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:

IL-6 biology: implications for clinical targeting in rheumatic disease

This article has been updated

Key Points

  • IL-6 can signal via the membrane-bound and the soluble IL-6 receptor (IL-6R); classic signalling via the membrane-bound receptor is regenerative and protects from bacterial infections, whereas trans-signalling via the soluble receptor is proinflammatory

  • The soluble gp130Fc fusion protein specifically blocks IL-6 trans-signalling without affecting classic signalling

  • Preclinical models strongly suggest the efficacy of IL-6-directed therapies for a variety of immunological conditions

  • The approval and use of tocilizumab, a first-in-class human monoclonal antibody directed at IL-6R, has demonstrated that this strategy is both highly effective and safe

  • New agents with unique bioengineering features targeting either IL-6 or the soluble IL-6R, with varying selectivity for classic signalling and trans-signalling pathways, are entering clinical trials and offer alternative strategies for IL-6-based therapies

  • Selective IL-6-based therapeutic targeting has several unique toxicity signatures, including paradoxical effects on surrogate markers of cardiovascular risk, and awaits clinical studies to determine net effects on morbidity and mortality

Abstract

IL-6 has been linked to numerous diseases associated with inflammation, including rheumatoid arthritis, inflammatory bowel disease, vasculitis and several types of cancer. Moreover, IL-6 is important in the induction of hepatic acute-phase proteins for the trafficking of acute and chronic inflammatory cells, the differentiation of adaptive T-cell responses, and tissue regeneration and homeostatic regulation. Studies have investigated IL-6 biology using cell-bound IL-6 receptors expressed predominantly on hepatocytes and certain haematopoietic cells versus activation mediated by IL-6 and soluble IL-6 receptors via a second protein, gp130, which is expressed throughout the body. Advances in this research elucidating the differential effects of IL-6 activation provide important insights into the role of IL-6 in health and disease, as well as its potential as a therapeutic target. Knowledge of the basic biology of IL-6 and its signalling pathways can better inform both the research agenda for IL-6-based targeted therapies as well as the clinical use of strategies affecting IL-6-mediated inflammation. This Review covers novel, emerging aspects of the biology of IL-6, which might lead to more specific blockade of IL-6 signalling without compromising the protective function of this cytokine in the body's defence against infections.

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

Figure 1: Signalling of IL-6 via the membrane-bound and soluble receptor.
Figure 2: Affinities between IL-6, IL-6R and gp130.
Figure 3: Role of IL-6 and sIL-6R in T-cell differentiation.

Similar content being viewed by others

Change history

  • 19 September 2014

    In the version of this article initially published online, findings from the Kuchroo et al. group were incorrectly reported in the 'Role in inflammation' section. This inaccuracy has been corrected for the HTML, PDF and print versions of the article.

References

  1. Naka, T., Nishimoto, N. & Kishimoto, T. The paradigm of IL-6: from basic science to medicine. Arthritis Res. 4 (Suppl. 3), S233–S242 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  2. 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).

    Article  CAS  PubMed  Google Scholar 

  3. Wolvekamp, M. C. & Marquet, R. L. Interleukin-6: historical background, genetics and biological significance. Immunol. Lett. 24, 1–9 (1990).

    Article  CAS  PubMed  Google Scholar 

  4. Nishimoto, N. Interleukin-6 as a therapeutic target in candidate inflammatory diseases. Clin. Pharmacol. Ther. 87, 483–487 (2006).

    Article  Google Scholar 

  5. Cronstein, B. N. Interleukin-6—a key mediator of systemic and local symptoms in rheumatoid arthritis. Bull. NYU Hosp. Jt Dis. 65 (Suppl. 1), S11–S15 (2007).

    PubMed  Google Scholar 

  6. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Scheller, J., Chalaris, A., Garbers, C. & Rose-John, S. ADAM17: a molecular switch to control inflammation and tissue regeneration. Trends Immunol. 32, 380–387 (2011).

    Article  CAS  PubMed  Google Scholar 

  9. Chow, D., He, X., Snow, A. L., Rose-John, S. & Garcia, K. C. Structure of an extracellular gp130 cytokine receptor signaling complex. Science 291, 2150–2155 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. Galun, E. & Rose-John, S. The regenerative activity of interleukin-6. Methods Mol. Biol. 982, 59–77 (2013).

    Article  CAS  PubMed  Google Scholar 

  11. Redlich, K. & Smolen, J. S. Inflammatory bone loss: pathogenesis and therapeutic intervention. Nat. Rev. Drug Discov. 11, 234–250 (2012).

    Article  CAS  PubMed  Google Scholar 

  12. Murakami, M. & Nishimoto, N. The value of blocking IL-6 outside of rheumatoid arthritis: current perspective. Curr. Opin. Rheumatol. 23, 273–277 (2011).

    Article  CAS  PubMed  Google Scholar 

  13. Rose-John, S. et al. Studies on the structure and regulation of the human hepatic interleukin-6 receptor. Eur. J. Biochem. 190, 79–83 (1990).

    Article  CAS  PubMed  Google Scholar 

  14. Scheller, J., Garbers, C. & Rose-John, S. Interleukin-6: from basic biology to selective blockade of pro-inflammatory activities. Semin. Immunol. 26, 2–12 (2014).

    Article  CAS  PubMed  Google Scholar 

  15. Scheller, J. & Rose-John, S. Interleukin-6 and its receptor: from bench to bedside. Med. Microbiol. Immunol. 195, 173–183 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. Scheller, J., Grötzinger, J. & Rose-John, S. Updating interleukin-6 classic- and trans-signaling. Signal Transduction 6, 240–259 (2006).

    Article  CAS  Google Scholar 

  17. O'Shea, J. J., Gadina, M. & Schreiber, R. D. Cytokine signaling in 2002: new surprises in the Jak/Stat pathway. Cell 109 (Suppl.), S121–S131 (2002).

    Article  CAS  PubMed  Google Scholar 

  18. Kishimoto, T. Interleukin-6: from basic science to medicine—40 years in immunology. Annu. Rev. Immunol. 23, 1–21 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Mullberg, J. et al. The soluble interleukin-6 receptor is generated by shedding. Eur. J. Immunol. 23, 473–480 (1993).

    Article  CAS  PubMed  Google Scholar 

  20. Mullberg, J., Schooltink, H., Stoyan, T., Heinrich, P. C. & Rose-John, S. Protein kinase C activity is rate limiting for shedding of the interleukin-6 receptor. Biochem. Biophys. Res. Commun. 189, 794–800 (1992).

    Article  CAS  PubMed  Google Scholar 

  21. Lust, J. A. et al. Isolation of an mRNA encoding a soluble form of the human interleukin-6 receptor. Cytokine 4, 96–100 (1992).

    Article  CAS  PubMed  Google Scholar 

  22. Horiuchi, S. et al. Soluble interleukin-6 receptors released from T cell or granulocyte/macrophage cell lines and human peripheral blood mononuclear cells are generated through an alternative splicing mechanism. Eur. J. Immunol. 24, 1945–1948 (1994).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Fischer, M. et al. A bioactive designer cytokine for human hematopoietic progenitor cell expansion. Nat. Biotechnol. 15, 142–145 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Galun, E. et al. Human interleukin-6 facilitates hepatitis B virus infection in vitro and in vivo. Virology 270, 299–309 (2000).

    Article  CAS  PubMed  Google Scholar 

  26. Peters, M. et al. Combined interleukin 6 and soluble interleukin 6 receptor accelerates murine liver regeneration. Gastroenterology 119, 1663–1671 (2000).

    Article  CAS  PubMed  Google Scholar 

  27. Hecht, N. et al. Hyper-IL-6 gene therapy reverses fulminant hepatic failure. Mol. Ther. 3, 683–687 (2001).

    Article  CAS  PubMed  Google Scholar 

  28. Audet, J., Miller, C. L., Rose-John, S., Piret, J. M. & Eaves, C. J. Distinct role of gp130 activation in promoting self-renewal divisions by mitogenically stimulated murine hematopoietic stem cells. Proc. Natl Acad. Sci. USA 98, 1757–1762 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. März, P. et al. Sympathetic neurons can produce and respond to interleukin 6. Proc. Natl Acad. Sci. USA 95, 3251–3256 (1998).

    Article  PubMed  PubMed Central  Google Scholar 

  30. März, P., Otten, U. & Rose-John, S. Neural activities of IL-6-type cytokines often depend on soluble cytokine receptors. Eur. J. Neurosci. 11, 2995–3004 (1999).

    Article  PubMed  Google Scholar 

  31. Klouche, M., Bhakdi, S., Hemmes, M. & Rose-John, S. Novel path to activation of vascular smooth muscle cells: up-regulation of gp130 creates an autocrine activation loop by IL-6 and its soluble receptor. J. Immunol. 163, 4583–4589 (1999).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  33. 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).

    Article  CAS  PubMed  Google Scholar 

  34. Mitsuyama, K. et al. STAT3 activation via interleukin 6 trans-signalling contributes to ileitis in SAMP1/Yit mice. Gut 55, 1263–1269 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 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).

    Article  CAS  PubMed  Google Scholar 

  36. 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).

    Article  CAS  PubMed  Google Scholar 

  37. 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).

    Article  CAS  PubMed  Google Scholar 

  38. Doganci, A. et al. The IL-6R alpha chain controls lung CD4+CD25+ TREG development and function during allergic airway inflammation in vivo. J. Clin. Invest. 115, 313–325 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhang, H. et al. IL-6 trans-signaling promotes pancreatitis-associated lung injury and lethality. J. Clin. Invest. 123, 1019–1031 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Becker, C. et al. TGF-β suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling. Immunity 21, 491–501 (2004).

    Article  CAS  PubMed  Google Scholar 

  41. Becker, C. et al. IL-6 signaling promotes tumor growth in colorectal cancer. Cell Cycle 4, 217–220 (2005).

    Article  CAS  PubMed  Google Scholar 

  42. Matsumoto, S. et al. Essential roles of IL-6 trans-signaling in colonic epithelial cells, induced by the IL-6/soluble-IL-6 receptor derived from lamina propria macrophages, on the development of colitis-associated premalignant cancer in a murine model. J. Immunol. 184, 1543–1551 (2010).

    Article  CAS  PubMed  Google Scholar 

  43. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 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).

    Article  CAS  PubMed  Google Scholar 

  45. Sodenkamp, J. et al. Therapeutic targeting of interleukin-6 trans-signaling does not affect the outcome of experimental tuberculosis. Immunobiology 217, 996–1004 (2012).

    Article  CAS  PubMed  Google Scholar 

  46. Scheller, J., Chalaris, A., Schmidt-Arras, D. & Rose-John, S. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim. Biophys. Acta 181, 878–888 (2011).

    Article  CAS  Google Scholar 

  47. Matthews, V. et al. Cellular cholesterol depletion triggers shedding of the human interleukin-6 receptor by ADAM10 and ADAM17 (TACE). J. Biol. Chem. 278, 38829–38839 (2003).

    Article  CAS  PubMed  Google Scholar 

  48. Black, R. A. et al. A metalloproteinase disintegrin that releases tumour-necrosis factor-α from cells. Nature 385, 729–733 (1997).

    Article  CAS  PubMed  Google Scholar 

  49. Peschon, J. J. et al. An essential role for ectodomain shedding in mammalian development. Science 282, 1281–1284 (1998).

    Article  CAS  PubMed  Google Scholar 

  50. Chalaris, A. et al. Critical role of the disintegrin metalloprotease ADAM17 for intestinal inflammation and regeneration in mice. J. Exp. Med. 207, 1617–1624 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  52. Waetzig, G. H. & Rose-John, S. Hitting a complex target: an update on interleukin-6 trans-signalling. Expert Opin. Ther. Targets 16, 225–236 (2012).

    Article  CAS  PubMed  Google Scholar 

  53. 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).

    Article  CAS  PubMed  Google Scholar 

  54. Rafiq, S. et al. A common variant of the interleukin 6 receptor (IL-6r) gene increases IL-6r and IL-6 levels, without other inflammatory effects. Genes Immun. 8, 552–559 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Scheller, J. & Rose-John, S. The interleukin 6 pathway and atherosclerosis. Lancet 380, 338 (2012).

    Article  PubMed  Google Scholar 

  57. 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).

    Article  CAS  PubMed  Google Scholar 

  58. Heinrich, P. C., Castell, J. V. & Andus, T. Interleukin-6 and the acute phase response. Biochem. J. 265, 621–636 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Febbraio, M. A., Rose-John, S. & Pedersen, B. K. Is interleukin-6 receptor blockade the Holy Grail for inflammatory diseases? Clin. Pharmacol. Ther. 87, 396–398 (2010).

    Article  CAS  PubMed  Google Scholar 

  60. Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).

    Article  CAS  PubMed  Google Scholar 

  61. Annunziato, F. & Romagnani, S. Heterogeneity of human effector CD4+ T cells. Arthritis Res. Ther. 11, 257 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Thiolat, A. et al. Interleukin-6 receptor blockade enhances CD39+ regulatory T cell development in rheumatoid arthritis and in experimental arthritis. Arthritis Rheum. 66, 273–283 (2014).

    Article  CAS  Google Scholar 

  64. 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).

    Article  CAS  PubMed  Google Scholar 

  65. Dominitzki, S. et al. Cutting edge: trans-signaling via the soluble IL-6R abrogates the induction of FoxP3 in naive CD4+CD25 T cells. J. Immunol. 179, 2041–2045 (2007).

    Article  CAS  PubMed  Google Scholar 

  66. O'Shea, J. J. & Plenge, R. JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. Immunity 36, 542–550 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Tanaka, T., Narazaki, M. & Kishimoto, T. Therapeutic targeting of the interleukin-6 receptor. Annu. Rev. Pharmacol. Toxicol. 52, 199–219 (2012).

    Article  CAS  PubMed  Google Scholar 

  68. Gabay, C. et al. Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial. Lancet 381, 1541–1550 (2013).

    Article  CAS  PubMed  Google Scholar 

  69. US National Library of Medicine. ClinicalTrials.gov [online], (2014).

  70. Singh, J. A. et al. Biologics for rheumatoid arthritis: an overview of Cochrane reviews. Cochrane Database of Systematic Reviews, Issue 4. Art. No.: CD007848 http://dx.doi.org/10.1002/14651858.CD007848.pub2.

  71. 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).

    Article  CAS  PubMed  Google Scholar 

  72. 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).

    Article  CAS  PubMed  Google Scholar 

  73. de Boysson, H., Fevrier, 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).

    Article  PubMed  Google Scholar 

  74. Shima, Y. et al. The skin of patients with systemic sclerosis softened during the treatment with anti-IL-6 receptor antibody tocilizumab. Rheumatology (Oxford) 49, 2408–2412 (2010).

    Article  CAS  Google Scholar 

  75. Hagihara, K., Kawase, I., Tanaka, T. & Kishimoto, T. Tocilizumab ameliorates clinical symptoms in polymyalgia rheumatica. J. Rheumatol. 37, 1075–1076 (2010).

    Article  PubMed  Google Scholar 

  76. Illei, G. G. et al. Tocilizumab in systemic lupus erythematosus: data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study. Arthritis Rheum. 62, 542–552 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Kieseier, B. C. et al. Disease amelioration with tocilizumab in a treatment-resistant patient with neuromyelitis optica: implication for cellular immune responses. JAMA Neurol. 70, 390–393 (2013).

    Article  PubMed  Google Scholar 

  78. Weyand, C. M. & Goronzy, J. J. Immune mechanisms in medium and large-vessel vasculitis. Nat. Rev. Rheumatol. 9, 731–740 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Unizony, S. et al. Tocilizumab for the treatment of large-vessel vasculitis (giant cell arteritis, Takayasu arteritis) and polymyalgia rheumatica. Arthritis Care Res. 64, 1720–1729 (2012).

    Article  CAS  Google Scholar 

  80. Salvarani, C. et al. Tocilizumab: a novel therapy for patients with large-vessel vasculitis. Rheumatology (Oxford) 51, 151–156 (2012).

    Article  CAS  Google Scholar 

  81. US National Library of Medicine. ClinicalTrials.gov [online], (2014).

  82. Sieper, J. et al. Sarilumab for the treatment of ankylosing spondylitis: results of a phase II, randomised, double-blind, placebo-controlled study (ALIGN). Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis-2013-204963.

  83. Sieper, J., Porter-Brown, B., Thompson, L., Harari, O. & Dougados, M. Assessment of short-term symptomatic efficacy of tocilizumab in ankylosing spondylitis: results of randomised, placebo-controlled trials. Ann. Rheum. Dis. 73, 95–100 (2014).

    Article  CAS  PubMed  Google Scholar 

  84. Navarro, G., Taroumian, S., Barroso, N., Duan, L. & Furst, D. Tocilizumab in rheumatoid arthritis: A meta-analysis of efficacy and selected clinical conundrums. Semin. Arthritis Rheum. 43, 458–469 (2014).

    Article  CAS  PubMed  Google Scholar 

  85. Schiff, M. H. et al. Integrated safety in tocilizumab clinical trials. Arthritis Res. Ther. 13, R141 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Furst, D. E. et al. Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2012. Ann. Rheum. Dis. 72 (Suppl. 2), ii2–ii34 (2013).

    Article  CAS  PubMed  Google Scholar 

  87. Huizinga, T. W. et al. Sarilumab, a fully human monoclonal antibody against IL-6Rα in patients with rheumatoid arthritis and an inadequate response to methotrexate: efficacy and safety results from the randomised SARIL-RA-MOBILITY Part A trial. Ann. Rheum. Dis. 73, 1626–1634 (2014).

    Article  CAS  PubMed  Google Scholar 

  88. Szepietowski, J. C. et al. Phase I, randomized, double-blind, placebo-controlled, multiple intravenous, dose-ascending study of sirukumab in cutaneous or systemic lupus erythematosus. Arthritis Rheum. 65, 2661–2671 (2013).

    CAS  PubMed  Google Scholar 

  89. Jain, A. & Singh, J. A. Harms of TNF inhibitors in rheumatic diseases: a focused review of the literature. Immunotherapy 5, 265–299 (2013).

    Article  CAS  PubMed  Google Scholar 

  90. Ladel, C. H. et al. Lethal tuberculosis in interleukin-6-deficient mutant mice. Infect. Immun. 65, 4843–4849 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Kitas, G. D. & Gabriel, S. E. Cardiovascular disease in rheumatoid arthritis: state of the art and future perspectives. Ann. Rheum. Dis. 70, 8–14 (2011).

    Article  PubMed  Google Scholar 

  92. Robertson, J., Peters, M. J., McInnes, I. B. & Sattar, N. Changes in lipid levels with inflammation and therapy in RA: a maturing paradigm. Nat. Rev. Rheumatol. 9, 513–523 (2013).

    Article  CAS  PubMed  Google Scholar 

  93. Schultz, O. et al. Effects of inhibition of interleukin-6 signalling on insulin sensitivity and lipoprotein (a) levels in human subjects with rheumatoid diseases. PLoS ONE 5, e14328 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. McInnes, I. B. et al. Effect of interleukin-6 receptor blockade on surrogates of vascular risk in rheumatoid arthritis: MEASURE, a randomised, placebo-controlled study. Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis-2013-204345.

Download references

Acknowledgements

The work of S.R.-J. is supported by grants from the Deutsche Forschungsgemeinschaft Bonn, Germany (SFB654, project C5; SFB841, project C1; SFB877 project A1) and by the Cluster of Excellence 'Inflammation at Interfaces'.

Author information

Authors and Affiliations

Authors

Contributions

Both authors contributed equally to all aspects of this manuscript.

Corresponding author

Correspondence to Leonard H. Calabrese.

Ethics declarations

Competing interests

L.H.C. declares that he has acted as a consultant to Genentech Roche, Sanofi-Aventis, UCB, Bristol–Myers Squib and Pfizer, and has acted as a speaker for Genentech and Bristol–Myers Squib. S.R. J. declares that he is an inventor on patents owned by CONARIS Research Institute, which develops the sgp130Fc protein together with Ferring Pharmaceuticals, and he has stock ownership in CONARIS.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Calabrese, L., Rose-John, S. IL-6 biology: implications for clinical targeting in rheumatic disease. Nat Rev Rheumatol 10, 720–727 (2014). https://doi.org/10.1038/nrrheum.2014.127

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrrheum.2014.127

This article is cited by

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