, Volume 37, Issue 3, pp 824–832

IL-33 Neutralization Suppresses Lupus Disease in Lupus-Prone Mice



IL-33 is a new member of the IL-1 family that plays a role in inflammation. In this study, we evaluated the potential of IL-33 inhibition as a treatment for systemic lupus erythematosus (SLE) using the lupus-prone model MRL/lpr mice and the underlying mechanisms of action. We treated mice with anti-mouse IL-33 antibody (anti-IL-33Ab) via intraperitoneal injection every other day from week 14 until week 20 for 6 weeks. A control group received the same amount of IgG control. Renal damage and mouse survival were compared. Cytokines, antibodies, immune complex, Tregs, myeloid-derived suppressor cells (MDSCs), and Th17 cells were also analyzed. Correlations between serum IL-33 and SLE disease activity index in human SLE were also investigated. MRL/lpr mice treated with anti-IL-33Ab showed reduced proteinuria and reduced serum anti-dsDNA levels. Nephritis, immune complex deposits, and the circulating antibodies and immune complex besides the mortality were significantly reduced by anti-IL-33Ab. Anti-IL-33Ab remarkably increased Tregs and MDSCs and reduced the Th17 cells and IL-1β, IL-6, and IL-17 levels in MRL/lpr mice. These results suggest that IL-33 inhibition may inhibit SLE via expansion of Tregs and MDSCs and inhibition of Th17 cells and proinflammatory responses, indicating that blockade of IL-33 has a protective effect on SLE.


systemic lupus erythematosus IL-33 myeloid-derived suppressor cells lupus-prone mice 


  1. 1.
    Kurowska-Stolarska, M., A. Hueber, B. Stolarski, and I.B. McInnes. 2011. Interleukin-33: a novel mediator with a role in distinct disease pathologies. Journal of Internal Medicine 269: 29–35.PubMedCrossRefGoogle Scholar
  2. 2.
    Lloyd, C.M. 2010. IL-33 family members and asthma–bridging innate and adaptive immune responses. Current Opinion in Immunology 22: 800–806.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Mirchandani, A.S., R.J. Salmond, and F.Y. Liew. 2012. Interleukin-33 and the function of innate lymphoid cells. Trends in Immunology 33: 389–396.PubMedCrossRefGoogle Scholar
  4. 4.
    McLaren, J.E., D.R. Michael, R.C. Salter, T.G. Ashlin, C.J. Calder, A.M. Miller, et al. 2010. IL-33 reduces macrophage foam cell formation. The Journal of Immunology 185: 1222–1229.PubMedCrossRefGoogle Scholar
  5. 5.
    Miller, A.M., D. Xu, D.L. Asquith, L. Denby, Y. Li, N. Sattar, et al. 2008. IL-33 reduces the development of atherosclerosis. The Journal of Experimental Medicine 205: 339–346.PubMedCentralPubMedCrossRefGoogle Scholar
  6. 6.
    Moffatt, M.F., I.G. Gut, F. Demenais, D.P. Strachan, E. Bouzigon, S. Heath, et al. 2010. A large-scale, consortium-based genomewide association study of asthma. The New England Journal of Medicine 363: 1211–1221.PubMedCrossRefGoogle Scholar
  7. 7.
    Xu, D., H.R. Jiang, P. Kewin, Y. Li, R. Mu, A.R. Fraser, et al. 2008. IL-33 exacerbates antigen-induced arthritis by activating mast cells. Proceedings of the National Academy of Sciences of the United States of America 105: 10913–10918.PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Talabot-Ayer, D., T. McKee, P. Gindre, S. Bas, D.L. Baeten, C. Gabay, et al. 2012. Distinct serum and synovial fluid interleukin (IL)-33 levels in rheumatoid arthritis, psoriatic arthritis and osteoarthritis. Joint, Bone, Spine 79: 32–37.PubMedCrossRefGoogle Scholar
  9. 9.
    Humrich, J.Y., H. Morbach, R. Undeutsch, P. Enghard, S. Rosenberger, O. Weigert, et al. 2010. Homeostatic imbalance of regulatory and effector T cells due to IL-2 deprivation amplifies murine lupus. Proceedings of the National Academy of Sciences of the United States of America 107: 204–209.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Trigunaite A, Khan A, Der E, Song A, Varikuti S, Jørgensen TN. Gr1(high) CD11b(+) cells suppress B cell differentiation and lupus-like disease in lupus-prone male mice. Arthritis Rheum. 2013. doi:10.1002/art.38048.
  11. 11.
    Gabrilovich, D.I., and S. Nagaraj. 2009. Myeloid-derived suppressor cells as regulators of the immune system. Nature Reviews Immunology 9: 162–174.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Peranzoni, E., S. Zilio, I. Marigo, L. Dolcetti, P. Zanovello, S. Mandruzzato, et al. 2010. Myeloid-derived suppressor cell heterogeneity and subset definition. Current Opinion in Immunology 22: 238–244.PubMedCrossRefGoogle Scholar
  13. 13.
    Ioannou, M., T. Alissafi, I. Lazaridis, G. Deraos, J. Matsoukas, A. Gravanis, et al. 2012. Crucial role of granulocytic myeloid-derived suppressor cells in the regulation of central nervous system autoimmune disease. The Journal of Immunology 188: 1136–1146.PubMedCrossRefGoogle Scholar
  14. 14.
    Fujii, W., E. Ashihara, H. Hirai, H. Nagahara, N. Kajitani, K. Fujioka, et al. 2013. Myeloid-derived suppressor cells play crucial roles in the regulation of mouse collagen-induced arthritis. The Journal of Immunology 191: 1073–1081.PubMedCrossRefGoogle Scholar
  15. 15.
    Tsokos, G.C. 2011. Systemic lupus erythematosus. The New England Journal of Medicine 365: 2110–2121.PubMedCrossRefGoogle Scholar
  16. 16.
    Kim, Y.H., T.Y. Yang, C.S. Park, S.H. Ahn, B.K. Son, J.H. Kim, et al. 2012. Anti-IL-33 antibody has a therapeutic effect in a murine model of allergic rhinitis. Allergy 67: 183–190.PubMedCrossRefGoogle Scholar
  17. 17.
    Sekine, H., K.L. Graham, S. Zhao, M.K. Elliott, P. Ruiz, P.J. Utz, et al. 2006. Role of MHC-linked genes in autoantigen selection and renal disease in a murine model of systemic lupus erythematosus. The Journal of Immunology 177: 7423–7434.PubMedCrossRefGoogle Scholar
  18. 18.
    Wellmann, U., M. Letz, A. Schneider, K. Amann, and T.H. Winkler. 2001. An Ig μ-heavy chain transgene inhibits systemic lupus erythematosus immunopathology in autoimmune (NZB × NZW)F1 mice. International Immunology 13: 1461–1469.PubMedCrossRefGoogle Scholar
  19. 19.
    Lateef, A., and M. Petri. 2012. Unmet medical needs in systemic lupus erythematosus. Arthritis Research and Therapy 14(Suppl 4): S4.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Yang, Z., Y. Liang, W. Xi, C. Li, and R. Zhong. 2011. Association of increased serum IL-33 levels with clinical and laboratory characteristics of systemic lupus erythematosus in Chinese population. Clinical and Experimental Medicine 11: 75–80.PubMedCrossRefGoogle Scholar
  21. 21.
    Mok, M.Y., F.P. Huang, W.K. Ip, Y. Lo, F.Y. Wong, E.Y. Chan, et al. 2010. Serum levels of IL-33 and soluble ST2 and their association with disease activity in systemic lupus erythematosus. Rheumatology (Oxford) 49: 520–527.CrossRefGoogle Scholar
  22. 22.
    Oboki, K., T. Ohno, N. Kajiwara, K. Arae, H. Morita, A. Ishii, et al. 2010. IL-33 is a crucial amplifier of innate rather than acquired immunity. Proceedings of the National Academy of Sciences of the United States of America 107: 18581–18586.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Hong, Y.S., S.J. Moon, Y.B. Joo, C.H. Jeon, M.L. Cho, J.H. Ju, et al. 2011. Measurement of interleukin-33 (IL-33) and IL-33 receptors (sST2 and ST2L) in patients with rheumatoid arthritis. Journal of Korean Medical Science 26: 1132–1139.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Kunisch, E., S. Chakilam, M. Gandesiri, and R.W. Kinne. 2012. IL-33 regulates TNF-α dependent effects in synovial fibroblasts. International Journal of Molecular Medicine 29: 530–540.PubMedCentralPubMedGoogle Scholar
  25. 25.
    Yin, B., G. Ma, C.Y. Yen, Z. Zhou, G.X. Wang, C.M. Divino, et al. 2010. Myeloid-derived suppressor cells prevent type 1 diabetes in murine models. The Journal of Immunology 185: 5828–5834.PubMedCrossRefGoogle Scholar
  26. 26.
    Wolf, D., K. Hochegger, A.M. Wolf, H.F. Rumpold, G. Gastl, H. Tilg, et al. 2005. CD4 + CD25+ regulatory T cells inhibit experimental anti-glomerular basement membrane glomerulonephritis in mice. Journal of the American Society of Nephrology 16: 1360–1370.PubMedCrossRefGoogle Scholar
  27. 27.
    Weigert, O., C. von Spee, R. Undeutsch, L. Kloke, J.Y. Humrich, and G. Riemekasten. 2013. CD4 + Foxp3+ regulatory T cells prolong drug-induced disease remission in (NZBxNZW) F1 lupus mice. Arthritis Research and Therapy 15: R35.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Shin, M.S., N. Lee, and I. Kang. 2011. Effector T-cell subsets in systemic lupus erythematosus: update focusing on Th17 cells. Current Opinion in Rheumatology 23: 444–448.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Ambrosi, A., A. Espinosa, and M. Wahren-Herlenius. 2012. IL-17: a new actor in IFN-driven systemic autoimmune diseases. European Journal of Immunology 42: 2274–2284.PubMedCrossRefGoogle Scholar
  30. 30.
    Ma, J., J. Yu, X. Tao, L. Cai, J. Wang, and S.G. Zheng. 2010. The imbalance between regulatory and IL-17-secreting CD4+ T cells in lupus patients. Clinical Rheumatology 29: 1251–1258.PubMedCrossRefGoogle Scholar
  31. 31.
    Mengya, Z., M. Hanyou, L. Dong, L. Xiaohong, and Z. Lihua. 2013. Th17/Treg imbalance induced by increased incidence of atherosclerosis in patients with systemic lupus erythematosus (SLE). Clinical Rheumatology 32: 1045–1052.CrossRefGoogle Scholar
  32. 32.
    Zhao, J., H. Wang, C. Dai, H. Wang, H. Zhang, Y. Huang, et al. 2013. P2X7 blockade attenuates lupus nephritis by inhibiting NLRP3/ASC/caspase-1 activation. Arthritis and Rheumatism 65: 3176–3185.PubMedCrossRefGoogle Scholar
  33. 33.
    Duan, L., J. Chen, H. Zhang, H. Yang, P. Zhu, A. Xiong, et al. 2012. Interleukin-33 ameliorates experimental colitis through promoting Th2/Foxp3+ regulatory T-cell responses in mice. Molecular Medicine 18: 753–761.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Jiang, H.R., M. Milovanović, D. Allan, W. Niedbala, A.G. Besnard, S.Y. Fukada, et al. 2012. IL-33 attenuates EAE by suppressing IL-17 and IFN-γ production and inducing alternatively activated macrophages. European Journal of Immunology 42: 1804–1814.PubMedCrossRefGoogle Scholar
  35. 35.
    Mu, R., H.Q. Huang, Y.H. Li, C. Li, H. Ye, and Z.G. Li. 2010. Elevated serum interleukin 33 is associated with autoantibody production in patients with rheumatoid arthritis. The Journal of Rheumatology 37: 2006–2013.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Institute of Immunology of Fujian Union Hospital Affiliated to Fujian Medical UniversityFuzhouChina
  2. 2.Cadre’s WardFujian Union Hospital Affiliated to Fujian Medical UniversityFuzhouChina
  3. 3.Department of RheumatologyFujian Union Hospital Affiliated To Fujian Medical UniversityFuzhouChina

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