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.

IL-6 as a keystone cytokine in health and disease

A Corrigendum to this article was published on 18 October 2017

This article has been updated

Abstract

Interleukin 6 (IL-6) has a broad effect on cells of the immune system and those not of the immune system and often displays hormone-like characteristics that affect homeostatic processes. IL-6 has context-dependent pro- and anti-inflammatory properties and is now regarded as a prominent target for clinical intervention. However, the signaling cassette that controls the activity of IL-6 is complicated, and distinct intervention strategies can inhibit this pathway. Clinical experience with antagonists of IL-6 has raised new questions about how and when to block this cytokine to improve disease outcome and patient wellbeing. Here we discuss the effect of IL-6 on innate and adaptive immunity and the possible advantages of various antagonists of IL-6 and consider how the immunobiology of IL-6 may inform clinical decisions.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Two distinct modes of IL-6 receptor signaling.

Debbie Maizels/Nature Publishing Group

Figure 2: IL-6 control of B cells and humoral immunity.

Debbie Maizels/Nature Publishing Group

Figure 3: Effect of IL-6 on T cell activities.

Debbie Maizels/Nature Publishing Group

Figure 4: Therapeutic targeting of IL-6 and its receptor.

Debbie Maizels/Nature Publishing Group

Change history

  • 17 August 2017

    In the version of this article initially published, some of the labels in Figure 4a,b were incorrect. In Figure 4a, in the group of IL-6 blockers (top right), 'ALX-0061' should be removed and 'Siltuximab' and 'MEDI 5117' should be added, and in the group of IL-6R blockers (middle right), 'Siltuximab' and 'ALD518' should be removed and 'ALX-0061' should be added. In Figure 4b, in the group of inhibitors at bottom left, 'MEDI 5517' should be revised to 'MEDI 5117'. These errors have been corrected in the HTML and PDF versions of the article.

  • 18 October 2017

    Nat. Immunol. 16, 448–457 (2015); published online 21 April 2015; corrected after print 17 August 2017 In the version of this article initially published, some of the labels in Figure 4a,b were incorrect. In Figure 4a, in the group of IL-6 blockers (top right), 'ALX-0061' should be removed and 'Siltuximab' and 'MEDI 5117' should be added, and in the group of IL-6R blockers (middle right), 'Siltuximab' and 'ALD518' should be removed and 'ALX-0061' should be added.

References

  1. 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).

    CAS  Article  PubMed  Google Scholar 

  2. 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  Google Scholar 

  3. Hueber, W. et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut 61, 1693–1700 (2012).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  5. 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  Article  Google Scholar 

  6. 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).

    CAS  Article  PubMed  Google Scholar 

  7. Yasukawa, K. et al. Structure and expression of human B cell stimulatory factor-2 (BSF-2/IL-6) gene. EMBO J. 6, 2939–2945 (1987).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. Woloski, B.M. & Fuller, G.M. Identification and partial characterization of hepatocyte-stimulating factor from leukemia cell lines: comparison with interleukin 1. Proc. Natl. Acad. Sci. USA 82, 1443–1447 (1985).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. Klimpel, G.R. Soluble factor(s) from LPS-activated macrophages induce cytotoxic T cell differentiation from alloantigen-primed spleen cells. J. Immunol. 125, 1243–1249 (1980).

    CAS  PubMed  Google Scholar 

  10. Yoshizaki, K. et al. Isolation and characterization of B cell differentiation factor (BCDF) secreted from a human B lymphoblastoid cell line. J. Immunol. 132, 2948–2954 (1984).

    CAS  PubMed  Google Scholar 

  11. Andus, T. et al. Recombinant human B cell stimulatory factor 2 (BSF-2/IFN-beta 2) regulates beta-fibrinogen and albumin mRNA levels in Fao-9 cells. FEBS Lett. 221, 18–22 (1987).

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  14. Rohleder, N., Aringer, M. & Boentert, M. Role of interleukin-6 in stress, sleep, and fatigue. Ann. NY Acad. Sci. 1261, 88–96 (2012).

    CAS  Article  PubMed  Google Scholar 

  15. Bethin, K.E., Vogt, S.K. & Muglia, L.J. Interleukin-6 is an essential, corticotropin-releasing hormone-independent stimulator of the adrenal axis during immune system activation. Proc. Natl. Acad. Sci. USA 97, 9317–9322 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. Hodes, G.E. et al. Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress. Proc. Natl. Acad. Sci. USA 111, 16136–16141 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 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  Article  PubMed  Google Scholar 

  18. Masuda, K. et al. Arid5a controls IL-6 mRNA stability, which contributes to elevation of IL-6 level in vivo. Proc. Natl. Acad. Sci. USA 110, 9409–9414 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. Sarwar, N. et al. Clock gene Per1 regulates the production of CCL2 and interleukin-6 through p38, JNK1 and NF-κB activation in spinal astrocytes. Mol. Cell. Neurosci. 59, 37–46 (2014).

    Article  CAS  Google Scholar 

  20. Viswanathan, S.R. et al. Lin28 promotes transformation and is associated with advanced human malignancies. Nat. Genet. 41, 843–848 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. Waage, A., Brandtzaeg, P., Halstensen, A., Kierulf, P. & Espevik, T. The complex pattern of cytokines in serum from patients with meningococcal septic shock. Association between interleukin 6, interleukin 1, and fatal outcome. J. Exp. Med. 169, 333–338 (1989).

    CAS  Article  PubMed  Google Scholar 

  22. Fraunberger, P. et al. Prognostic value of interleukin 6, procalcitonin, and C-reactive protein levels in intensive care unit patients during first increase of fever. Shock 26, 10–12 (2006).

    CAS  Article  PubMed  Google Scholar 

  23. Mroczko, B., Groblewska, M., Gryko, M., Kedra, B. & Szmitkowski, M. Diagnostic usefulness of serum interleukin 6 (IL-6) and C-reactive protein (CRP) in the differentiation between pancreatic cancer and chronic pancreatitis. J. Clin. Lab. Anal. 24, 256–261 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. Panichi, V. et al. Interleukin-6 is a stronger predictor of total and cardiovascular mortality than C-reactive protein in haemodialysis patients. Nephrol. Dial. Transplant. 19, 1154–1160 (2004).

    CAS  Article  PubMed  Google Scholar 

  25. Dienz, O. et al. Essential role of IL-6 in protection against H1N1 influenza virus by promoting neutrophil survival in the lung. Mucosal Immunol. 5, 258–266 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. Garbers, C. et al. Inhibition of classic signaling is a novel function of soluble glycoprotein 130 (sgp130), which is controlled by the ratio of interleukin 6 and soluble interleukin 6 receptor. J. Biol. Chem. 286, 42959–42970 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. Hoge, J. et al. IL-6 controls the innate immune response against Listeria monocytogenes via classical IL-6 signaling. J. Immunol. 190, 703–711 (2013).

    CAS  Article  PubMed  Google Scholar 

  28. Kopf, M. et al. Impaired immune and acute-phase responses in interleukin-6-deficient mice. Nature 368, 339–342 (1994).

    CAS  Article  PubMed  Google Scholar 

  29. Longhi, M.P. et al. Interleukin-6 is crucial for recall of influenza-specific memory CD4 T cells. PLoS Pathog. 4, e1000006 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  30. Neveu, W.A. et al. IL-6 is required for airway mucus production induced by inhaled fungal allergens. J. Immunol. 183, 1732–1738 (2009).

    CAS  PubMed  Article  Google Scholar 

  31. Smith, K.A. & Maizels, R.M. IL-6 controls susceptibility to helminth infection by impeding Th2 responsiveness and altering the Treg phenotype in vivo. Eur. J. Immunol. 44, 150–161 (2014).

    CAS  Article  PubMed  Google Scholar 

  32. van der Poll, T. et al. Interleukin-6 gene-deficient mice show impaired defense against pneumococcal pneumonia. J. Infect. Dis. 176, 439–444 (1997).

    CAS  Article  PubMed  Google Scholar 

  33. 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  Article  PubMed  Google Scholar 

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

    PubMed  PubMed Central  Article  Google Scholar 

  35. Gealy, C. et al. Posttranscriptional suppression of interleukin-6 production by human cytomegalovirus. J. Virol. 79, 472–485 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. Fielding, C.A. et al. Viral IL-6 blocks neutrophil infiltration during acute inflammation. J. Immunol. 175, 4024–4029 (2005).

    CAS  Article  PubMed  Google Scholar 

  37. Moore, P.S., Boshoff, C., Weiss, R.A. & Chang, Y. Molecular mimicry of human cytokine and cytokine response pathway genes by KSHV. Science 274, 1739–1744 (1996).

    CAS  Article  PubMed  Google Scholar 

  38. Chatterjee, M., Osborne, J., Bestetti, G., Chang, Y. & Moore, P.S. Viral IL-6-induced cell proliferation and immune evasion of interferon activity. Science 298, 1432–1435 (2002).

    CAS  PubMed  Article  Google Scholar 

  39. Jones, K.D. et al. Involvement of interleukin-10 (IL-10) and viral IL-6 in the spontaneous growth of Kaposi's sarcoma herpesvirus-associated infected primary effusion lymphoma cells. Blood 94, 2871–2879 (1999).

    CAS  PubMed  Article  Google Scholar 

  40. Chang, Y. et al. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science 266, 1865–1869 (1994).

    CAS  Article  PubMed  Google Scholar 

  41. Eugster, H.P., Frei, K., Kopf, M., Lassmann, H. & Fontana, A. IL-6-deficient mice resist myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis. Eur. J. Immunol. 28, 2178–2187 (1998).

    CAS  Article  PubMed  Google Scholar 

  42. Ohshima, S. et al. Interleukin-6 plays a key role in the development of antigen-induced arthritis. Proc. Natl. Acad. Sci. USA 95, 8222–8226 (1998).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. Alonzi, T. et al. Interleukin 6 is required for the development of collagen-induced arthritis. J. Exp. Med. 187, 461–468 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. Richards, H.B. et al. Interleukin 6 dependence of anti-DNA antibody production: evidence for two pathways of autoantibody formation in pristane-induced lupus. J. Exp. Med. 188, 985–990 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. Lattanzio, G. et al. Defective development of pristane-oil-induced plasmacytomas in interleukin-6-deficient BALB/c mice. Am. J. Pathol. 151, 689–696 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Screpanti, I. et al. Inactivation of the IL6-gene prevents development of multicentric Castleman's disease in C/EBPβ-deficient mice. J. Exp. Med. 184, 1561–1566 (1996).

    CAS  Article  PubMed  Google Scholar 

  47. Suematsu, S. et al. IgG1 plasmacytosis in interleukin 6 transgenic mice. Proc. Natl. Acad. Sci. USA 86, 7547–7551 (1989).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. Campbell, I.L. et al. Neurologic disease induced in transgenic mice by cerebral overexpression of interleukin 6. Proc. Natl. Acad. Sci. USA 90, 10061–10065 (1993).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. Steiner, M.K., Syrkina, O.L., Kolliputi, N., Mark, E.J., Hales, C.A. & Waxman, A.B. Interleukin-6 overexpression induces pulmonary hypertension. Circ. Res. 104, 236–244 (2009).

    CAS  Article  PubMed  Google Scholar 

  50. DiCosmo, B.F. et al. Airway epithelial cell expression of interleukin-6 in transgenic mice. Uncoupling of airway inflammation and bronchial hyperreactivity. J. Clin. Invest. 94, 2028–2035 (1994).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 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  Article  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  53. Collaboration, I.R.G.C.E.R.F. et al. Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies. Lancet 379, 1205–1213 (2012).

  54. Deloukas, P. et al. Large-scale association analysis identifies new risk loci for coronary artery disease. Nat. Genet. 45, 25–33 (2013).

    CAS  Article  PubMed  Google Scholar 

  55. Fishman, D. et al. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J. Clin. Invest. 102, 1369–1376 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. Stahl, E.A. et al. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat. Genet. 42, 508–514 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  59. Taga, T., Kawanishi, Y., Hardy, R.R., Hirano, T. & Kishimoto, T. Receptors for B cell stimulatory factor 2. Quantitation, specificity, distribution, and regulation of their expression. J. Exp. Med. 166, 967–981 (1987).

    CAS  Article  PubMed  Google Scholar 

  60. Yamasaki, K. et al. Cloning and expression of the human interleukin-6 (BSF-2/IFNβ2) receptor. Science 241, 825–828 (1988).

    CAS  Article  PubMed  Google Scholar 

  61. 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  Article  PubMed  Google Scholar 

  62. Heinrich, P.C. et al. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem. J. 374, 1–20 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. 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  Article  PubMed  PubMed Central  Google Scholar 

  64. Jones, G.W. et al. Loss of CD4+ T cell IL-6R expression during inflammation underlines a role for IL-6 trans signaling in the local maintenance of Th17 cells. J. Immunol. 184, 2130–2139 (2010).

    CAS  Article  PubMed  Google Scholar 

  65. 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  Article  PubMed  Google Scholar 

  66. 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  Article  Google Scholar 

  67. Sommer, J. et al. Interleukin-6, but not the interleukin-6 receptor plays a role in recovery from dextran sodium sulfate-induced colitis. Int. J. Mol. Med. 34, 651–660 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. 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  Article  Google Scholar 

  69. 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  Article  PubMed  Google Scholar 

  70. Crabé, S. et al. The IL-27 p28 subunit binds cytokine-like factor 1 to form a cytokine regulating NK and T cell activities requiring IL-6R for signaling. J. Immunol. 183, 7692–7702 (2009).

    Article  CAS  PubMed  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  72. Yasukawa, H. et al. IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages. Nat. Immunol. 4, 551–556 (2003).

    CAS  Article  PubMed  Google Scholar 

  73. Croker, B.A. et al. SOCS3 negatively regulates IL-6 signaling in vivo. Nat. Immunol. 4, 540–545 (2003).

    CAS  Article  PubMed  Google Scholar 

  74. 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  Article  Google Scholar 

  75. Jenkins, B.J. et al. Pathologic consequences of STAT3 hyperactivation by IL-6 and IL-11 during hematopoiesis and lymphopoiesis. Blood 109, 2380–2388 (2007).

    CAS  Article  PubMed  Google Scholar 

  76. 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  Article  Google Scholar 

  77. Jones, G.W. et al. Imbalanced gp130 signalling in ApoE-deficient mice protects against atherosclerosis. Atherosclerosis 238, 321–328 (2015).

    CAS  Article  PubMed  Google Scholar 

  78. 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  Article  PubMed  Google Scholar 

  79. 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  Article  Google Scholar 

  80. 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  Article  PubMed  Google Scholar 

  81. 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  Article  PubMed  Google Scholar 

  82. Schobitz, B. et al. Soluble interleukin-6 (IL-6) receptor augments central effects of IL-6 in vivo. FASEB J. 9, 659–664 (1995).

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  84. Campbell, I.L. et al. Trans-signaling is a dominant mechanism for the pathogenic actions of interleukin-6 in the brain. J. Neurosci. 34, 2503–2513 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. Atreya, R. et al. Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in Crohn disease and experimental colitis in vivo. Nat. Med. 6, 583–588 (2000).

    CAS  Article  PubMed  Google Scholar 

  86. Briso, E.M., Dienz, O. & Rincon, M. Cutting edge: soluble IL-6R is produced by IL-6R ectodomain shedding in activated CD4 T cells. J. Immunol. 180, 7102–7106 (2008).

    CAS  PubMed  Article  Google Scholar 

  87. Modur, V., Li, Y., Zimmerman, G.A., Prescott, S.M. & McIntyre, T.M. Retrograde inflammatory signaling from neutrophils to endothelial cells by soluble interleukin-6 receptor α. J. Clin. Invest. 100, 2752–2756 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. McLoughlin, R.M. et al. Differential regulation of neutrophil-activating chemokines by IL-6 and its soluble receptor isoforms. J. Immunol. 172, 5676–5683 (2004).

    CAS  Article  PubMed  Google Scholar 

  89. Hurst, S.M. et al. Il-6 and its soluble receptor orchestrate a temporal switch in the pattern of leukocyte recruitment seen during acute inflammation. Immunity 14, 705–714 (2001).

    CAS  Article  PubMed  Google Scholar 

  90. Jones, S.A. et al. C-reactive protein: a physiological activator of interleukin 6 receptor shedding. J. Exp. Med. 189, 599–604 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. Marin, V. et al. The IL-6-soluble IL-6Rα autocrine loop of endothelial activation as an intermediate between acute and chronic inflammation: an experimental model involving thrombin. J. Immunol. 167, 3435–3442 (2001).

    CAS  Article  PubMed  Google Scholar 

  92. Marin, V. et al. Chemotactic agents induce IL-6Rα shedding from polymorphonuclear cells: involvement of a metalloproteinase of the TNF-α-converting enzyme (TACE) type. Eur. J. Immunol. 32, 2965–2970 (2002).

    CAS  Article  PubMed  Google Scholar 

  93. Liao, W., Lin, J.X., Wang, L., Li, P. & Leonard, W.J. Modulation of cytokine receptors by IL-2 broadly regulates differentiation into helper T cell lineages. Nat. Immunol. 12, 551–559 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. Curnow, S.J. et al. Inhibition of T cell apoptosis in the aqueous humor of patients with uveitis by IL-6/soluble IL-6 receptor trans-signaling. J. Immunol. 173, 5290–5297 (2004).

    CAS  Article  PubMed  Google Scholar 

  95. 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  Article  PubMed  Google Scholar 

  96. Novick, D., Engelmann, H., Wallach, D. & Rubinstein, M. Soluble cytokine receptors are present in normal human urine. J. Exp. Med. 170, 1409–1414 (1989).

    CAS  Article  PubMed  Google Scholar 

  97. Honda, M. et al. Human soluble IL-6 receptor: its detection and enhanced release by HIV infection. J. Immunol. 148, 2175–2180 (1992).

    CAS  PubMed  Google Scholar 

  98. Baran, P., Nitz, R., Grotzinger, J., Scheller, J. & Garbers, C. Minimal interleukin 6 (IL-6) receptor stalk composition for IL-6 receptor shedding and IL-6 classic signaling. J. Biol. Chem. 288, 14756–14768 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. Garbers, C. et al. Species specificity of ADAM10 and ADAM17 proteins in interleukin-6 (IL-6) trans-signaling and novel role of ADAM10 in inducible IL-6 receptor shedding. J. Biol. Chem. 286, 14804–14811 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  100. Rose-John, S. IL-6 trans-signaling via the soluble IL-6 receptor: importance for the pro-inflammatory activities of IL-6. Int. J. Biol. Sci. 8, 1237–1247 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. 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  Article  PubMed  Google Scholar 

  102. Esteve, E. et al. Polymorphisms in the interleukin-6 receptor gene are associated with body mass index and with characteristics of the metabolic syndrome. Clin. Endocrinol. 65, 88–91 (2006).

    CAS  Article  Google Scholar 

  103. Song, Y. et al. The interaction between the interleukin 6 receptor gene genotype and dietary energy intake on abdominal obesity in Japanese men. Metabolism 56, 925–930 (2007).

    CAS  Article  PubMed  Google Scholar 

  104. Lin, M., Rose-John, S., Grotzinger, J., Conrad, U. & Scheller, J. Functional expression of a biologically active fragment of soluble gp130 as an ELP-fusion protein in transgenic plants: purification via inverse transition cycling. Biochem. J. 398, 577–583 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. Zhou, Y., Horiuchi, S., Yamamoto, M. & Yamamoto, N. Elevated serum levels of the soluble form of gp130, the IL-6 signal transducer, in HTLV-1 infection and no involvement of alternative splicing for its generation. Microbiol. Immunol. 42, 109–116 (1998).

    CAS  Article  PubMed  Google Scholar 

  106. 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  Article  PubMed  Google Scholar 

  107. Tanaka, M. et al. Cloning of novel soluble gp130 and detection of its neutralizing autoantibodies in rheumatoid arthritis. J. Clin. Invest. 106, 137–144 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  108. Diamant, M. et al. Cloning and expression of an alternatively spliced mRNA encoding a soluble form of the human interleukin-6 signal transducer gp130. FEBS Lett. 412, 379–384 (1997).

    CAS  Article  PubMed  Google Scholar 

  109. Sharkey, A.M. et al. Stage-specific expression of cytokine and receptor messenger ribonucleic acids in human preimplantation embryos. Biol. Reprod. 53, 974–981 (1995).

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  111. Müller-Newen, G. et al. Soluble IL-6 receptor potentiates the antagonistic activity of soluble gp130 on IL-6 responses. J. Immunol. 161, 6347–6355 (1998).

    PubMed  Google Scholar 

  112. Narazaki, M. et al. 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, 1120–1126 (1993).

    CAS  Article  PubMed  Google Scholar 

  113. Hombría, J.C., Brown, S., Hader, S. & Zeidler, M.P. Characterisation of Upd2, a Drosophila JAK/STAT pathway ligand. Dev. Biol. 288, 420–433 (2005).

    Article  CAS  PubMed  Google Scholar 

  114. Brown, S., Hu, N. & Hombria, J.C. Identification of the first invertebrate interleukin JAK/STAT receptor, the Drosophila gene domeless. Curr. Biol. 11, 1700–1705 (2001).

    CAS  Article  PubMed  Google Scholar 

  115. Kingsolver, M.B. & Hardy, R.W. Making connections in insect innate immunity. Proc. Natl. Acad. Sci. USA 109, 18639–18640 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  116. Woodcock, K.J. et al. Macrophage-derived upd3 cytokine causes impaired glucose homeostasis and reduced lifespan in Drosophila fed a lipid-rich diet. Immunity 42, 133–144 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  118. 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  Article  Google Scholar 

  119. Chou, D.B. et al. Stromal-derived IL-6 alters the balance of myeloerythroid progenitors during Toxoplasma gondii infection. J. Leukoc. Biol. 92, 123–131 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. 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  Article  PubMed  Google Scholar 

  121. Chen, Q. et al. Central role of IL-6 receptor signal-transducing chain gp130 in activation of L-selectin adhesion by fever-range thermal stress. Immunity 20, 59–70 (2004).

    CAS  Article  PubMed  Google Scholar 

  122. Romano, M. et al. Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment. Immunity 6, 315–325 (1997).

    CAS  Article  PubMed  Google Scholar 

  123. Matsumiya, T. et al. Soluble interleukin-6 receptor α inhibits the cytokine-Induced fractalkine/CX3CL1 expression in human vascular endothelial cells in culture. Exp. Cell Res. 269, 35–41 (2001).

    CAS  Article  PubMed  Google Scholar 

  124. Chalaris, A. et al. Apoptosis is a natural stimulus of IL6R shedding and contributes to the proinflammatory trans-signaling function of neutrophils. Blood 110, 1748–1755 (2007).

    CAS  Article  PubMed  Google Scholar 

  125. McLoughlin, R.M. et al. Interplay between IFN-γ and IL-6 signaling governs neutrophil trafficking and apoptosis during acute inflammation. J. Clin. Invest. 112, 598–607 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  126. 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  Article  Google Scholar 

  127. Lauder, S.N. et al. Interleukin-6 limits influenza-induced inflammation and protects against fatal lung pathology. Eur. J. Immunol. 43, 2613–2625 (2013).

    CAS  Article  PubMed  Google Scholar 

  128. Lally, F. et al. A novel mechanism of neutrophil recruitment in a coculture model of the rheumatoid synovium. Arthritis Rheum. 52, 3460–3469 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  129. Chomarat, P., Banchereau, J., Davoust, J. & Palucka, A.K. IL-6 switches the differentiation of monocytes from dendritic cells to macrophages. Nat. Immunol. 1, 510–514 (2000).

    CAS  Article  PubMed  Google Scholar 

  130. Bleier, J.I., Pillarisetty, V.G., Shah, A.B. & DeMatteo, R.P. Increased and long-term generation of dendritic cells with reduced function from IL-6-deficient bone marrow. J. Immunol. 172, 7408–7416 (2004).

    CAS  Article  PubMed  Google Scholar 

  131. Jenkins, B.J. et al. Imbalanced gp130-dependent signaling in macrophages alters macrophage colony-stimulating factor responsiveness via regulation of c-fms expression. Mol. Cell. Biol. 24, 1453–1463 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  132. Hegde, S., Pahne, J. & Smola-Hess, S. Novel immunosuppressive properties of interleukin-6 in dendritic cells: inhibition of NF-κB binding activity and CCR7 expression. FASEB J. 18(12): 1439–1441 (2004).

    CAS  Article  PubMed  Google Scholar 

  133. Tilg, H., Trehu, E., Atkins, M.B., Dinarello, C.A. & Mier, J.W. Interleukin-6 (IL-6) as an anti-inflammatory cytokine: induction of circulating IL-1 receptor antagonist and soluble tumor necrosis factor receptor p55. Blood 83, 113–118 (1994).

    CAS  Article  PubMed  Google Scholar 

  134. Beaman, M.H., Hunter, C.A. & Remington, J.S. Enhancement of intracellular replication of Toxoplasma gondii by IL-6. Interactions with IFN-γ and TNF-α. J. Immunol. 153, 4583–4587 (1994).

    CAS  PubMed  Google Scholar 

  135. Nagabhushanam, V. et al. Innate inhibition of adaptive immunity: mycobacterium tuberculosis-induced IL-6 inhibits macrophage responses to IFN-γ. J. Immunol. 171, 4750–4757 (2003).

    CAS  Article  PubMed  Google Scholar 

  136. Yoshizaki, K. et al. Pathogenic significance of interleukin-6 (IL-6/BSF-2) in Castleman's disease. Blood 74, 1360–1367 (1989).

    CAS  Article  PubMed  Google Scholar 

  137. Nishimoto, N. et al. Improvement in Castleman's disease by humanized anti-interleukin-6 receptor antibody therapy. Blood 95, 56–61 (2000).

    CAS  Article  PubMed  Google Scholar 

  138. Rosser, E.C. et al. Regulatory B cells are induced by gut microbiota-driven interleukin-1β and interleukin-6 production. Nat. Med. 20, 1334–1339 (2014).

    CAS  Article  PubMed  Google Scholar 

  139. Barr, T.A. et al. B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6-producing B cells. J. Exp. Med. 209, 1001–1010 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  140. Barr, T.A., Brown, S., Mastroeni, P. & Gray, D. TLR and B cell receptor signals to B cells differentially program primary and memory Th1 responses to Salmonella enterica. J. Immunol. 185, 2783–2789 (2010).

    CAS  PubMed  Article  Google Scholar 

  141. 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  Article  Google Scholar 

  142. Nurieva, R.I. et al. Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity 29, 138–149 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  143. Dienz, O. et al. The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4+ T cells. J. Exp. Med. 206, 69–78 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  144. Harker, J.A., Lewis, G.M., Mack, L. & Zuniga, E.I. Late interleukin-6 escalates T follicular helper cell responses and controls a chronic viral infection. Science 334, 825–829 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  145. Rincón, M., Anguita, J., Nakamura, T., Fikrig, E. & Flavell, R.A. Interleukin(IL)-6 directs the differentiation of IL-4-producing CD4+ T cells. J. Exp. Med. 185, 461–469 (1997).

    PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  147. Veldhoen, M., Hocking, R.J., Atkins, C.J., Locksley, R.M. & Stockinger, B. TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24, 179–189 (2006).

    CAS  Article  PubMed  Google Scholar 

  148. Harrington, L.E. et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat. Immunol. 6, 1123–1132 (2005).

    CAS  Article  PubMed  Google Scholar 

  149. Zhou, L. et al. IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat. Immunol. 8, 967–974 (2007).

    CAS  PubMed  Article  Google Scholar 

  150. Acosta-Rodriguez, E.V., Napolitani, G., Lanzavecchia, A. & Sallusto, F. Interleukins 1β and 6 but not transforming growth factor-β are essential for the differentiation of interleukin 17-producing human T helper cells. Nat. Immunol. 8, 942–949 (2007).

    CAS  Article  PubMed  Google Scholar 

  151. Korn, T. et al. IL-21 initiates an alternative pathway to induce proinflammatory TH17 cells. Nature 448, 484–487 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  152. Veldhoen, M. et al. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453, 106–109 (2008).

    CAS  PubMed  Article  Google Scholar 

  153. Ivanov, I.I. et al. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121–1133 (2006).

    CAS  Article  PubMed  Google Scholar 

  154. 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).

    CAS  PubMed  Article  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  156. 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  Article  Google Scholar 

  157. 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  Article  Google Scholar 

  158. 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  Article  Google Scholar 

  159. McGeachy, M.J. et al. TGF-β and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain TH-17 cell-mediated pathology. Nat. Immunol. 8, 1390–1397 (2007).

    CAS  Article  PubMed  Google Scholar 

  160. 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  Article  PubMed  PubMed Central  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  162. 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  Article  Google Scholar 

  163. Sharma, M.D. et al. An inherently bifunctional subset of Foxp3+ T helper cells is controlled by the transcription factor eos. Immunity 38, 998–1012 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  164. Sharma, S. et al. T cell immunoglobulin and mucin protein-3 (Tim-3)/Galectin-9 interaction regulates influenza A virus-specific humoral and CD8 T-cell responses. Proc. Natl. Acad. Sci. USA 108, 19001–19006 (2011).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  165. Wohlfert, E.A. et al. GATA3 controls Foxp3+ regulatory T cell fate during inflammation in mice. J. Clin. Invest. 121, 4503–4515 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  166. O'Connor, R.A., Floess, S., Huehn, J., Jones, S.A. & Anderton, S.M. Foxp3+ Treg cells in the inflamed CNS are insensitive to IL-6-driven IL-17 production. Eur. J. Immunol. 42, 1174–1179 (2012).

    CAS  Article  PubMed  Google Scholar 

  167. Chaudhry, A. et al. CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science 326, 986–991 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  168. Durant, L. et al. Diverse targets of the transcription factor STAT3 contribute to T cell pathogenicity and homeostasis. Immunity 32, 605–615 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  169. 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 

  170. 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  Article  PubMed  Google Scholar 

  171. Sato, K. et al. Reshaping a human antibody to inhibit the interleukin 6-dependent tumor cell growth. Cancer Res. 53, 851–856 (1993).

    CAS  PubMed  Google Scholar 

  172. Schroers, A., Hecht, O., Kallen, K.J., Pachta, M., Rose-John, S., Grotzinger, J. Dynamics of the gp130 cytokine complex: a model for assembly on the cellular membrane. Protein Science 14, 783–790 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  174. Shaw, S. et al. Discovery and characterization of olokizumab: a humanized antibody targeting interleukin-6 and neutralizing gp130-signaling. MAbs 6, 774–782 (2014).

    Article  PubMed  Google Scholar 

  175. Genovese, M.C. et al. Efficacy and safety of olokizumab in patients with rheumatoid arthritis with an inadequate response to TNF inhibitor therapy: outcomes of a randomised phase IIb study. Ann. Rheum. Dis. 73, 1607–1615 (2014).

    CAS  PubMed  Article  Google Scholar 

  176. Lissilaa, R. et al. Although IL-6 trans-signaling is sufficient to drive local immune responses, classical IL-6 signaling is obligate for the induction of T cell-mediated autoimmunity. J. Immunol. 185, 5512–5521 (2010).

    CAS  Article  PubMed  Google Scholar 

  177. Barkhausen, T. et al. Selective blockade of interleukin-6 trans-signaling improves survival in a murine polymicrobial sepsis model. Crit. Care Med. 39, 1407–1413 (2011).

    CAS  Article  PubMed  Google Scholar 

  178. 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  Article  Google Scholar 

  179. Spehlmann, M.E. et al. Trp53 deficiency protects against acute intestinal inflammation. J. Immunol. 191, 837–847 (2013).

    CAS  PubMed  Article  Google Scholar 

  180. 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  Article  PubMed  Google Scholar 

  181. Taniguchi, K. et al. A gp130-Src-YAP module links inflammation to epithelial regeneration. Nature 519, 57–62 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  182. 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  Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Christopher A Hunter or Simon A Jones.

Ethics declarations

Competing interests

S.A.J. has received funding support from Hoffman-La Roche, Ferring Pharmaceuticals and NovImmune and during the past 5 years has acted as an advisory consultant for Roche, Chugai Pharmaceuticals, NovImmune, Genentech, Sanofi Regeneron, Johnson & Johnson, Janssen Pharmaceuticals, Eleven Biotherapeutics and UCB. C.A.H. has received support from Amgen, Johnson & Johnson, and Janssen Pharmaceuticals, has acted as an advisory consultant for Medimmune and Biogen and is a member of the scientific advisory board of Surface Oncology.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Hunter, C., Jones, S. IL-6 as a keystone cytokine in health and disease. Nat Immunol 16, 448–457 (2015). https://doi.org/10.1038/ni.3153

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.3153

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing