Review Article | Published:

Anti-inflammatory and immune-regulatory cytokines in rheumatoid arthritis

Nature Reviews Rheumatology (2018) | Download Citation


Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by a failure of spontaneous resolution of inflammation. Although the pro-inflammatory cytokines and mediators that trigger RA have been the focus of intense investigations, the regulatory and anti-inflammatory cytokines responsible for the suppression and resolution of disease in a context-dependent manner have been less well characterized. However, knowledge of the pathways that control the suppression and resolution of inflammation in RA is clinically relevant and conceptually important for understanding the pathophysiology of the disease and for the development of treatments that enable long-term remission. Cytokine-mediated processes such as the activation of T helper 2 cells by IL-4 and IL-13, the resolution of inflammation by IL-9, IL-5-induced eosinophil expansion, IL-33-mediated macrophage polarization, the production of IL-10 by regulatory B cells and IL-27-mediated suppression of lymphoid follicle formation are all involved in governing the regulation and resolution of inflammation in RA. By better understanding these immune-regulatory signalling pathways, new therapeutic strategies for RA can be envisioned that aim to balance and resolve, rather than suppress, inflammation.

Key points

  • Anti-inflammatory cytokines counterbalance the chronic activation of innate and adaptive immune cells in rheumatoid arthritis (RA).

  • Macrophage polarization towards an immune-regulatory phenotype is mediated by cytokines involved in type 2 immune responses and in eosinophil activation, such as IL-4, IL-5, IL-13 and IL-33.

  • Regulatory T cell activation in RA depends on the release of IL-9 from group 2 innate lymphoid cells.

  • Regulatory B cells are activated during inflammation and mitigate adaptive immune responses in experimental arthritis via the release of IL-10.

  • Inducing anti-inflammatory pathways and the resolution of inflammation is an attractive therapeutic option for patients with RA to achieve long-term disease control.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

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


  1. 1.

    McInnes, I. B. & Schett, G. The pathogenesis of rheumatoid arthritis. N. Engl. J. Med. 365, 2205–2219 (2011).

  2. 2.

    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).

  3. 3.

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

  4. 4.

    Cascao, R., Rosario, H. S., Souto-Carneiro, M. M. & Fonseca, J. E. Neutrophils in rheumatoid arthritis: more than simple final effectors. Autoimmun. Rev. 9, 531–535 (2010).

  5. 5.

    Hueber, A. J. et al. Mast cells express IL-17A in rheumatoid arthritis synovium. J. Immunol. 184, 3336–3340 (2010).

  6. 6.

    Haringman, J. J. et al. Synovial tissue macrophages: a sensitive biomarker for response to treatment in patients with rheumatoid arthritis. Ann. Rheum. Dis. 64, 834–838 (2005).

  7. 7.

    Murray, P. J. et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41, 14–20 (2014).

  8. 8.

    Ambarus, C. A., Noordenbos, T., de Hair, M. J., Tak, P. P. & Baeten, D. L. Intimal lining layer macrophages but not synovial sublining macrophages display an IL-10 polarized-like phenotype in chronic synovitis. Arthritis Res. Ther. 14, R74 (2012).

  9. 9.

    Dayer, J. M., Beutler, B. & Cerami, A. Cachectin/tumor necrosis factor stimulates collagenase and prostaglandin E2 production by human synovial cells and dermal fibroblasts. J. Exp. Med. 162, 2163–2168 (1985).

  10. 10.

    Bertolini, D. R., Nedwin, G. E., Bringman, T. S., Smith, D. D. & Mundy, G. R. Stimulation of bone resorption and inhibition of bone formation in vitro by human tumour necrosis factors. Nature 319, 516–518 (1986).

  11. 11.

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

  12. 12.

    McInnes, I. B. & Schett, G. Pathogenetic insights from the treatment of rheumatoid arthritis. Lancet 389, 2328–2337 (2017).

  13. 13.

    Haschka, J. et al. Relapse rates in patients with rheumatoid arthritis in stable remission tapering or stopping antirheumatic therapy: interim results from the prospective randomised controlled RETRO study. Ann. Rheum. Dis. 75, 45–51 (2016).

  14. 14.

    Hermann, J. A., Hall, M. A., Maini, R. N., Feldmann, M. & Brennan, F. M. Important immunoregulatory role of interleukin-11 in the inflammatory process in rheumatoid arthritis. Arthritis Rheum. 41, 1388–1397 (1998).

  15. 15.

    Walmsley, M., Butler, D. M., Marinova-Mutafchieva, L. & Feldmann, M. An anti-inflammatory role for interleukin-11 in established murine collagen-induced arthritis. Immunology 95, 31–37 (1998).

  16. 16.

    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).

  17. 17.

    Tak, P. P. et al. The effects of interferon beta treatment on arthritis. Rheumatology 38, 362–369 (1999).

  18. 18.

    van Holten, J. et al. Treatment with recombinant interferon-beta reduces inflammation and slows cartilage destruction in the collagen-induced arthritis model of rheumatoid arthritis. Arthritis Res. Ther. 6, R239–R249 (2004).

  19. 19.

    van Holten, J. et al. A multicentre, randomised, double blind, placebo controlled phase II study of subcutaneous interferon beta-1a in the treatment of patients with active rheumatoid arthritis. Ann. Rheum. Dis. 64, 64–69 (2005).

  20. 20.

    Genovese, M. C., Chakravarty, E. F., Krishnan, E. & Moreland, L. W. A randomized, controlled trial of interferon-beta-1a (Avonex(R)) in patients with rheumatoid arthritis: a pilot study [ISRCTN03626626]. Arthritis Res. Ther. 6, R73–R77 (2004).

  21. 21.

    Kaplan, M. H., Schindler, U., Smiley, S. T. & Grusby, M. J. STAT6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity 4, 313–319 (1996).

  22. 22.

    Nelms, K., Keegan, A. D., Zamorano, J., Ryan, J. J. & Paul, W. E. The IL-4 receptor: signaling mechanisms and biologic functions. Annu. Rev. Immunol. 17, 701–738 (1999).

  23. 23.

    May, R. D. & Fung, M. Strategies targeting the IL-4/IL-13 axes in disease. Cytokine 75, 89–116 (2015).

  24. 24.

    Raza, K. et al. Early rheumatoid arthritis is characterized by a distinct and transient synovial fluid cytokine profile of T cell and stromal cell origin. Arthritis Res. Ther. 7, R784–R795 (2005).

  25. 25.

    Omata, Y. et al. Group 2 innate lymphoid cells attenuate inflammatory arthritis and protect from bone destruction in mice. Cell Rep. 24, 169–180 (2018).

  26. 26.

    Bessis, N. et al. Modulation of proinflammatory cytokine production in tumour necrosis factor-alpha (TNF-alpha)-transgenic mice by treatment with cells engineered to secrete IL-4, IL-10 or IL-13. Clin. Exp. Immunol. 111, 391–396 (1998).

  27. 27.

    Bessis, N. et al. Attenuation of collagen-induced arthritis in mice by treatment with vector cells engineered to secrete interleukin-13. Eur. J. Immunol. 26, 2399–2403 (1996).

  28. 28.

    Finnegan, A., Mikecz, K., Tao, P. & Glant, T. T. Proteoglycan (aggrecan)-induced arthritis in BALB/c mice is a Th1-type disease regulated by Th2 cytokines. J. Immunol. 163, 5383–5390 (1999).

  29. 29.

    Horsfall, A. C. et al. Suppression of collagen-induced arthritis by continuous administration of IL-4. J. Immunol. 159, 5687–5696 (1997).

  30. 30.

    Joosten, L. A. et al. Role of interleukin-4 and interleukin-10 in murine collagen-induced arthritis. Protective effect of interleukin-4 and interleukin-10 treatment on cartilage destruction. Arthritis Rheum. 40, 249–260 (1997).

  31. 31.

    Joosten, L. A. et al. Protection against cartilage and bone destruction by systemic interleukin-4 treatment in established murine type II collagen-induced arthritis. Arthritis Res. 1, 81–91 (1999).

  32. 32.

    Yamada, A. et al. Interleukin-4 inhibition of osteoclast differentiation is stronger than that of interleukin-13 and they are equivalent for induction of osteoprotegerin production from osteoblasts. Immunology 120, 573–579 (2007).

  33. 33.

    Fujii, T., Kitaura, H., Kimura, K., Hakami, Z. W. & Takano-Yamamoto, T. IL-4 inhibits TNF-α-mediated osteoclast formation by inhibition of RANKL expression in TNF-α-activated stromal cells and direct inhibition of TNF-α-activated osteoclast precursors via a T cell-independent mechanism in vivo. Bone 51, 771–780 (2012).

  34. 34.

    Osada, Y., Shimizu, S., Kumagai, T., Yamada, S. & Kanazawa, T. Schistosoma mansoni infection reduces severity of collagen-induced arthritis via down-regulation of pro-inflammatory mediators. Int. J. Parasitol. 39, 457–464 (2009).

  35. 35.

    Salinas-Carmona, M. C. et al. Spontaneous arthritis in MRL/lpr mice is aggravated by Staphylococcus aureus and ameliorated by Nippostrongylus brasiliensis infections. Autoimmunity 42, 25–32 (2009).

  36. 36.

    Shi, M. et al. Infection with an intestinal helminth parasite reduces Freund’s complete adjuvant-induced monoarthritis in mice. Arthritis Rheum. 63, 434–444 (2011).

  37. 37.

    Song, X. et al. Impact of Schistosoma japonicum infection on collagen-induced arthritis in DBA/1 mice: a murine model of human rheumatoid arthritis. PLoS ONE 6, e23453 (2011).

  38. 38.

    Osada, Y., Yamada, S., Nakae, S., Sudo, K. & Kanazawa, T. Reciprocal effects of Schistosoma mansoni infection on spontaneous autoimmune arthritis in IL-1 receptor antagonist-deficient mice. Parasitol. Int. 64, 13–17 (2015).

  39. 39.

    Chen, Z. et al. Th2 and eosinophil responses suppress inflammatory arthritis. Nat. Commun. 7, 11596 (2016).

  40. 40.

    Hirayama, T., Dai, S., Abbas, S., Yamanaka, Y. & Abu-Amer, Y. Inhibition of inflammatory bone erosion by constitutively active STAT-6 through blockade of JNK and NF-kappaB activation. Arthritis Rheum. 52, 2719–2729 (2005).

  41. 41.

    Hart, P. H., Ahern, M. J., Smith, M. D. & Finlay-Jones, J. J. Regulatory effects of IL-13 on synovial fluid macrophages and blood monocytes from patients with inflammatory arthritis. Clin. Exp. Immunol. 99, 331–337 (1995).

  42. 42.

    Isomaki, P., Luukkainen, R., Toivanen, P. & Punnonen, J. The presence of interleukin-13 in rheumatoid synovium and its antiinflammatory effects on synovial fluid macrophages from patients with rheumatoid arthritis. Arthritis Rheum. 39, 1693–1702 (1996).

  43. 43.

    Wenzel, S. et al. Dupilumab in persistent asthma with elevated eosinophil levels. N. Engl. J. Med. 368, 2455–2466 (2013).

  44. 44.

    Atkins, M. B. et al. Phase I evaluation of thrice-daily intravenous bolus interleukin-4 in patients with refractory malignancy. J. Clin. Oncol. 10, 1802–1809 (1992).

  45. 45.

    Shanafelt, A. B. et al. An immune cell-selective interleukin 4 agonist. Proc. Natl Acad. Sci. USA 95, 9454–9458 (1998).

  46. 46.

    Lopez, A. F. et al. Recombinant human interleukin 5 is a selective activator of human eosinophil function. J. Exp. Med. 167, 219–224 (1988).

  47. 47.

    Collins, P. D., Marleau, S., Griffiths-Johnson, D. A., Jose, P. J. & Williams, T. J. Cooperation between interleukin-5 and the chemokine eotaxin to induce eosinophil accumulation in vivo. J. Exp. Med. 182, 1169–1174 (1995).

  48. 48.

    Mattes, J. et al. Intrinsic defect in T cell production of interleukin (IL)-13 in the absence of both IL-5 and eotaxin precludes the development of eosinophilia and airways hyperreactivity in experimental asthma. J. Exp. Med. 195, 1433–1444 (2002).

  49. 49.

    Yamada, T. et al. Eosinophils promote resolution of acute peritonitis by producing proresolving mediators in mice. FASEB J. 25, 561–568 (2011).

  50. 50.

    Masterson, J. C. et al. Eosinophil-mediated signalling attenuates inflammatory responses in experimental colitis. Gut 64, 1236–1247 (2015).

  51. 51.

    Stolarski, B., Kurowska-Stolarska, M., Kewin, P., Xu, D. & Liew, F. Y. IL-33 exacerbates eosinophil-mediated airway inflammation. J. Immunol. 185, 3472–3480 (2010).

  52. 52.

    Gebreselassie, N. G. et al. Eosinophils preserve parasitic nematode larvae by regulating local immunity. J. Immunol. 188, 417–425 (2012).

  53. 53.

    Wu, D. et al. Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science 332, 243–247 (2011).

  54. 54.

    Isobe, Y., Kato, T. & Arita, M. Emerging roles of eosinophils and eosinophil-derived lipid mediators in the resolution of inflammation. Front. Immunol. 3, 270 (2012).

  55. 55.

    Duffney, P. F. et al. Key roles for lipid mediators in the adaptive immune response. J. Clin. Invest. 128, 2724–2731 (2018).

  56. 56.

    Linch, S. N. et al. Interleukin 5 is protective during sepsis in an eosinophil-independent manner Am. J. Respir. Crit. Care Med. 186, 246–254 (2012).

  57. 57.

    Schmitz, J. et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 23, 479–490 (2005).

  58. 58.

    Martin, N. T. & Martin, M. U. Interleukin 33 is a guardian of barriers and a local alarmin. Nat. Immunol. 17, 122–131 (2016).

  59. 59.

    Xu, D. et al. IL-33 exacerbates antigen-induced arthritis by activating mast cells. Proc. Natl Acad. Sci. USA 105, 10913–10918 (2008).

  60. 60.

    Verri, W. A. Jr. et al. IL-33 induces neutrophil migration in rheumatoid arthritis and is a target of anti-TNF therapy. Ann. Rheum. Dis. 69, 1697–1703 (2010).

  61. 61.

    Xu, D. et al. IL-33 exacerbates autoantibody-induced arthritis. J. Immunol. 184, 2620–2626 (2010).

  62. 62.

    Matsuyama, Y. et al. Increased levels of interleukin 33 in sera and synovial fluid from patients with active rheumatoid arthritis. J. Rheumatol 37, 18–25 (2010).

  63. 63.

    Mu, R. et al. Elevated serum interleukin 33 is associated with autoantibody production in patients with rheumatoid arthritis. J. Rheumatol 37, 2006–2013 (2010).

  64. 64.

    Kamradt, T. & Drube, S. A complicated liaison: IL-33 and IL-33R in arthritis pathogenesis. Arthritis Res. Ther. 15, 115 (2013).

  65. 65.

    Martin, P. et al. Disease severity in K/B×N serum transfer-induced arthritis is not affected by IL-33 deficiency. Arthritis Res. Ther. 15, R13 (2013).

  66. 66.

    Palmer, G. et al. Inhibition of interleukin-33 signaling attenuates the severity of experimental arthritis. Arthritis Rheum. 60, 738–749 (2009).

  67. 67.

    Talabot-Ayer, D. et al. Immune-mediated experimental arthritis in IL-33 deficient mice. Cytokine 69, 68–74 (2014).

  68. 68.

    Drube, S. et al. The receptor tyrosine kinase c-Kit controls IL-33 receptor signaling in mast cells. Blood 115, 3899–3906 (2010).

  69. 69.

    Licona-Limon, P., Kim, L. K., Palm, N. W. & Flavell, R. A. TH2, allergy and group 2 innate lymphoid cells. Nat. Immunol. 14, 536–542 (2013).

  70. 70.

    Duerr, C. U. & Fritz, J. H. Regulation of group 2 innate lymphoid cells. Cytokine 87, 1–8 (2016).

  71. 71.

    Biton, J. et al. In vivo expansion of activated Foxp3+ regulatory T cells and establishment of a type 2 immune response upon IL-33 treatment protect against experimental arthritis. J. Immunol. 197, 1708–1719 (2016).

  72. 72.

    Stier, M. T. et al. IL-33 promotes the egress of group 2 innate lymphoid cells from the bone marrow. J. Exp. Med. 215, 263–281 (2018).

  73. 73.

    Matta, B. M. et al. Peri-allo HCT IL-33 administration expands recipient T-regulatory cells that protect mice against acute GVHD. Blood 128, 427–439 (2016).

  74. 74.

    Rauber, S. et al. Resolution of inflammation by interleukin-9-producing type 2 innate lymphoid cells. Nat. Med. 23, 938–944 (2017).

  75. 75.

    Zaiss, M. M. et al. IL-33 shifts the balance from osteoclast to alternatively activated macrophage differentiation and protects from TNF-alpha-mediated bone loss. J. Immunol. 186, 6097–6105 (2011).

  76. 76.

    Goswami, R. & Kaplan, M. H. A brief history of IL-9. J. Immunol. 186, 3283–3288 (2011).

  77. 77.

    Bauer, J. H., Liu, K. D., You, Y., Lai, S. Y. & Goldsmith, M. A. Heteromerization of the γc chain with the interleukin-9 receptor alpha subunit leads to STAT activation and prevention of apoptosis. J. Biol. Chem. 273, 9255–9260 (1998).

  78. 78.

    Veldhoen, M. et al. Transforming growth factor-beta ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat. Immunol. 9, 1341–1346 (2008).

  79. 79.

    Elyaman, W. et al. IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells. Proc. Natl Acad. Sci. USA 106, 12885–12890 (2009).

  80. 80.

    Nowak, E. C. et al. IL-9 as a mediator of Th17-driven inflammatory disease. J. Exp. Med. 206, 1653–1660 (2009).

  81. 81.

    Hughes-Austin, J. M. et al. Multiple cytokines and chemokines are associated with rheumatoid arthritis-related autoimmunity in first-degree relatives without rheumatoid arthritis: Studies of the Aetiology of Rheumatoid Arthritis (SERA). Ann. Rheum. Dis. 72, 901–907 (2013).

  82. 82.

    Ciccia, F. et al. Potential involvement of IL-9 and Th9 cells in the pathogenesis of rheumatoid arthritis. Rheumatology 54, 2264–2272 (2015).

  83. 83.

    Kundu-Raychaudhuri, S., Abria, C. & Raychaudhuri, S. P. IL-9, a local growth factor for synovial T cells in inflammatory arthritis. Cytokine 79, 45–51 (2016).

  84. 84.

    Chowdhury, K. et al. Synovial IL-9 facilitates neutrophil survival, function and differentiation of Th17 cells in rheumatoid arthritis. Arthritis Res. Ther. 20, 18 (2018).

  85. 85.

    Parker, J. M. et al. Safety profile and clinical activity of multiple subcutaneous doses of MEDI-528, a humanized anti-interleukin-9 monoclonal antibody, in two randomized phase 2a studies in subjects with asthma. BMC Pulm Med. 11, 14 (2011).

  86. 86.

    Angkasekwinai, P., Chang, S. H., Thapa, M., Watarai, H. & Dong, C. Regulation of IL-9 expression by IL-25 signaling. Nat. Immunol. 11, 250–256 (2010).

  87. 87.

    Nakatsukasa, H. et al. The DNA-binding inhibitor Id3 regulates IL-9 production in CD4(+) T cells. Nat. Immunol. 16, 1077–1084 (2015).

  88. 88.

    Mern, D. S., Hoppe-Seyler, K., Hoppe-Seyler, F., Hasskarl, J. & Burwinkel, B. Targeting Id1 and Id3 by a specific peptide aptamer induces E-box promoter activity, cell cycle arrest, and apoptosis in breast cancer cells. Breast Cancer Res. Treat. 124, 623–633 (2010).

  89. 89.

    Mauri, C. & Menon, M. Human regulatory B cells in health and disease: therapeutic potential. J. Clin. Invest. 127, 772–779 (2017).

  90. 90.

    Meng, X. et al. Hypoxia-inducible factor-1α is a critical transcription factor for IL-10-producing B cells in autoimmune disease. Nat. Commun. 9, 251 (2018).

  91. 91.

    Katsikis, P. D., Chu, C. Q., Brennan, F. M., Maini, R. N. & Feldmann, M. Immunoregulatory role of interleukin 10 in rheumatoid arthritis. J. Exp. Med. 179, 1517–1527 (1994).

  92. 92.

    Park, M. J. et al. Interleukin-10 produced by myeloid-derived suppressor cells is critical for the induction of Tregs and attenuation of rheumatoid inflammation in mice. Sci. Rep. 8, 3753 (2018).

  93. 93.

    Cush, J. J. et al. Elevated interleukin-10 levels in patients with rheumatoid arthritis. Arthritis Rheum. 38, 96–104 (1995).

  94. 94.

    Bober, L. A. et al. Regulatory effects of interleukin-4 and interleukin-10 on human neutrophil function ex vivo and on neutrophil influx in a rat model of arthritis. Arthritis Rheum. 43, 2660–2667 (2000).

  95. 95.

    Smallie, T. et al. IL-10 inhibits transcription elongation of the human TNF gene in primary macrophages. J. Exp. Med. 207, 2081–2088 (2010).

  96. 96.

    Maini, R. et al. rHuIL-10 in subjects with active rheumatoid arthritis: a phase I and cytokine response study [abstract]. Arthritis Rheum. 40 (Suppl), S224 (1997).

  97. 97.

    St Clair, E. W. Interleukin 10 treatment for rheumatoid arthritis. Ann. Rheum. Dis. 58 (Suppl.1), I99–I102 (1999).

  98. 98.

    van Roon, J. et al. Interleukin 10 treatment of patients with rheumatoid arthritis enhances Fc gamma receptor expression on monocytes and responsiveness to immune complex stimulation. J. Rheumatol 30, 648–651 (2003).

  99. 99.

    Yoshida, H. & Hunter, C. A. The immunobiology of interleukin-27. Annu. Rev. Immunol. 33, 417–443 (2015).

  100. 100.

    Wong, C. K. et al. Effects of inflammatory cytokine IL-27 on the activation of fibroblast-like synoviocytes in rheumatoid arthritis. Arthritis Res. Ther. 12, R129 (2010).

  101. 101.

    Goldberg, R. et al. Suppression of ongoing adjuvant-induced arthritis by neutralizing the function of the p28 subunit of IL-27. J. Immunol. 173, 1171–1178 (2004).

  102. 102.

    Awasthi, A. et al. A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells. Nat. Immunol. 8, 1380–1389 (2007).

  103. 103.

    Hirahara, K. et al. Interleukin-27 priming of T cells controls IL-17 production in trans via induction of the ligand PD-L1. Immunity 36, 1017–1030 (2012).

  104. 104.

    Kalliolias, G. D., Gordon, R. A. & Ivashkiv, L. B. Suppression of TNF-α and IL-1 signaling identifies a mechanism of homeostatic regulation of macrophages by IL-27. J. Immunol. 185, 7047–7056 (2010).

  105. 105.

    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).

  106. 106.

    Shen, H., Xia, L., Xiao, W. & Lu, J. Increased levels of interleukin-27 in patients with rheumatoid arthritis. Arthritis Rheum. 63, 860–861 (2011).

  107. 107.

    Tanida, S. et al. IL-27-producing CD14(+) cells infiltrate inflamed joints of rheumatoid arthritis and regulate inflammation and chemotactic migration. Cytokine 55, 237–244 (2011).

  108. 108.

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

  109. 109.

    Pickens, S. R. et al. Local expression of interleukin-27 ameliorates collagen-induced arthritis. Arthritis Rheum. 63, 2289–2298 (2011).

  110. 110.

    Rajaiah, R., Puttabyatappa, M., Polumuri, S. K. & Moudgil, K. D. Interleukin-27 and interferon-gamma are involved in regulation of autoimmune arthritis. J. Biol. Chem. 286, 2817–2825 (2011).

  111. 111.

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

  112. 112.

    Meka, R. R. et al. IL-27-induced modulation of autoimmunity and its therapeutic potential. Autoimmun. Rev. 14, 1131–1141 (2015).

  113. 113.

    Timmer, T. C. et al. Inflammation and ectopic lymphoid structures in rheumatoid arthritis synovial tissues dissected by genomics technology: identification of the interleukin-7 signaling pathway in tissues with lymphoid neogenesis. Arthritis Rheum. 56, 2492–2502 (2007).

  114. 114.

    Figueiredo, C. P. et al. Antimodified protein antibody response pattern influences the risk for disease relapse in patients with rheumatoid arthritis tapering disease modifying antirheumatic drugs. Ann. Rheum. Dis. 76, 399–407 (2017).

  115. 115.

    Maizels, R. M. & McSorley, H. J. Regulation of the host immune system by helminth parasites. J. Allergy Clin. Immunol. 138, 666–675 (2016).

  116. 116.

    Pineda, M. A. et al. The parasitic helminth product ES-62 suppresses pathogenesis in collagen-induced arthritis by targeting the interleukin-17-producing cellular network at multiple sites. Arthritis Rheum. 64, 3168–3178 (2012).

  117. 117.

    McInnes, I. B. et al. A novel therapeutic approach targeting articular inflammation using the filarial nematode-derived phosphorylcholine-containing glycoprotein ES-62. J. Immunol. 171, 2127–2133 (2003).

  118. 118.

    Harnett, M. M. et al. The phosphorycholine moiety of the filarial nematode immunomodulator ES-62 is responsible for its anti-inflammatory action in arthritis. Ann. Rheum. Dis. 67, 518–523 (2008).

  119. 119.

    Al-Riyami, L. et al. Designing anti-inflammatory drugs from parasitic worms: a synthetic small molecule analogue of the Acanthocheilonema viteae product ES-62 prevents development of collagen-induced arthritis. J. Med. Chem. 56, 9982–10002 (2013).

  120. 120.

    Rodgers, D. T. et al. Protection against collagen-induced arthritis in mice afforded by the parasitic worm product, ES-62, is associated with restoration of the levels of interleukin-10-producing B cells and reduced plasma cell infiltration of the joints. Immunology 141, 457–466 (2014).

  121. 121.

    Pineda, M. A., Rodgers, D. T., Al-Riyami, L., Harnett, W. & Harnett, M. M. ES-62 protects against collagen-induced arthritis by resetting interleukin-22 toward resolution of inflammation in the joints. Arthritis Rheumatol. 66, 1492–1503 (2014).

  122. 122.

    Rzepecka, J. et al. Prophylactic and therapeutic treatment with a synthetic analogue of a parasitic worm product prevents experimental arthritis and inhibits IL-1β production via NRF2-mediated counter-regulation of the inflammasome. J. Autoimmun. 60, 59–73 (2015).

  123. 123.

    Finlay, C. M. et al. Helminth products protect against autoimmunity via innate type 2 cytokines IL-5 and IL-33, which promote eosinophilia. J. Immunol. 196, 703–714 (2016).

  124. 124.

    Lund, M. E. et al. A parasite-derived 68-mer peptide ameliorates autoimmune disease in murine models of type 1 diabetes and multiple sclerosis. Sci. Rep. 6, 37789 (2016).

  125. 125.

    Martinez, F. O. & Gordon, S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000 Prime Rep. 6, 13 (2014).

  126. 126.

    Vats, D. et al. Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation. Cell Metab. 4, 13–24 (2006).

  127. 127.

    Li, Y. et al. Immune responsive gene 1 (IRG1) promotes endotoxin tolerance by increasing A20 expression in macrophages through reactive oxygen species. J. Biol. Chem. 288, 16225–16234 (2013).

  128. 128.

    Lampropoulou, V. et al. Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of Inflammation. Cell Metab. 24, 158–166 (2016).

Download references


The work of the authors is supported by the National Natural Science Foundation of China (81501344 to Z.C.), the Natural Science Foundation of Anhui Province (1608085MH172 to Z.C.) and by the German Research Council (CRC1181 to A.B. and G.S. and SPP1937 to A.R.).

Author information


  1. Department of Rheumatology and Immunology, The First Affiliated Hospital of the University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China

    • Zhu Chen
  2. Department of Internal Medicine 3, Friedrich Alexander University Erlangen-Nuremberg and Universitatsklinikum Erlangen, Erlangen, Germany

    • Aline Bozec
    • , Andreas Ramming
    •  & Georg Schett


  1. Search for Zhu Chen in:

  2. Search for Aline Bozec in:

  3. Search for Andreas Ramming in:

  4. Search for Georg Schett in:


Z.C. and G.S. wrote the article. All authors researched data for the article, made substantial contributions to discussions of the content and reviewed and/or edited the manuscript before submission.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Georg Schett.

About this article

Publication history