Skip to main content

Thank you for visiting 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.

The contribution from interleukin-27 towards rheumatoid inflammation: insights from gene expression


We aimed to assess expression of genes encoding the heterodimeric IL-27 cytokine and constituent subunits of the Il-27 receptor in rheumatoid arthritis (RA), including in extra-articular, subcutaneous rheumatoid nodules. Comparing between nodules and joint synovia, significantly elevated expression of IL27A within nodules, and comparable IL27B expression, identified nodules as a significant source of IL-27 in RA. T-lymphocytes were the main source of IL27RA transcript, and IL27RA expression correlated with a number of plasma cytokines, as well as tissue TNF expression in both nodules and RA synovia. In synovia, correlations between IL27A, IL27RA IL17A and CD21L expression, and significantly elevated expression of the genes encoding IL-27, associated the presence of IL-27 with B cell-dominated synovial inflammation. Impact from nodule derived IL-27 on systemic or synovial inflammation in RA remains unknown and further study of these implications is required. Our study raises questions regarding the appropriate circumstances for the blockade or administration of IL-27 as a potential therapeutic adjunct in RA.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Gene expression in synovial and nodule tissues.
Fig. 2: Significant correlations in gene expression within rheumatoid tissues.
Fig. 3: Gene expression in paired synovia and nodules.
Fig. 4: Expression of IL27A and IL27RA in rheumatoid subcutaneous nodule tissue.
Fig. 5: IL-27 localisation in subcutaneous nodules.
Fig. 6: Expression of IL-27 and IL27R in synovial tissue.


  1. 1.

    Bastian D, Wu Y, Betts BC, Yu XZ. The IL-12 cytokine and receptor family in graft-vs-host disease. Front Immunol. 2019;10:988.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Stumhofer JS, Tait ED, Quinn WJ, Hosken N, Spudy B, Goenka R, et al. A role for Il-27p28 as an antagonist of gp130-mediated signalling. Nat Immunol. 2010;11:1119–26.

    CAS  Article  Google Scholar 

  3. 3.

    Pflanz S, Timans JC, Cheung J, Rosales R, Kanzler H, Hibbert L, et al. IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naïve CD4+ T cells. Immunity. 2002;16:779–90.

    CAS  Article  Google Scholar 

  4. 4.

    Petes C, Mariani MK, Yang Y, Grandvaux N, Gee K. Interleukin (IL)-6 inhibits IL-27- and IL-30-mediated inflammatory responses in human monocytes. Front Immunol. 2018;9:256.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Muller SI, Friedl A, Aschenbrenner I, Esser-von Bieren J, Zacharias M, Devergne O, et al. A folding switch regulates interleukin biogenesis and secretion of it α-subunit as a cytokine. Proc Nat Acad Sci USA. 2019;116:1585–90.

    Article  Google Scholar 

  6. 6.

    Laroni A, Gandhi R, Beynon V, Weiner HL. IL-27 imparts immunoregulatory function to human NK cells subsets. PLoS ONE. 6:e26173.

  7. 7.

    Jankowski M, Kopinski P, Goc A. Interleukin-27: biological properties and clinical application. Arch Immunol Ther Exp. 2010;58:417–25.

    CAS  Article  Google Scholar 

  8. 8.

    Wong CK, Chen DP, Tam LS, Li EK, Yin YB, Lam CW. Effects of inflammatory cytokineIL-27 on the activation of fibroblast-like synoviocytes in rheumatoid arthritis. Arth Res Ther. 2010;12:R129.

    Article  Google Scholar 

  9. 9.

    Goldberg R, Wildbaum G, Zohar Y, Maor G, Karin N. Suppression of ongoing adjuvant-induced arthritis by neutralising the function of the p28 subunit of IL-27. J Immunol. 2004;173:1171–8.

    CAS  Article  Google Scholar 

  10. 10.

    Jones GW, Bombardieri M, Greenhill CJ, McLeod L, Nerviani A, Rocher-Ros V, et al. Interleukin-27 inhibits ectopic lymphoid-like structure development in early inflammatory arthritis. J Exp Med. 2015;212:1793–802.

    CAS  Article  Google Scholar 

  11. 11.

    Shen H, Xia L, Xiao W, Lu J. Increased levels of interleukin-27 in patients with rheumatoid arthritis. Arth Rheum. 2011;63:860–1.

    CAS  Article  Google Scholar 

  12. 12.

    Tanida S, Yoshitomi H, Ishikawa M, Kasahara T, Murata, Shibuya H, et al. IL-27-producing CD14(+) cells infiltrate inflamed joints of rheumatoid arthritis and regulate inflammation and chemotactic migration. Cytokine. 2011;55:237–44.

    CAS  Article  Google Scholar 

  13. 13.

    Baker KF, Skelton AJ, Lendrem DW, Scadeng A, Thompson B, Pratt AG, et al. Predicting drug-free remission in rheumatoid arthritis: a prospective interventional cohort study. J Autoimmun. 2019;105:102298.

    Article  Google Scholar 

  14. 14.

    Hessian PA, Highton J, Kean A, Sun CK, Chin M. Cytokine profile of the rheumatoid nodule suggests that it is a Th1 granuloma. Arth Rheum. 2003;48:334–8.

    CAS  Article  Google Scholar 

  15. 15.

    Dorosz SA, Ginolhac A, Kahne T, Naumann M, Salamann Sauter T. et al. Role of calprotectin as a modulator of the IL27-mediated proinflammatory effect on endothelial cells. Mediators Inflamm. 2015;2015:737310.

    Article  Google Scholar 

  16. 16.

    McKelvey KJ, Millier MJ, Doyle TC, Stamp LK, Highton J, Hessian PA. Co-expression of CD21l and IL17A defines a subset of rheumatoid synovia, characterised by large lymphoid aggregates and high inflammation. PLoS ONE. 2018;16:e0202135.

    Article  Google Scholar 

  17. 17.

    Humby F, Bombardieri M, Manzo A, Kelly S, Blades MC, Kirkham B, et al. Ectopic lymphoid structures support ongoing production of class-switched autoantibodies in rheumatoid synovium. PLoS Med. 2009;6:e1.

    Article  Google Scholar 

  18. 18.

    Palmer DG, Hogg N, Denholm I, Allen CA, Highton J, Hessian PA. Comparison of phenotype expression by mononuclear phagocytes within subcutaneous gouty tophi and rheumatoid nodules. Rheumatol Int. 1987;7:187–93.

    CAS  Article  Google Scholar 

  19. 19.

    Soni S, O’Dea KP, Tan YY, Cho K, Abe E, Romano R, et al. ATP directs cytokine trafficking and promotes novel membrane TNF signalling via micro-vesicles. FASEB J. 2019;33:6442–55.

    CAS  Article  Google Scholar 

  20. 20.

    Highton J, Hessian PA, Stamp L. The rheumatoid nodule: peripheral or central to rheumatoid arthritis. Rheumatology. 2007;46:1385–7.

    CAS  Article  Google Scholar 

  21. 21.

    Highton J, Hung N, Hessian P, Wilsher M. Pulmonary rheumatoid nodules demonstrating features usually associated with synovial membrane. Rheumatology. 2007;46:811–4.

    CAS  Article  Google Scholar 

  22. 22.

    Stamp LK, Eason A, Lehnigk U, Highton J, Hessian PA. Different T cell subsets in the nodule and synovial membrane: absence of interleukin-17A in rheumatoid nodules. Arth Rheum. 2008;58:1601–8.

    CAS  Article  Google Scholar 

  23. 23.

    Liu H, Rohowsky-Kochan C. Interleukin-27-mediated suppression of human Th17 cells is associated with activation of STAT1 and suppressor of cytokine signalling protein 1. J Interferon Cytokine Res. 2011;31:459–69.

    CAS  Article  Google Scholar 

  24. 24.

    Larousserie F, Pflanz S, Coulomb-L’Hermine A, Brousse N, Kastelein R, Cevergne O. Expression of IL-27 in human Th1-associated granulomatous diseases. J Path. 2004;202:164–71.

    CAS  Article  Google Scholar 

  25. 25.

    Cao Y, Doodes PD, Glant TT, Finnegan A. IL-27 induces a Th1 immune response and susceptibility to experimental arthritis. J Immunol. 2008;180:922–30.

    CAS  Article  Google Scholar 

  26. 26.

    Gong F, Pan Y-H, Huang X, Chen J, Xiao J, Zhu H. Interleukin-27 as a potential therapeutic target for rheumatoid arthritis: has the time come? Clin Rheumatol. 2013;32:1425–8.

    Article  Google Scholar 

  27. 27.

    Jones GW, Hill DG, Cardua A, Jones SA. Il-27: a double agent in the IL-6 family. Clin Exp Immunol. 2018;193:37–46.

    CAS  Article  Google Scholar 

  28. 28.

    Canete JD, Celis R, Yeremenko N, Sanmarti R, van Duivenvoorde L, Ramirez J, et al. Ectopic lymphoid neogenesis is strongly associated with activation of the IL-23 pathway in rheumatoid synovitis. Arth Res Ther. 2015;17:173.

    CAS  Article  Google Scholar 

  29. 29.

    Batten M, Ramamoorrthi N, Kijavin NM, Ma CS, Cox J, Dengler HS, et al. IL-27 supports germinal centre function by enhancing IL-21 production and the function of T follicular helper cells. J Exp Med. 2010;201:2895–906.

    Article  Google Scholar 

  30. 30.

    Vijayan D, Mohd Redzwan N, Avery DT, Wirasinha RC, Brink R, Walters G, et al. IL-27 directly enhances germinal centre B cell activity and potentiates Lupus in sanroque mice. J Immunol. 2016;197:3008–17.

    CAS  Article  Google Scholar 

  31. 31.

    Wang RX, Yu CR, Dambuza IM, Mahdi RM, Dolinska MB, Sergeev YV, et al. Interleukin-35 induces regulatory B cells that suppress autoimmune disease. Nat Med. 2014;20:633–41.

    Article  Google Scholar 

  32. 32.

    Villarino AV, Larkin J, Saris CJ, Caton AJ, Lucas S, Wong T, et al. Positive and negative regulation of the IL-27 receptor during lymphoid cell activation. J Immunol. 2005;15:7684–91.

    Article  Google Scholar 

  33. 33.

    Mehta AK, Gracias DT, Croft M. TNF activity and T cells. Cytokine. 2018;101:14–18.

    CAS  Article  Google Scholar 

  34. 34.

    Millier MJ, Stamp LK, Hessian PA. Digital-PCR for gene expression: Impact from inherent tissue RNA degradation. Sci Rep. 2018;7:17235.

    CAS  Article  Google Scholar 

Download references


Thanks to Sam Smith-Bell for his help with IL6 and TNF expression data and Jill Drake for help with coordination of patient data. Histology support was provided by the Otago micro and nanoscale imaging unit. This work was supported by grants from the Health Research Council of New Zealand and an Otago Medical Research Foundation, Jack Thomson grant.

Author information



Corresponding author

Correspondence to Paul A. Hessian.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

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

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Millier, M.J., Lazaro, K., Stamp, L.K. et al. The contribution from interleukin-27 towards rheumatoid inflammation: insights from gene expression. Genes Immun 21, 249–259 (2020).

Download citation

Further reading


Quick links