. Distinct effects of IL-6 classic and trans-signaling in bone fracture healing. Am. J. Pathol. 188, 474–490 (2018).

    CAS  PubMed  Google Scholar 

  35. Yan, J. et al. Interleukin-30 (IL27p28) alleviates experimental sepsis by modulating cytokine profile in NKT cells. J. Hepatol. 64, 1128–1136 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Garbers, C. et al. 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. J. Biol. Chem. 288, 4346–4354 (2013).

    CAS  PubMed  Google Scholar 

  37. Jones, S. A., Scheller, J. & Rose-John, S. Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. J. Clin. Invest. 121, 3375–3383 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Chalaris, A., Garbers, C., Rabe, B., Rose-John, S. & Scheller, J. The soluble Interleukin 6 receptor: generation and role in inflammation and cancer. Eur. J. Cell Biol. 90, 484–494 (2011).

    CAS  PubMed  Google Scholar 

  39. Jones, S. A. Directing transition from innate to acquired immunity: defining a role for IL-6. J. Immunol. 175, 3463–3468 (2005).

    CAS  PubMed  Google Scholar 

  40. Jones, S. A., Horiuchi, S., Topley, N., Yamamoto, N. & Fuller, G. M. The soluble interleukin 6 receptor: mechanisms of production and implications in disease. FASEB J. 15, 43–58 (2001).

    CAS  PubMed  Google Scholar 

  41. Rose-John, S. & Heinrich, P. C. Soluble receptors for cytokines and growth factors: generation and biological function. Biochem. J. 300, 281–290 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Peters, M. et al. The function of the soluble interleukin 6 (IL-6) receptor in vivo: sensitization of human soluble IL-6 receptor transgenic mice towards IL-6 and prolongation of the plasma half-life of IL-6. J. Exp. Med. 183, 1399–1406 (1996).

    CAS  PubMed  Google Scholar 

  43. Gearing, D. P. & Cosman, D. Homology of the p40 subunit of natural killer cell stimulatory factor (NKSF) with the extracellular domain of the interleukin-6 receptor. Cell 66, 9–10 (1991).

    CAS  PubMed  Google Scholar 

  44. Chehboun, S. et al. Epstein-Barr virus-induced gene 3 (EBI3) can mediate IL-6 trans-signaling. J. Biol. Chem. 292, 6644–6656 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Davis, S. et al. Released form of CNTF receptor alpha component as a soluble mediator of CNTF responses. Science 259, 1736–1739 (1993).

    CAS  PubMed  Google Scholar 

  46. Lokau, J. et al. Proteolytic cleavage governs interleukin-11 trans-signaling. Cell Rep. 14, 1761–1773 (2016).

    CAS  PubMed  Google Scholar 

  47. Yamada, O., Ozaki, K., Akiyama, M. & Kawauchi, K. JAK-STAT and JAK-PI3K-mTORC1 pathways regulate telomerase transcriptionally and posttranslationally in ATL cells. Mol. Cancer Ther. 11, 1112–1121 (2012).

    CAS  PubMed  Google Scholar 

  48. Thiem, S. et al. mTORC1 inhibition restricts inflammation-associated gastrointestinal tumorigenesis in mice. J. Clin. Invest. 123, 767–781 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Taniguchi, K. et al. A gp130-Src-YAP module links inflammation to epithelial regeneration. Nature 519, 57–62 (2015). This study offers new insights into gp130 control of tissue regeneration and maintenance of immune homeostasis.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Holland, S. M. et al. STAT3 mutations in the hyper-IgE syndrome. N. Engl. J. Med. 357, 1608–1619 (2007).

    CAS  PubMed  Google Scholar 

  51. Kreins, A. Y. et al. Human TYK2 deficiency: mycobacterial and viral infections without hyper-IgE syndrome. J. Exp. Med. 212, 1641–1662 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Ernst, M. & Jenkins, B. J. Acquiring signalling specificity from the cytokine receptor gp130. Trends Genet. 20, 23–32 (2004).

    CAS  PubMed  Google Scholar 

  53. Freeman, A. F. & Holland, S. M. Clinical manifestations of hyper IgE syndromes. Dis. Markers 29, 123–130 (2010).

    PubMed  PubMed Central  Google Scholar 

  54. Rebouissou, S. et al. Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours. Nature 457, 200–204 (2009).

    CAS  PubMed  Google Scholar 

  55. Stark, G. R. & Darnell, J. E. Jr. The JAK-STAT pathway at twenty. Immunity 36, 503–514 (2012). This is a comprehensive overview including a historical perspective on the modulation of JAK–STAT signalling and its implications on cytokine biology.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Yoshimura, A., Naka, T. & Kubo, M. SOCS proteins, cytokine signalling and immune regulation. Nat. Rev. Immunol. 7, 454–465 (2007).

    CAS  PubMed  Google Scholar 

  57. Boulay, J. L., O’Shea, J. J. & Paul, W. E. Molecular phylogeny within type I cytokines and their cognate receptors. Immunity 19, 159–163 (2003).

    CAS  PubMed  Google Scholar 

  58. Yang, J. et al. Unphosphorylated STAT3 accumulates in response to IL-6 and activates transcription by binding to NFkappaB. Genes Dev. 21, 1396–1408 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Löffler, D. et al. Interleukin-6 dependent survival of multiple myeloma cells involves the Stat3-mediated induction of microRNA-21 through a highly conserved enhancer. Blood 110, 1330–1333 (2007).

    PubMed  Google Scholar 

  60. Yu, L. et al. Clinical utility of a STAT3-regulated miRNA-200 family signature with prognostic potential in early gastric cancer. Clin. Cancer Res. 24, 1459–1472 (2018).

    CAS  PubMed  Google Scholar 

  61. Qing, Y. & Stark, G. R. Alternative activation of STAT1 and STAT3 in response to interferon-gamma. J. Biol. Chem. 279, 41679–41685 (2004).

    CAS  PubMed  Google Scholar 

  62. Costa-Pereira, A. P. et al. Mutational switch of an IL-6 response to an interferon-gamma-like response. Proc. Natl Acad. Sci. USA 99, 8043–8047 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Yang, X. P. et al. Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5. Nat. Immunol. 12, 247–254 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Avalle, L., Pensa, S., Regis, G., Novelli, F. & Poli, V. STAT1 and STAT3 in tumorigenesis: a matter of balance. JAKSTAT 1, 65–72 (2012).

    PubMed  PubMed Central  Google Scholar 

  65. Hirahara, K. et al. Signal transduction pathways and transcriptional regulation in Th17 cell differentiation. Cytokine Growth Factor Rev. 21, 425–434 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Hirahara, K. et al. Asymmetric action of STAT transcription factors drives transcriptional outputs and cytokine specificity. Immunity 42, 877–889 (2015). This study compares the transcriptional outputs of IL-6 and IL-27 in CD4 + T cells and illustrates the relationship between cytokine activation of STAT1 and STAT3.

    CAS  PubMed  Google Scholar 

  67. Hunter, C. A. & Kastelein, R. Interleukin-27: balancing protective and pathological immunity. Immunity 37, 960–969 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Jenkins, B. J. Transcriptional regulation of pattern recognition receptors by Jak/STAT signaling, and the implications for disease pathogenesis. J. Interferon Cytokine Res. 34, 750–758 (2014).

    CAS  PubMed  Google Scholar 

  69. Guo, R. F. & Ward, P. A. Role of C5a in inflammatory responses. Annu. Rev. Immunol. 23, 821–852 (2005).

    CAS  PubMed  Google Scholar 

  70. Greenhill, C. J. et al. IL-6 trans-signaling modulates TLR4-dependent inflammatory responses via STAT3. J. Immunol. 186, 1199–1208 (2011).

    CAS  PubMed  Google Scholar 

  71. Riedemann, N. C. et al. Regulatory role of C5a in LPS-induced IL-6 production by neutrophils during sepsis. FASEB J. 18, 370–372 (2004).

    CAS  PubMed  Google Scholar 

  72. Riedemann, N. C. et al. Protective effects of IL-6 blockade in sepsis are linked to reduced C5a receptor expression. J. Immunol. 170, 503–507 (2003).

    CAS  PubMed  Google Scholar 

  73. Strey, C. W. et al. The proinflammatory mediators C3a and C5a are essential for liver regeneration. J. Exp. Med. 198, 913–923 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Mansell, A. & Jenkins, B. J. Dangerous liaisons between interleukin-6 cytokine and toll-like receptor families: a potent combination in inflammation and cancer. Cytokine Growth Factor Rev. 24, 249–256 (2013).

    CAS  PubMed  Google Scholar 

  75. Silver, J. S., Stumhofer, J. S., Passos, S., Ernst, M. & Hunter, C. A. IL-6 mediates the susceptibility of glycoprotein 130 hypermorphs to Toxoplasma gondii. J. Immunol. 187, 350–360 (2011).

    CAS  PubMed  Google Scholar 

  76. Larrea, E. et al. Oncostatin M enhances the antiviral effects of type I interferon and activates immunostimulatory functions in liver epithelial cells. J. Virol. 83, 3298–3311 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Patterson, B. K. et al. Leukemia inhibitory factor inhibits HIV-1 replication and is upregulated in placentae from nontransmitting women. J. Clin. Invest. 107, 287–294 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Modur, V. et al. Oncostatin M is a proinflammatory mediator. in vivo effects correlate with endothelial cell expression of inflammatory cytokines and adhesion molecules. J. Clin. Invest. 100, 158–168 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Ayaub, E. A. et al. Overexpression of OSM and IL-6 impacts the polarization of pro-fibrotic macrophages and the development of bleomycin-induced lung fibrosis. Sci. Rep. 7, 13281 (2017).

    PubMed  PubMed Central  Google Scholar 

  80. Chu, D. K. et al. Therapeutic potential of anti-IL-6 therapies for granulocytic airway inflammation in asthma. Allergy Asthma Clin. Immunol. 11, 14 (2015).

    PubMed  PubMed Central  Google Scholar 

  81. Chen, Q. et al. IL-11 receptor alpha in the pathogenesis of IL-13-induced inflammation and remodeling. J. Immunol. 174, 2305–2313 (2005).

    CAS  PubMed  Google Scholar 

  82. Dixit, A. et al. Frontline science: proliferation of Ly6C(+) monocytes during urinary tract infections is regulated by IL-6 trans-signaling. J. Leukoc. Biol. 103, 13–22 (2018).

    CAS  PubMed  Google Scholar 

  83. Xing, Z. et al. IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses. J. Clin. Invest. 101, 311–320 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Romani, L. et al. Impaired neutrophil response and CD4+ T helper cell 1 development in interleukin 6-deficient mice infected with Candida albicans. J. Exp. Med. 183, 1345–1355 (1996).

    CAS  PubMed  Google Scholar 

  85. Jones, S. A., Fraser, D. J., Fielding, C. A. & Jones, G. W. Interleukin-6 in renal disease and therapy. Nephrol. Dial Transplant 30, 564–574 (2015).

    CAS  PubMed  Google Scholar 

  86. Garbers, C. et al. The interleukin-6 receptor Asp358Ala single nucleotide polymorphism rs2228145 confers increased proteolytic conversion rates by ADAM proteases. Biochim. Biophys. Acta 1842, 1485–1494 (2014).

    CAS  PubMed  Google Scholar 

  87. IL6R Genetics Consortium Emerging Risk Factors Collaboration et al. Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies. Lancet 379, 1205–1213 (2012). References 89 and 90 emphasize the clinical importance of genetic variants within the IL-6R system.

    PubMed Central  Google Scholar 

  88. Ferreira, R. C. et al. Functional IL6R 358Ala allele impairs classical IL-6 receptor signaling and influences risk of diverse inflammatory diseases. PLOS Genet. 9, e1003444 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Wong, P. K. et al. Interleukin-6 modulates production of T lymphocyte-derived cytokines in antigen-induced arthritis and drives inflammation-induced osteoclastogenesis. Arthritis Rheum. 54, 158–168 (2006).

    CAS  PubMed  Google Scholar 

  90. Sims, N. A. gp130 signaling in bone cell biology: multiple roles revealed by analysis of genetically altered mice. Mol. Cell Endocrinol. 310, 30–39 (2009).

    CAS  PubMed  Google Scholar 

  91. Nakamura, K., Nonaka, H., Saito, H., Tanaka, M. & Miyajima, A. Hepatocyte proliferation and tissue remodeling is impaired after liver injury in oncostatin M receptor knockout mice. Hepatology 39, 635–644 (2004).

    PubMed  Google Scholar 

  92. Hams, E. et al. Oncostatin M receptor-beta signaling limits monocytic cell recruitment in acute inflammation. J. Immunol. 181, 2174–2180 (2008).

    CAS  PubMed  Google Scholar 

  93. Esashi, E. et al. Oncostatin M deficiency leads to thymic hypoplasia, accumulation of apoptotic thymocytes and glomerulonephritis. Eur. J. Immunol. 39, 1664–1670 (2009).

    CAS  PubMed  Google Scholar 

  94. Yoshida, H. & Hunter, C. A. The immunobiology of interleukin-27. Annu. Rev. Immunol. 33, 417–443 (2015). This is an excellent commentary on the biological properties of IL-27.

    CAS  PubMed  Google Scholar 

  95. Villarino, A. V. et al. IL-27 limits IL-2 production during Th1 differentiation. J. Immunol. 176, 237–247 (2006).

    CAS  PubMed  Google Scholar 

  96. Hall, A. O. et al. The cytokines interleukin 27 and interferon-gamma promote distinct Treg cell populations required to limit infection-induced pathology. Immunity 37, 511–523 (2012).

    PubMed  PubMed Central  Google Scholar 

  97. Stumhofer, J. S. et al. Interleukins 27 and 6 induce STAT3-mediated T cell production of interleukin 10. Nat. Immunol. 8, 1363–1371 (2007).

    CAS  PubMed  Google Scholar 

  98. Villarino, A. et al. The IL-27R (WSX-1) is required to suppress T cell hyperactivity during infection. Immunity 19, 645–655 (2003).

    CAS  PubMed  Google Scholar 

  99. Young, A. et al. Cutting edge: suppression of GM-CSF expression in murine and human T cells by IL-27. J. Immunol. 189, 2079–2083 (2012).

    CAS  PubMed  Google Scholar 

  100. Stumhofer, J. S. et al. Interleukin 27 negatively regulates the development of interleukin 17-producing T helper cells during chronic inflammation of the central nervous system. Nat. Immunol. 7, 937–945 (2006). This study provides an early example of how IL-27 may counteract some of the activities controlled by IL-6.

    CAS  PubMed  Google Scholar 

  101. Nosko, A. et al. T-Bet enhances regulatory T cell fitness and directs control of Th1 responses in crescentic GN. J. Am. Soc. Nephrol. 28, 185–196 (2017).

    CAS  PubMed  Google Scholar 

  102. Fielding, C. A. et al. Interleukin-6 signaling drives fibrosis in unresolved inflammation. Immunity 40, 40–50 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Iwakura, Y., Ishigame, H., Saijo, S. & Nakae, S. Functional specialization of interleukin-17 family members. Immunity 34, 149–162 (2011).

    CAS  PubMed  Google Scholar 

  104. Liu, L. et al. Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J. Exp. Med. 208, 1635–1648 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Dileepan, T. et al. Robust antigen specific th17 T cell response to group A Streptococcus is dependent on IL-6 and intranasal route of infection. PLOS Pathog. 7, e1002252 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Diveu, C. et al. IL-27 blocks RORc expression to inhibit lineage commitment of Th17 cells. J. Immunol. 182, 5748–5756 (2009).

    CAS  PubMed  Google Scholar 

  107. Son, H.-J. et al. Oncostatin M suppresses activation of IL-17/Th17 via SOCS3 regulation in CD4(+) T cells. J. Immunol. 198, 1484–1491 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Zhang, X. et al. IL-11 induces Th17 cell responses in patients with early relapsing-remitting multiple sclerosis. J. Immunol. 194, 5139–5149 (2015).

    CAS  PubMed  Google Scholar 

  109. Lucas, S., Ghilardi, N., Li, J. & de Sauvage, F. J. IL-27 regulates IL-12 responsiveness of naïve CD4+ T cells through Stat1-dependent and -independent mechanisms. Proc. Natl Acad. Sci. USA 100, 15047–15052 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Peters, A. et al. IL-27 induces Th17 differentiation in the absence of STAT1 signaling. J. Immunol. 195, 4144–4153 (2015).

    CAS  PubMed  Google Scholar 

  111. Jones, G. W. et al. Exacerbated inflammatory arthritis in response to hyperactive gp130 signalling is independent of IL-17A. Ann. Rheum. Dis. 72, 1738–1742 (2013).

    CAS  PubMed  Google Scholar 

  112. Quintana, F. J. et al. Aiolos promotes TH17 differentiation by directly silencing Il2 expression. Nat. Immunol. 13, 770–777 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Kimura, A., Naka, T., Nohara, K., Fujii-Kuriyama, Y. & Kishimoto, T. Aryl hydrocarbon receptor regulates Stat1 activation and participates in the development of Th17 cells. Proc. Natl Acad. Sci. USA 105, 9721–9726 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Moon, S. J. et al. In vivo action of IL-27: reciprocal regulation of Th17 and Treg cells in collagen-induced arthritis. Exp. Mol. Med. 45, e46 (2013).

    PubMed  PubMed Central  Google Scholar 

  115. Korn, T. et al. IL-6 controls Th17 immunity in vivo by inhibiting the conversion of conventional T cells into Foxp3+ regulatory T cells. Proc. Natl Acad. Sci. USA 105, 18460–18465 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Pasare, C. & Medzhitov, R. Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells. Science 299, 1033–1036 (2003).

    CAS  PubMed  Google Scholar 

  117. Vasconcellos, R., Carter, N. A., Rosser, E. C. & Mauri, C. IL-12p35 subunit contributes to autoimmunity by limiting IL-27-driven regulatory responses. J. Immunol. 187, 3402–3412 (2011).

    CAS  PubMed  Google Scholar 

  118. Fujimoto, M. et al. The influence of excessive IL-6 production in vivo on the development and function of Foxp3+ regulatory T cells. J. Immunol. 186, 32–40 (2011).

    CAS  PubMed  Google Scholar 

  119. Komori, T. & Morikawa, Y. Oncostatin M in the development of metabolic syndrome and its potential as a novel therapeutic target. Anat. Sci. Int. 93, 169–176 (2017).

    PubMed  Google Scholar 

  120. Mauer, J. et al. Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin. Nat. Immunol. 15, 423–430 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Kraakman, M. J. et al. Blocking IL-6 trans-signaling prevents high-fat diet-induced adipose tissue macrophage recruitment but does not improve insulin resistance. Cell Metab. 21, 403–416 (2015).

    CAS  PubMed  Google Scholar 

  122. Petruzzelli, M. et al. A switch from white to brown fat increases energy expenditure in cancer-associated cachexia. Cell Metab. 20, 433–447 (2014).

    CAS  PubMed  Google Scholar 

  123. Flint, T. R. et al. Tumor-induced IL-6 reprograms host metabolism to suppress anti-tumor immunity. Cell Metab. 24, 672–684 (2016). References 122–126 describe the importance of IL-6 cytokines in metabolism.

    CAS  PubMed  PubMed Central  Google Scholar 

  124. McFarland-Mancini, M. M. et al. Differences in wound healing in mice with deficiency of IL-6 versus IL-6 receptor. J. Immunol. 184, 7219–7228 (2010).

    CAS  PubMed  Google Scholar 

  125. Ramsay, A. J. et al. The role of interleukin-6 in mucosal IgA antibody responses in vivo. Science 264, 561–563 (1994).

    CAS  PubMed  Google Scholar 

  126. Kallen, K. J. The role of transsignalling via the agonistic soluble IL-6 receptor in human diseases. Biochim. Biophys. Acta 1592, 323–343 (2002).

    CAS  PubMed  Google Scholar 

  127. Mozaffarian, A. et al. Mechanisms of oncostatin M-induced pulmonary inflammation and fibrosis. J. Immunol. 181, 7243–7253 (2008).

    CAS  PubMed  Google Scholar 

  128. Ruzicka, T. et al. Anti-interleukin-31 receptor A antibody for atopic dermatitis. N. Engl. J. Med. 376, 826–835 (2017).

    CAS  PubMed  Google Scholar 

  129. Schafer, S. et al. IL-11 is a crucial determinant of cardiovascular fibrosis. Nature 552, 110–115 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Hong, F. et al. Opposing roles of STAT1 and STAT3 in T cell-mediated hepatitis: regulation by SOCS. J. Clin. Invest. 110, 1503–1513 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Zhang, W. et al. Interleukin 6 underlies angiotensin II-induced hypertension and chronic renal damage. Hypertension 59, 136–144 (2012).

    CAS  PubMed  Google Scholar 

  132. Booth, A. J. et al. Connective tissue growth factor promotes fibrosis downstream of TGFbeta and IL-6 in chronic cardiac allograft rejection. Am. J. Transplant 10, 220–230 (2010).

    CAS  PubMed  Google Scholar 

  133. Nakashima, C., Otsuka, A. & Kabashima, K. Interleukin-31 and interleukin-31 receptor-new therapeutic targets for atopic dermatitis. Exp. Dermatol. 27, 327–331 (2018).

    CAS  PubMed  Google Scholar 

  134. Zhang, X. L., Topley, N., Ito, T. & Phillips, A. Interleukin-6 regulation of transforming growth factor (TGF)-beta receptor compartmentalization and turnover enhances TGF-beta1 signaling. J. Biol. Chem. 280, 12239–12245 (2005).

    CAS  PubMed  Google Scholar 

  135. Neveu, W. A. et al. 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 (2010).

    PubMed  PubMed Central  Google Scholar 

  136. Simmons, E. M. et al. Plasma cytokine levels predict mortality in patients with acute renal failure. Kidney Int. 65, 1357–1365 (2004).

    CAS  PubMed  Google Scholar 

  137. Horii, Y. et al. Involvement of IL-6 in mesangial proliferative glomerulonephritis. J. Immunol. 143, 3949–3955 (1989).

    CAS  PubMed  Google Scholar 

  138. Nechemia-Arbely, Y. et al. IL-6/IL-6R axis plays a critical role in acute kidney injury. J. Am. Soc. Nephrol. 19, 1106–1115 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Grivennikov, S. et al. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell 15, 103–113 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Qiu, Z., Fujimura, M., Kurashima, K., Nakao, S. & Mukaida, N. Enhanced airway inflammation and decreased subepithelial fibrosis in interleukin 6-deficient mice following chronic exposure to aerosolized antigen. Clin. Exp. Allergy 34, 1321–1328 (2004).

    CAS  PubMed  Google Scholar 

  141. Ivashkiv, L. B. & Hu, X. The JAK/STAT pathway in rheumatoid arthritis: pathogenic or protective? Arthritis Rheum. 48, 2092–2096 (2003).

    PubMed  Google Scholar 

  142. Walker, J. G. & Smith, M. D. The Jak-STAT pathway in rheumatoid arthritis. J. Rheumatol 32, 1650–1653 (2005).

    CAS  PubMed  Google Scholar 

  143. Nowell, M. A. et al. Regulation of pre-B cell colony-enhancing factor by STAT-3-dependent interleukin-6 trans-signaling: implications in the pathogenesis of rheumatoid arthritis. Arthritis Rheum. 54, 2084–2095 (2006).

    CAS  PubMed  Google Scholar 

  144. Nowell, M. A. et al. Therapeutic targeting of IL-6 trans signaling counteracts STAT3 control of experimental inflammatory arthritis. J. Immunol. 182, 613–622 (2009).

    CAS  PubMed  Google Scholar 

  145. Atsumi, T. et al. A point mutation of Tyr-759 in interleukin 6 family cytokine receptor subunit gp130 causes autoimmune arthritis. J. Exp. Med. 196, 979–990 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Jenkins, B. J. et al. Hyperactivation of Stat3 in gp130 mutant mice promotes gastric hyperproliferation and desensitizes TGF-beta signaling. Nat. Med. 11, 845–852 (2005).

    CAS  PubMed  Google Scholar 

  147. Fielding, C. A. et al. IL-6 regulates neutrophil trafficking during acute inflammation via STAT3. J. Immunol. 181, 2189–2195 (2008).

    CAS  PubMed  Google Scholar 

  148. Romas, E. et al. The role of gp130-mediated signals in osteoclast development: regulation of interleukin 11 production by osteoblasts and distribution of its receptor in bone marrow cultures. J. Exp. Med. 183, 2581–2291 (1996).

    CAS  PubMed  Google Scholar 

  149. Le Goff, B. et al. Oncostatin M acting via OSMR, augments the actions of IL-1 and TNF in synovial fibroblasts. Cytokine 68, 101–109 (2014).

    PubMed  Google Scholar 

  150. Matsushita, K. et al. LIF/STAT3/SOCS3 signaling pathway in murine bone marrow stromal cells suppresses osteoblast differentiation. J. Cell. Biochem. 115, 1262–1268 (2014).

    CAS  PubMed  Google Scholar 

  151. Walker, E. C. et al. Oncostatin M promotes bone formation independently of resorption when signaling through leukemia inhibitory factor receptor in mice. J. Clin. Invest. 120, 582–592 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Kalliolias, G. D., Zhao, B., Triantafyllopoulou, A., Park-Min, K. H. & Ivashkiv, L. B. Interleukin-27 inhibits human osteoclastogenesis by abrogating RANKL-mediated induction of nuclear factor of activated T cells c1 and suppressing proximal RANK signaling. Arthritis Rheum. 62, 402–413 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Udagawa, N. et al. Interleukin (IL)-6 induction of osteoclast differentiation depends on IL-6 receptors expressed on osteoblastic cells but not on osteoclast progenitors. J. Exp. Med. 182, 1461–1468 (1995).

    CAS  PubMed  Google Scholar 

  154. Nowell, M. A. et al. Soluble IL-6 receptor governs IL-6 activity in experimental arthritis: blockade of arthritis severity by soluble glycoprotein 130. J. Immunol. 171, 3202–3209 (2003). This study provides an early example of the importance of cytokine trans -signalling in chronic inflammatory disease.

    CAS  PubMed  Google Scholar 

  155. Richards, P. J. et al. Functional characterization of a soluble gp130 isoform and its therapeutic capacity in an experimental model of inflammatory arthritis. Arthritis Rheum. 54, 1662–1672 (2006).

    CAS  PubMed  Google Scholar 

  156. Desgeorges, A. et al. Concentrations and origins of soluble interleukin 6 receptor-alpha in serum and synovial fluid. J. Rheumatol 24, 1510–1516 (1997).

    CAS  PubMed  Google Scholar 

  157. Kotake, S. et al. 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 (1996).

    CAS  PubMed  Google Scholar 

  158. Robak, T., Gladalska, A., Stepien, H. & Robak, E. Serum levels of interleukin-6 type cytokines and soluble interleukin-6 receptor in patients with rheumatoid arthritis. Mediators Inflamm. 7, 347–353 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Meka, R. R., Venkatesha, S. H., Dudics, S., Acharya, B. & Moudgil, K. D. IL-27-induced modulation of autoimmunity and its therapeutic potential. Autoimmun Rev. 14, 1131–1141 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Pitzalis, C., Jones, G. W., Bombardieri, M. & Jones, S. A. Ectopic lymphoid-like structures in infection, cancer and autoimmunity. Nat. Rev. Immunol. 14, 447–462 (2014).

    CAS  PubMed  Google Scholar 

  161. Jones, G. W. et al. Interleukin-27 inhibits ectopic lymphoid-like structure development in early inflammatory arthritis. J. Exp. Med. 212, 1793–1802 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Orr, C. et al. Synovial tissue research: a state-of-the-art review. Nat. Rev. Rheumatol 13, 463–475 (2017).

    PubMed  Google Scholar 

  163. Rangel-Moreno, J. et al. The development of inducible bronchus-associated lymphoid tissue depends on IL-17. Nat. Immunol. 12, 639–646 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Peters, A. et al. Th17 cells induce ectopic lymphoid follicles in central nervous system tissue inflammation. Immunity 35, 986–996 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Ma, C. S., Deenick, E. K., Batten, M. & Tangye, S. G. The origins, function, and regulation of T follicular helper cells. J. Exp. Med. 209, 1241–1253 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Taniguchi, K. & Karin, M. IL-6 and related cytokines as the critical lynchpins between inflammation and cancer. Semin. Immunol. 26, 54–74 (2014).

    CAS  PubMed  Google Scholar 

  167. Yu, H., Lee, H., Herrmann, A., Buettner, R. & Jove, R. Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat. Rev. Cancer 14, 736–746 (2014).

    CAS  PubMed  Google Scholar 

  168. Li, N., Grivennikov, S. I. & Karin, M. The unholy trinity: inflammation, cytokines, and STAT3 shape the cancer microenvironment. Cancer Cell 19, 429–431 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Tye, H. et al. STAT3-driven upregulation of TLR2 promotes gastric tumorigenesis independent of tumor inflammation. Cancer Cell 22, 466–478 (2012). This study presents the seminal discovery that IL-6 family cytokines (via JAK–STAT signalling) elicit crosstalk with pattern recognition receptors to promote tumorigenesis.

    CAS  PubMed  Google Scholar 

  170. Ernst, M. et al. STAT3 and STAT1 mediate IL-11-dependent and inflammation-associated gastric tumorigenesis in gp130 receptor mutant mice. J. Clin. Invest. 118, 1727–1738 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Sullivan, N. J. et al. Interleukin-6 induces an epithelial-mesenchymal transition phenotype in human breast cancer cells. Oncogene 28, 2940–2947 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Gawlik-Rzemieniewska, N. & Bednarek, I. The role of NANOG transcriptional factor in the development of malignant phenotype of cancer cells. Cancer Biol. Ther. 17, 1–10 (2016).

    CAS  PubMed  Google Scholar 

  173. Johnstone, C. N., Chand, A., Putoczki, T. L. & Ernst, M. Emerging roles for IL-11 signaling in cancer development and progression: focus on breast cancer. Cytokine Growth Factor Rev. 26, 489–498 (2015).

    CAS  PubMed  Google Scholar 

  174. Winship, A. L., Van Sinderen, M., Donoghue, J., Rainczuk, K. & Dimitriadis, E. Targeting interleukin-11 receptor-α impairs human endometrial cancer cell proliferation and invasion in vitro and reduces tumor growth and metastasis in vivo. Mol. Cancer Ther. 15, 720–730 (2016).

    CAS  PubMed  Google Scholar 

  175. Li, X. et al. LIF promotes tumorigenesis and metastasis of breast cancer through the AKT-mTOR pathway. Oncotarget 5, 788–801 (2014).

    PubMed  PubMed Central  Google Scholar 

  176. Yue, X. et al. Leukemia inhibitory factor promotes EMT through STAT3-dependent miR-21 induction. Oncotarget 7, 3777–3790 (2016).

    PubMed  Google Scholar 

  177. Junk, D. J. et al. Oncostatin M promotes cancer cell plasticity through cooperative STAT3-SMAD3 signaling. Oncogene 36, 4001–4013 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Zeng, H. et al. Feedback activation of leukemia inhibitory factor receptor limits response to histone deacetylase inhibitors in breast cancer. Cancer Cell 30, 459–473 (2016).

    CAS  PubMed  Google Scholar 

  179. Shien, K. et al. JAK1/STAT3 activation through a proinflammatory cytokine pathway leads to resistance to molecularly targeted therapy in non-small cell lung cancer. Mol. Cancer Ther. 16, 2234–2245 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Pencik, J. et al. STAT3 regulated ARF expression suppresses prostate cancer metastasis. Nat. Commun. 6, 7736 (2015).

    CAS  PubMed  Google Scholar 

  181. Cocco, C. et al. Interleukin-27 acts as multifunctional antitumor agent in multiple myeloma. Clin. Cancer Res. 16, 4188–4197 (2010).

    CAS  PubMed  Google Scholar 

  182. Pan, C. M., Wang, M. L., Chiou, S. H., Chen, H. Y. & Wu, C. W. Oncostatin M suppresses metastasis of lung adenocarcinoma by inhibiting SLUG expression through coordination of STATs and PIASs signalings. Oncotarget 7, 60395–60406 (2016).

    PubMed  PubMed Central  Google Scholar 

  183. Tsukamoto, H. et al. Immune-suppressive effects of interleukin-6 on T cell-mediated anti-tumor immunity. Cancer Sci. 109, 523–530 (2018).

    CAS  PubMed  Google Scholar 

  184. Xu, D. H. et al. The role of IL-11 in immunity and cancer. Cancer Lett. 373, 156–163 (2016).

    CAS  PubMed  Google Scholar 

  185. Shiga, K. et al. Cancer-associated fibroblasts: their characteristics and their roles in tumor growth. Cancers (Basel) 7, 2443–2458 (2015).

    Google Scholar 

  186. Fabbi, M., Carbotti, G. & Ferrini, S. Dual roles of IL-27 in cancer biology and immunotherapy. Mediators Inflamm. 2017, 3958069 (2017).

    PubMed  PubMed Central  Google Scholar 

  187. Garbers, C., Heink, S., Korn, T. & Rose-John, S. Interleukin-6: designing specific therapeutics for a complex cytokine. Nat. Rev. Drug Discov. 17, 395–412 (2018).

    CAS  PubMed  Google Scholar 

  188. Klein, B., Lu, Z. Y., Gaillard, J. P., Harousseau, J. L. & Bataille, R. Inhibiting IL-6 in human multiple myeloma. Curr. Top. Microbiol. Immunol. 182, 237–244 (1992).

    CAS  PubMed  Google Scholar 

  189. Lu, Z. Y. et al. High amounts of circulating interleukin (IL)-6 in the form of monomeric immune complexes during anti-IL-6 therapy. Towards a new methodology for measuring overall cytokine production in human in vivo. Eur. J. Immunol. 22, 2819–2824 (1992).

    CAS  PubMed  Google Scholar 

  190. de Boysson, H., Février, J., Nicolle, A., Auzary, C. & Geffray, L. Tocilizumab in the treatment of the adult-onset Still’s disease: current clinical evidence. Clin. Rheumatol 32, 141–147 (2013).

    PubMed  Google Scholar 

  191. Bae, S. C. & Lee, Y. H. Comparison of the efficacy and tolerability of tocilizumab, sarilumab, and sirukumab in patients with active rheumatoid arthritis: a Bayesian network meta-analysis of randomized controlled trials. Clin. Rheumatol 37, 1471–1479 (2018).

    PubMed  Google Scholar 

  192. De Benedetti, F. et al. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N. Engl. J. Med. 367, 2385–2395 (2012).

    PubMed  Google Scholar 

  193. Genovese, M. C. et al. Two years of sarilumab in patients with rheumatoid arthritis and an inadequate response to MTX: safety, efficacy and radiographic outcomes. Rheumatology 57, 1423–1431 (2018).

    PubMed  PubMed Central  Google Scholar 

  194. Norelli, M. et al. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat. Med. 24, 739–748 (2018).

    CAS  PubMed  Google Scholar 

  195. Tanaka, Y. & Martin Mola, E. IL-6 targeting compared to TNF targeting in rheumatoid arthritis: studies of olokizumab, sarilumab and sirukumab. Ann. Rheum. Dis. 73, 1595–1597 (2014). This is a review article discussing the activities of IL-6-directed biological drug therapies with TNF-targeting interventions.

    CAS  PubMed  Google Scholar 

  196. Varghese, J. N. et al. Structure of the extracellular domains of the human interleukin-6 receptor alpha -chain. Proc. Natl Acad. Sci. USA 99, 15959–15964 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Adams, R. et al. Discovery of a junctional epitope antibody that stabilizes IL-6 and gp80 protein:protein interaction and modulates its downstream signaling. Sci. Rep. 7, 37716 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. Lacroix, M. et al. Novel insights into interleukin 6 (IL-6) cis- and trans-signaling pathways by differentially manipulating the assembly of the IL-6 signaling complex. J. Biol. Chem. 290, 26943–26953 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  200. Smolen, J. S. et al. Consensus statement on blocking the effects of interleukin-6 and in particular by interleukin-6 receptor inhibition in rheumatoid arthritis and other inflammatory conditions. Ann. Rheum. Dis. 72, 482–492 (2013).

    CAS  PubMed  Google Scholar 

  201. Schoels, M. M. et al. Blocking the effects of interleukin-6 in rheumatoid arthritis and other inflammatory rheumatic diseases: systematic literature review and meta-analysis informing a consensus statement. Ann. Rheum. Dis. 72, 583–589 (2013).

    CAS  PubMed  Google Scholar 

  202. Nishimoto, N. et al. Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumab. Ann. Rheum. Dis. 66, 1162–1167 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Yokota, S. 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 371, 998–1006 (2008).

    CAS  PubMed  Google Scholar 

  204. Yokota, S. et al. Longterm safety and effectiveness of the anti-interleukin 6 receptor monoclonal antibody tocilizumab in patients with systemic juvenile idiopathic arthritis in Japan. J. Rheumatol 41, 759–767 (2014).

    CAS  PubMed  Google Scholar 

  205. Wright, H. L., Cross, A. L., Edwards, S. W. & Moots, R. J. Effects of IL-6 and IL-6 blockade on neutrophil function in vitro and in vivo. Rheumatology 53, 1321–1331 (2014).

    CAS  PubMed  Google Scholar 

  206. Liu, F., Poursine-Laurent, J., Wu, H. Y. & Link, D. C. Interleukin-6 and the granulocyte colony-stimulating factor receptor are major independent regulators of granulopoiesis in vivo but are not required for lineage commitment or terminal differentiation. Blood 90, 2583–2590 (1997).

    CAS  PubMed  Google Scholar 

  207. Navarini, A. A., French, L. E. & Hofbauer, G. F. Interrupting IL-6-receptor signaling improves atopic dermatitis but associates with bacterial superinfection. J. Allergy Clin. Immunol. 128, 1128–1130 (2011).

    CAS  PubMed  Google Scholar 

  208. Rose-John, S., Winthrop, K. & Calabrese, L. The role of IL-6 in host defence against infections: immunobiology and clinical implications. Nat. Rev. Rheumatol. 13, 399–409 (2017).

    CAS  PubMed  Google Scholar 

  209. Puel, A. et al. Recurrent staphylococcal cellulitis and subcutaneous abscesses in a child with autoantibodies against IL-6. J. Immunol. 180, 647–654 (2008).

    CAS  PubMed  Google Scholar 

  210. Genovese, M. C. et al. Transaminase levels and hepatic events during tocilizumab treatment: pooled analysis of long-term clinical trial safety data in rheumatoid arthritis. Arthritis Rheumatol. 69, 1751–1761 (2017).

    CAS  PubMed  Google Scholar 

  211. Choy, E., Ganeshalingam, K., Semb, A. G., Szekanecz, Z. & Nurmohamed, M. Cardiovascular risk in rheumatoid arthritis: recent advances in the understanding of the pivotal role of inflammation, risk predictors and the impact of treatment. Rheumatology 53, 2143–2154 (2014). This study provides a clinical perspective on the link between systemic chronic inflammation and changes in cardiovascular risk.

    CAS  PubMed  PubMed Central  Google Scholar 

  212. Gabay, C. et al. Comparison of lipid and lipid-associated cardiovascular risk marker changes after treatment with tocilizumab or adalimumab in patients with rheumatoid arthritis. Ann. Rheum. Dis. 75, 1806–1812 (2016).

    PubMed  Google Scholar 

  213. Tamura, T. et al. Ectopic upregulation of membrane-bound IL6R drives vascular remodeling in pulmonary arterial hypertension. J. Clin. Invest. 128, 1956–1970 (2018).

    PubMed  PubMed Central  Google Scholar 

  214. Kim, S. C. et al. Cardiovascular safety of tocilizumab versus tumor necrosis factor inhibitors in patients with rheumatoid arthritis: a multi-database cohort study. Arthritis Rheumatol. 69, 1154–1164 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  215. Nozawa, T., Imagawa, T. & Ito, S. Coronary-artery aneurysm in tocilizumab-treated children with Kawasaki’s Disease. N. Engl. J. Med. 377, 1894–1896 (2017).

    PubMed  Google Scholar 

  216. Smeeth, L. et al. Risk of myocardial infarction and stroke after acute infection or vaccination. N. Engl. J. Med. 351, 2611–2618 (2004).

    CAS  PubMed  Google Scholar 

  217. Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119–1131 (2017).

    CAS  PubMed  Google Scholar 

  218. Bayliss, T. J., Smith, J. T., Schuster, M., Dragnev, K. H. & Rigas, J. R. A humanized anti-IL-6 antibody (ALD518) in non-small cell lung cancer. Expert Opin. Biol. Ther. 11, 1663–1668 (2011).

    CAS  PubMed  Google Scholar 

  219. Ando, K. et al. Possible role for tocilizumab, an anti-interleukin-6 receptor antibody, in treating cancer cachexia. J. Clin. Oncol. 31, e69–72 (2013).

    PubMed  Google Scholar 

  220. Heo, T. H., Wahler, J. & Suh, N. Potential therapeutic implications of IL-6/IL-6R/gp130-targeting agents in breast cancer. Oncotarget 7, 15460–15473 (2016).

    PubMed  PubMed Central  Google Scholar 

  221. Teachey, D. T. et al. Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T cell therapy for acute lymphoblastic leukemia. Cancer Discov. 6, 664–679 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  222. Chen, F. et al. Measuring IL-6 and sIL-6R in serum from patients treated with tocilizumab and/or siltuximab following CAR T cell therapy. J. Immunol. Methods 434, 1–8 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  223. Choy, E. H. et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of an anti- oncostatin M monoclonal antibody in rheumatoid arthritis: results from phase II randomized, placebo-controlled trials. Arthritis Res. Ther. 15, R132–R132 (2013).

    PubMed  PubMed Central  Google Scholar 

  224. West, N. R. et al. Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease. Nat. Med. 23, 579–589 (2017). This study showcases the inflammatory role of OSM in inflammatory bowel disease and its potential utility as a clinical biomarker for therapy.

    CAS  PubMed  PubMed Central  Google Scholar 

  225. Dwaine, F. E. & Christopher, G. T. Intracompartmental delivery of CNTF as therapy for Huntingtons disease and retinitis pigmentosa. Curr. Gene Ther. 6, 147–159 (2006).

    Google Scholar 

  226. Lipinski, D. M. et al. CNTF gene therapy confers lifelong neuroprotection in a mouse model of human retinitis pigmentosa. Mol. Ther. 23, 1308–1319 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  227. Sieving, P. A. et al. Ciliary neurotrophic factor (CNTF) for human retinal degeneration: phase I trial of CNTF delivered by encapsulated cell intraocular implants. Proc. Natl Acad. Sci. USA 103, 3896–3901 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  228. Moreland, L. et al. Results of a phase-I/II randomized, masked, placebo-controlled trial of recombinant human interleukin-11 (rhIL-11) in the treatment of subjects with active rheumatoid arthritis. Arthritis Res. 3, 247–252 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  229. Metcalfe, S. M. LIF in the regulation of T cell fate and as a potential therapeutic. Genes Immun. 12, 157 (2011).

    CAS  PubMed  Google Scholar 

  230. Niedbala, W. et al. Interleukin 27 attenuates collagen-induced arthritis. Ann. Rheum. Dis. 67, 1474–1479 (2008).

    CAS  PubMed  Google Scholar 

  231. Kalliolias, G. D. & Ivashkiv, L. B. IL-27 activates human monocytes via STAT1 and suppresses IL-10 production but the inflammatory functions of IL-27 are abrogated by TLRs and p38. J. Immunol. 180, 6325–6333 (2008).

    CAS  PubMed  Google Scholar 

  232. Shkhyan, R. et al. Drug-induced modulation of gp130 signalling prevents articular cartilage degeneration and promotes repair. Ann. Rheum. Dis. 77, 760–769 (2018).

    PubMed  Google Scholar 

  233. Xu, S., Grande, F., Garofalo, A. & Neamati, N. Discovery of a novel orally active small-molecule gp130 inhibitor for the treatment of ovarian cancer. Mol. Cancer Ther. 12, 937–949 (2013).

    CAS  PubMed  Google Scholar 

  234. Hayashi, M. et al. Suppression of bone resorption by madindoline A, a novel nonpeptide antagonist to gp130. Proc. Natl Acad. Sci. USA 99, 14728–14733 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  235. Hong, S. S. et al. A novel small-molecule inhibitor targeting the IL-6 receptor beta subunit, glycoprotein 130. J. Immunol. 195, 237–245 (2015).

    CAS  PubMed  Google Scholar 

  236. Schwartz, D. M. et al. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat. Rev. Drug Discov. 17, 78 (2017).

    PubMed  PubMed Central  Google Scholar 

  237. Collins, A. S. et al. Hepatitis C virus (HCV)-induced suppressor of cytokine signaling (SOCS) 3 regulates proinflammatory TNF-alpha responses. J. Leukoc. Biol. 96, 255–263 (2014).

    PubMed  Google Scholar 

  238. Shouda, T. et al. Induction of the cytokine signal regulator SOCS3/CIS3 as a therapeutic strategy for treating inflammatory arthritis. J. Clin. Invest. 108, 1781–1178 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  239. Hong, D. et al. AZD9150, a next-generation antisense oligonucleotide inhibitor of STAT3 with early evidence of clinical activity in lymphoma and lung cancer. Sci. Transl Med. 7, 314ra185 (2015).

    PubMed  PubMed Central  Google Scholar 

  240. Zhang, Q. et al. Serum-resistant CpG-STAT3 decoy for targeting survival and immune checkpoint signaling in acute myeloid leukemia. Blood 127, 1687–1700 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  241. Siveen, K. S. et al. Targeting the STAT3 signaling pathway in cancer: role of synthetic and natural inhibitors. Biochim. Biophys. Acta 1845, 136–154 (2014).

    CAS  PubMed  Google Scholar 

  242. Stephens, J. M. & Elks, C. M. Oncostatin M: potential implications for malignancy and metabolism. Curr. Pharm. Des. 23, 3645–3657 (2017).

    CAS  PubMed  Google Scholar 

  243. Covarrubias, A. J. & Horng, T. IL-6 strikes a balance in metabolic inflammation. Cell Metab. 19, 898–899 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  244. Komori, T., Tanaka, M., Senba, E., Miyajima, A. & Morikawa, Y. Lack of oncostatin M receptor β leads to adipose tissue inflammation and insulin resistance by switching macrophage phenotype. J. Biol. Chem. 288, 21861–21875 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  245. Vigne, S. et al. IL-27-induced type 1 regulatory T-cells produce oxysterols that constrain IL-10 production. Front. Immunol. 8, 1184 (2017).

    PubMed  PubMed Central  Google Scholar 

  246. Andrews, N. C. Disorders of iron metabolism. N. Engl. J. Med. 341, 1986–1995 (1999).

    CAS  PubMed  Google Scholar 

  247. Isaacs, J. D., Harari, O., Kobold, U., Lee, J. S. & Bernasconi, C. Effect of tocilizumab on haematological markers implicates interleukin-6 signalling in the anaemia of rheumatoid arthritis. Arthritis Res. Ther. 15, R204 (2013).

    PubMed  PubMed Central  Google Scholar 

  248. Nemeth, E. et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J. Clin. Invest. 113, 1271–1276 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  249. Kanda, J. et al. Oncostatin M and leukemia inhibitory factor increase hepcidin expression in hepatoma cell lines. Int. J. Hematol. 90, 545–552 (2009).

    CAS  PubMed  Google Scholar 

  250. Wallenius, V. et al. Interleukin-6-deficient mice develop mature-onset obesity. Nat. Med. 8, 75–79 (2002).

    CAS  PubMed  Google Scholar 

  251. Smolen, J. S. et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet 371, 987–997 (2008).

    CAS  PubMed  Google Scholar 

  252. White, U. A. & Stephens, J. M. The gp130 receptor cytokine family: regulators of adipocyte development and function. Curr. Pharm. Des. 17, 340–346 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  253. Cron, L., Allen, T. & Febbraio, M. A. The role of gp130 receptor cytokines in the regulation of metabolic homeostasis. J. Exp. Biol. 219, 259–265 (2016).

    PubMed  Google Scholar 

  254. Kraakman, M. J. et al. Targeting gp130 to prevent inflammation and promote insulin action. Diabetes Obes. Metab. 15, 170–175 (2013).

    CAS  PubMed  Google Scholar 

  255. Gloaguen, I. et al. Ciliary neurotrophic factor corrects obesity and diabetes associated with leptin deficiency and resistance. Proc. Natl Acad. Sci. USA 94, 6456–6461 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  256. Sleeman, M. W. et al. Ciliary neurotrophic factor improves diabetic parameters and hepatic steatosis and increases basal metabolic rate in db/db mice. Proc. Natl Acad. Sci. USA 100, 14297–14302 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  257. Ettinger, M. P. et al. Recombinant variant of ciliary neurotrophic factor for weight loss in obese adults: a randomized, dose-ranging study. JAMA 289, 1826–1832 (2003).

    CAS  PubMed  Google Scholar 

  258. Sadagurski, M. et al. Human IL6 enhances leptin action in mice. Diabetologia 53, 525–535 (2010).

    CAS  PubMed  Google Scholar 

  259. Ellingsgaard, H. et al. Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nat. Med. 17, 1481–1489 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  260. Matthews, V. B. et al. Interleukin-6-deficient mice develop hepatic inflammation and systemic insulin resistance. Diabetologia 53, 2431–2441 (2010).

    CAS  PubMed  Google Scholar 

  261. White, J. P. et al. IL-6 regulation on skeletal muscle mitochondrial remodeling during cancer cachexia in the ApcMin/+ mouse. Skelet Muscle 2, 14 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  262. Yang, R. et al. Mitochondrial Ca²+ and membrane potential, an alternative pathway for Interleukin 6 to regulate CD4 cell effector function. Elife 4, e06376 (2015).

    PubMed Central  Google Scholar 

  263. Moreno-Aliaga, M. J. et al. Cardiotrophin-1 is a key regulator of glucose and lipid metabolism. Cell Metab. 14, 242–253 (2011).

    CAS  PubMed  Google Scholar 

  264. Knudsen, J. G. et al. Role of IL-6 in exercise training- and cold-induced UCP1 expression in subcutaneous white adipose tissue. PLOS One 9, e84910 (2014).

    PubMed  PubMed Central  Google Scholar 

  265. Sánchez-Infantes, D. et al. Oncostatin m impairs brown adipose tissue thermogenic function and the browning of subcutaneous white adipose tissue. Obes. (Silver Spring) 25, 85–93 (2017).

    Google Scholar 

  266. Ott, V., Fasshauer, M., Dalski, A., Klein, H. H. & Klein, J. Direct effects of ciliary neurotrophic factor on brown adipocytes: evidence for a role in peripheral regulation of energy homeostasis. J. Endocrinol. 173, R1–8 (2002).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  268. Skiniotis, G., Boulanger, M. J., Garcia, K. C. & Walz, T. Signaling conformations of the tall cytokine receptor gp130 when in complex with IL-6 and IL-6 receptor. Nat. Struct. Mol. Biol. 12, 545–551 (2005).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank R. Smith for editing and proofing the manuscript. S.A.J. holds research grants from Arthritis Research UK, GlaxoSmithKline and Kidney Research UK and additional funding support from the Systems Immunity University Research Institute at Cardiff University. B.J.J. is recipient of a Senior Medical Research Fellowship from the National Health and Medical Research Council of Australia (NHMRC) and is supported by research grants from the NHMRC, Cancer Council of Victoria and Avner Pancreatic Cancer Foundation. An Operational Infrastructure Support Program funded by the Victorian State Government supports research at the Hudson Institute of Medical Research.

Reviewer information

Nature Reviews Immunology thanks S. Rose-John and the other, anonymous reviewer(s) for their contribution to the peer review of this manuscript.

Author information

Authors and Affiliations

Authors

Contributions

Both authors contributed to the discussion of content, writing, review and editing of the manuscript.

Corresponding authors

Correspondence to Simon A. Jones or Brendan J. Jenkins.

Ethics declarations

Competing interests

B.J.J. has received funding support from Immix Biopharma and Opsona Therapeutics. S.A.J. has received funding support from Ferring Pharmaceuticals, GlaxoSmithKline, Hoffman-La Roche and NovImmune SA, and during the past 5 years, he has acted as an advisory consultant for Chugai Pharmaceuticals, Eleven Biotherapeutics, Genentech, Janssen Pharmaceuticals, Johnson & Johnson, NovImmune SA, Roche and Sanofi Regeneron.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Lymphokines

A subset of cytokines that are released by lymphocytes.

Adipokines

A subset of cytokines that are secreted by adipose tissue and are sometimes called adipocytokines.

Myokines

Cytokines produced and released by myocytes in response to muscle contraction.

Janus kinase–signal transducer and activator of transcription pathway

(JAK–STAT pathway). A cytokine receptor signalling mechanism used by certain cytokines to sense and interpret environmental cues during inflammation and immune homeostasis.

Pattern recognition receptors

Innate sensors that detect bacteria, viruses, fungi and other endogenous ligands generally associated with tissue damage.

Tumour microenvironment

A cellular and non-cellular compartment associated with a tumour that comprises the extracellular matrix, surrounding blood and lymphatic vessels, immune (inflammatory) cells, fibroblasts, neuroendocrine cells and adipocytes.

Cachexia

A wasting or weakening of the body owing to chronic illness or cancer.

Nanobody

An engineered single-domain antibody.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jones, S.A., Jenkins, B.J. Recent insights into targeting the IL-6 cytokine family in inflammatory diseases and cancer. Nat Rev Immunol 18, 773–789 (2018). https://doi.org/10.1038/s41577-018-0066-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41577-018-0066-7

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer