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Interleukin-33 biology with potential insights into human diseases

Nature Reviews Rheumatology volume 7, pages 321–329 (2011)Cite this article

Subjects

Abstract

Interleukin (IL)-33 is a member of the IL-1 family of cytokines. IL-33 is a nuclear protein that is also released into the extracellular space, and thus acts as a dual-function molecule, as does IL-1α. Extracellular IL-33 binds to the cell-surface receptor ST2, leading to the activation of intracellular signaling pathways similar to those used by IL-1. Unlike conventional cytokines, IL-33 might be secreted via unconventional pathways, and can be released upon cell injury as an alarmin. IL-33 is expressed in cells that are in contact with the environment, and acts as an early inducer of inflammation. Its production is then upregulated in inflamed tissues, thus contributing to the further amplification of inflammatory responses. Studies of IL-33-deficient mice will provide more information on intracellular functions of this cytokine. A large body of evidence supports the pathogenic role of IL-33 in asthma and possibly other inflammatory airway conditions. Furthermore, IL-33 has been shown to be involved in experimental models of arthritis and potentially has a pathogenic role in ulcerative colitis and fibrotic conditions, suggesting that IL-33 antagonists might be of interest for the treatment of asthma, rheumatoid arthritis and ulcerative colitis. However, IL-33 also appears to exert important functions in host defense against pathogens and to display cardioprotective properties, which might have implications for the clinical use of IL-33 blockade.

Key Points

  • Interleukin (IL)-33 is a member of the IL-1 family that is expressed as a 30 kD protein in the cell nucleus

  • IL-33 is not secreted following a conventional secretory pathway but is released as an alarmin following cell injury

  • Levels of IL-33 are elevated in the bronchial tissue of patients with asthma, and IL-33 is involved in experimental models of the disease, primarily by stimulating cells of the innate immune response

  • IL-33 levels are increased in rheumatoid arthritis, and IL-33 signaling is involved in the pathogenesis of several experimental models of arthritis

  • IL-33 contributes to host defense against parasitic and bacterial infections and exerts cardioprotective effects

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Figure 1: Schematic representation of the IL-33 protein.
Figure 2: IL-33 signaling.
Figure 3: Model for the effects of IL-33 in airway inflammation.
Figure 4: Model for the effects of IL-33 in arthritis.

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References

  1. 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).

    Article  CAS  PubMed  Google Scholar 

  2. Moussion, C., Ortega, N. & Girard, J. P. The IL-1-like cytokine IL-33 is constitutively expressed in the nucleus of endothelial cells and epithelial cells in vivo: a novel 'alarmin'? PLoS ONE 3, e3331 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Carriere, V. et al. IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo. Proc. Natl Acad. Sci. USA 104, 282–287 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. Roussel, L., Erard, M., Cayrol, C. & Girard, J. P. Molecular mimicry between IL-33 and KSHV for attachment to chromatin through the H2A–H2B acidic pocket. EMBO Rep. 9, 1006–1012 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Cayrol, C. & Girard, J. P. The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1. Proc. Natl Acad. Sci. USA 106, 9021–9026 (2009).

    Article  PubMed  Google Scholar 

  6. Talabot-Ayer, D., Lamacchia, C., Gabay, C. & Palmer, G. Interleukin-33 is biologically active independently of caspase-1 cleavage. J. Biol. Chem. 284, 19420–19426 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lüthi, A. U. et al. Suppression of interleukin-33 bioactivity through proteolysis by apoptotic caspases. Immunity 31, 84–98 (2009).

    Article  CAS  PubMed  Google Scholar 

  8. Oboki, K. et al. IL-33 is a crucial amplifier of innate rather than acquired immunity. Proc. Natl Acad. Sci. USA 107, 18581–18586 (2010).

    Article  PubMed  Google Scholar 

  9. Lingel, A. et al. Structure of IL-33 and its interaction with the ST2 and IL-1RAcP receptors—insight into heterotrimeric IL-1 signaling complexes. Structure 17, 1398–1410 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Baekkevold, E. S. et al. Molecular characterization of NF-HEV, a nuclear factor preferentially expressed in human high endothelial venules. Am. J. Pathol. 163, 69–79 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kuchler, A. M. et al. Nuclear interleukin-33 is generally expressed in resting endothelium but rapidly lost upon angiogenic or proinflammatory activation. Am. J. Pathol. 173, 1229–1242 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  13. Sponheim, J. et al. Inflammatory bowel disease-associated interleukin-33 is preferentially expressed in ulceration-associated myofibroblasts. Am. J. Pathol. 177, 2804–2815 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ohno, T. et al. Caspase-1, caspase-8, and calpain are dispensable for IL-33 release by macrophages. J. Immunol. 183, 7890–7897 (2009).

    Article  CAS  PubMed  Google Scholar 

  15. Hayakawa, M. et al. Mature interleukin-33 is produced by calpain-mediated cleavage in vivo. Biochem. Biophys. Res. Commun. 387, 218–222 (2009).

    Article  CAS  PubMed  Google Scholar 

  16. Ali, S., Nguyen, D. Q., Falk, W. & Martin, M. U. Caspase 3 inactivates biologically active full length interleukin-33 as a classical cytokine but does not prohibit nuclear translocation. Biochem. Biophys. Res. Commun. 391, 1512–1516 (2010).

    Article  CAS  PubMed  Google Scholar 

  17. Nile, C. J., Barksby, E., Jitprasertwong, P., Preshaw, P. M. & Taylor, J. J. Expression and regulation of interleukin-33 in human monocytes. Immunology 130, 172–180 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  18. 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).

    Article  CAS  PubMed  Google Scholar 

  19. Haraldsen, G., Balogh, J., Pollheimer, J., Sponheim, J. & Kuchler, A. M. Interleukin-33—cytokine of dual function or novel alarmin? Trends Immunol. 30, 227–233 (2009).

    Article  CAS  PubMed  Google Scholar 

  20. Lamkanfi, M. & Dixit, V. M. IL-33 raises alarm. Immunity 31, 5–7 (2009).

    Article  CAS  PubMed  Google Scholar 

  21. Hudson, C. A. et al. Induction of IL-33 expression and activity in central nervous system glia. J. Leukoc. Biol. 84, 631–643 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kobori, A. et al. Interleukin-33 expression is specifically enhanced in inflamed mucosa of ulcerative colitis. J. Gastroenterol. 45, 999–1007 (2010).

    Article  CAS  PubMed  Google Scholar 

  23. Kouzaki, H., Iijima, K., Kobayashi, T., O'Grady, S. M. & Kita, H. The danger signal, extracellular ATP, is a sensor for an airborne allergen and triggers IL-33 release and innate TH2-type responses. J. Immunol. doi:10.4049/jimmunol.1003020.

  24. Keller, M., Ruegg, A., Werner, S. & Beer, H. D. Active caspase-1 is a regulator of unconventional protein secretion. Cell 132, 818–831 (2008).

    Article  CAS  PubMed  Google Scholar 

  25. Prefontaine, D. et al. Increased expression of IL-33 in severe asthma: evidence of expression by airway smooth muscle cells. J. Immunol. 183, 5094–5103 (2009).

    Article  CAS  PubMed  Google Scholar 

  26. Pastorelli, L. et al. Epithelial-derived IL-33 and its receptor ST2 are dysregulated in ulcerative colitis and in experimental TH1/TH2 driven enteritis. Proc. Natl Acad. Sci. USA 107, 8017–8022 (2010).

    Article  CAS  PubMed  Google Scholar 

  27. Prefontaine, D. et al. Increased IL-33 expression by epithelial cells in bronchial asthma. J. Allergy Clin. Immunol. 125, 752–754 (2010).

    Article  CAS  PubMed  Google Scholar 

  28. Wood, I. S., Wang, B. & Trayhurn, P. IL-33, a recently identified interleukin-1 gene family member, is expressed in human adipocytes. Biochem. Biophys. Res. Commun. 384, 105–109 (2009).

    Article  CAS  PubMed  Google Scholar 

  29. Reh, D. D., Wang, Y., Ramanathan, M. Jr. & Lane, A. P. Treatment-recalcitrant chronic rhinosinusitis with polyps is associated with altered epithelial cell expression of interleukin-33. Am. J. Rhinol. Allergy 24, 105–109 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Shimosato, T. et al. CpG oligodeoxynucleotides induce strong up-regulation of interleukin 33 via Toll-like receptor 9. Biochem. Biophys. Res. Commun. 394, 81–86 (2010).

    Article  CAS  PubMed  Google Scholar 

  31. Oboki, K., Ohno, T., Kajiwara, N., Saito, H. & Nakae, S. IL-33 and IL-33 receptors in host defense and diseases. Allergol. Int. 59, 143–160 (2010).

    Article  CAS  PubMed  Google Scholar 

  32. Trajkovic, V., Sweet, M. J. & Xu, D. T1/ST2—an IL-1 receptor-like modulator of immune responses. Cytokine Growth Factor Rev. 15, 87–95 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Bergers, G., Reikerstorfer, A., Braselmann, S., Graninger, P. & Busslinger, M. Alternative promoter usage of the Fos-responsive gene Fit-1 generates mRNA isoforms coding for either secreted or membrane-bound proteins related to the IL-1 receptor. EMBO J. 13, 1176–1188 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Li, H. et al. The cloning and nucleotide sequence of human ST2L cDNA. Genomics 67, 284–290 (2000).

    Article  CAS  PubMed  Google Scholar 

  35. Hayakawa, H., Hayakawa, M., Kume, A. & Tominaga, S. Soluble ST2 blocks interleukin-33 signaling in allergic airway inflammation. J. Biol. Chem. 282, 26369–26380 (2007).

    Article  CAS  PubMed  Google Scholar 

  36. Yanagisawa, K., Tsukamoto, T., Takagi, T. & Tominaga, S. Murine ST2 gene is a member of the primary response gene family induced by growth factors. FEBS Lett. 302, 51–53 (1992).

    Article  CAS  PubMed  Google Scholar 

  37. Kumar, S., Tzimas, M. N., Griswold, D. E. & Young, P. R. Expression of ST2, an interleukin-1 receptor homologue, is induced by proinflammatory stimuli. Biochem. Biophys. Res. Commun. 235, 474–478 (1997).

    Article  CAS  PubMed  Google Scholar 

  38. Weinberg, E. O. et al. Expression and regulation of ST2, an interleukin-1 receptor family member, in cardiomyocytes and myocardial infarction. Circulation 106, 2961–2966 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Tago, K. et al. Tissue distribution and subcellular localization of a variant form of the human ST2 gene product, ST2V. Biochem. Biophys. Res. Commun. 285, 1377–1383 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. Ali, S. et al. IL-1 receptor accessory protein is essential for IL-33-induced activation of T lymphocytes and mast cells. Proc. Natl Acad. Sci. USA 104, 18660–18665 (2007).

    Article  PubMed  Google Scholar 

  41. Chackerian, A. A. et al. IL-1 receptor accessory protein and ST2 comprise the IL-33 receptor complex. J. Immunol. 179, 2551–2555 (2007).

    Article  CAS  PubMed  Google Scholar 

  42. Palmer, G. et al. The IL-1 receptor accessory protein (AcP) is required for IL-33 signaling and soluble AcP enhances the ability of soluble ST2 to inhibit IL-33. Cytokine 42, 358–364 (2008).

    Article  CAS  PubMed  Google Scholar 

  43. Ho, L. H. et al. IL-33 induces IL-13 production by mouse mast cells independently of IgE-FcεRI signals. J. Leukoc. Biol. 82, 1481–1490 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. Pecaric-Petkovic, T., Didichenko, S. A., Kaempfer, S., Spiegl, N. & Dahinden, C. A. Human basophils and eosinophils are the direct target leukocytes of the novel IL-1 family member IL-33. Blood 113, 1526–1534 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Yagami, A. et al. IL-33 mediates inflammatory responses in human lung tissue cells. J. Immunol. 185, 5743–5750 (2010).

    Article  CAS  PubMed  Google Scholar 

  46. Chow, J. Y., Wong, C. K., Cheung, P. F. & Lam, C. W. Intracellular signaling mechanisms regulating the activation of human eosinophils by the novel TH2 cytokine IL-33: implications for allergic inflammation. Cell. Mol. Immunol. 7, 26–34 (2010).

    Article  CAS  PubMed  Google Scholar 

  47. Yndestad, A. et al. Modulation of interleukin signalling and gene expression in cardiac myocytes by endothelin-1. Int. J. Biochem. Cell Biol. 42, 263–272 (2010).

    Article  CAS  PubMed  Google Scholar 

  48. Tare, N. et al. KU812 cells provide a novel in vitro model of the human IL-33/ST2L axis: functional responses and identification of signaling pathways. Exp. Cell Res. 316, 2527–2537 (2010).

    Article  CAS  PubMed  Google Scholar 

  49. Sanada, S. et al. IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling system. J. Clin. Invest. 117, 1538–1549 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Funakoshi-Tago, M. et al. TRAF6 is a critical signal transducer in IL-33 signaling pathway. Cell. Signal. 20, 1679–1686 (2008).

    Article  CAS  PubMed  Google Scholar 

  51. Funakoshi-Tago, M., Tago, K., Sato, Y., Tominaga, S. I. & Kasahara, T. JAK2 is an important signal transducer in IL-33-induced NF-κB activation. Cell. Signal. 23, 363–370 (2010).

    Article  CAS  PubMed  Google Scholar 

  52. Bulek, K. et al. The essential role of single Ig IL-1 receptor-related molecule/Toll IL-1R8 in regulation of TH2 immune response. J. Immunol. 182, 2601–2609 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  54. Mun, S. H. et al. Interleukin-33 stimulates formation of functional osteoclasts from human CD14+ monocytes. Cell. Mol. Life Sci. 67, 3883–3892 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Takayanagi, H. Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat. Rev. Immunol. 7, 292–304 (2007).

    Article  CAS  PubMed  Google Scholar 

  56. Ivashkiv, L. B. A signal-switch hypothesis for cross-regulation of cytokine and TLR signalling pathways. Nat. Rev. Immunol. 8, 816–822 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Smith, D. E. The biological paths of IL-1 family members IL-18 and IL-33. J. Leukoc. Biol. 89, 383–392 (2010).

    Article  CAS  PubMed  Google Scholar 

  58. Iikura, M. et al. IL-33 can promote survival, adhesion and cytokine production in human mast cells. Lab. Invest. 87, 971–978 (2007).

    Article  CAS  PubMed  Google Scholar 

  59. Moulin, D. et al. Interleukin (IL)-33 induces the release of pro-inflammatory mediators by mast cells. Cytokine 40, 216–225 (2007).

    Article  CAS  PubMed  Google Scholar 

  60. Komai-Koma, M. et al. IL-33 is a chemoattractant for human TH2 cells. Eur. J. Immunol. 37, 2779–2786 (2007).

    Article  CAS  PubMed  Google Scholar 

  61. Kurowska-Stolarska, M. et al. IL-33 induces antigen-specific IL-5+ T cells and promotes allergic-induced airway inflammation independent of IL-4. J. Immunol. 181, 4780–4790 (2008).

    Article  CAS  PubMed  Google Scholar 

  62. Cherry, W. B., Yoon, J., Bartemes, K. R., Iijima, K. & Kita, H. A novel IL-1 family cytokine, IL-33, potently activates human eosinophils. J. Allergy Clin. Immunol. 121, 1484–1490 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Smithgall, M. D. et al. IL-33 amplifies both TH1- and TH2-type responses through its activity on human basophils, allergen-reactive TH2 cells, iNKT and NK cells. Int. Immunol. 20, 1019–1030 (2008).

    Article  CAS  PubMed  Google Scholar 

  64. Suzukawa, M. et al. An IL-1 cytokine member, IL-33, induces human basophil activation via its ST2 receptor. J. Immunol. 181, 5981–5989 (2008).

    Article  CAS  PubMed  Google Scholar 

  65. Guo, L. et al. IL-1 family members and STAT activators induce cytokine production by TH2, TH17, and TH1 cells. Proc. Natl Acad. Sci. USA 106, 13463–13468 (2009).

    Article  PubMed  Google Scholar 

  66. Kroeger, K. M., Sullivan, B. M. & Locksley, R. M. IL-18 and IL-33 elicit TH2 cytokines from basophils via a MyD88- and p38α-dependent pathway. J. Leukoc. Biol. 86, 769–778 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Schneider, E. et al. IL-33 activates unprimed murine basophils directly in vitro and induces their in vivo expansion indirectly by promoting hematopoietic growth factor production. J. Immunol. 183, 3591–3597 (2009).

    Article  CAS  PubMed  Google Scholar 

  68. Allakhverdi, Z. et al. CD34+ hemopoietic progenitor cells are potent effectors of allergic inflammation. J. Allergy Clin. Immunol. 123, 472–478 (2009).

    Article  CAS  PubMed  Google Scholar 

  69. Rank, M. A. et al. IL-33-activated dendritic cells induce an atypical TH2-type response. J. Allergy Clin. Immunol. 123, 1047–1054 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Espinassous, Q. et al. IL-33 enhances lipopolysaccharide-induced inflammatory cytokine production from mouse macrophages by regulating lipopolysaccharide receptor complex. J. Immunol. 183, 1446–1455 (2009).

    Article  CAS  PubMed  Google Scholar 

  71. Kurowska-Stolarska, M. et al. IL-33 amplifies the polarization of alternatively activated macrophages that contribute to airway inflammation. J. Immunol. 183, 6469–6477 (2009).

    Article  CAS  PubMed  Google Scholar 

  72. Bourgeois, E. et al. The pro-TH2 cytokine IL-33 directly interacts with invariant NKT and NK cells to induce IFN-γ production. Eur. J. Immunol. 39, 1046–1055 (2009).

    Article  CAS  PubMed  Google Scholar 

  73. Kim, W. et al. A novel method for procuring a large quantity of mature murine eosinophils in vivo. J. Immunol. Methods 363, 90–94 (2010).

    Article  CAS  PubMed  Google Scholar 

  74. Schulze, J. et al. Interleukin-33 is expressed in differentiated osteoblasts and blocks osteoclast formation from bone marrow precursor cells. J. Bone Miner. Res. doi:10.1002/jbmr.269.

  75. Joshi, A. D. et al. Interleukin-33 contributes to both M1 and M2 chemokine marker expression in human macrophages. BMC Immunol. 11, 52 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Humphreys, N. E., Xu, D., Hepworth, M. R., Liew, F. Y. & Grencis, R. K. IL-33, a potent inducer of adaptive immunity to intestinal nematodes. J. Immunol. 180, 2443–2449 (2008).

    Article  CAS  PubMed  Google Scholar 

  77. Pushparaj, P. N. et al. The cytokine interleukin-33 mediates anaphylactic shock. Proc. Natl Acad. Sci. USA 106, 9773–9778 (2009).

    Article  PubMed  Google Scholar 

  78. Matsuba-Kitamura, S. et al. Contribution of IL-33 to induction and augmentation of experimental allergic conjunctivitis. Int. Immunol. 22, 479–489 (2010).

    Article  CAS  PubMed  Google Scholar 

  79. Yin, H. et al. IL-33 prolongs murine cardiac allograft survival through induction of TH2-type immune deviation. Transplantation 89, 1189–1197 (2010).

    Article  CAS  PubMed  Google Scholar 

  80. Rankin, A. L. et al. IL-33 induces IL-13-dependent cutaneous fibrosis. J. Immunol. 184, 1526–1535 (2010).

    Article  CAS  PubMed  Google Scholar 

  81. Hazlett, L. D. et al. IL-33 shifts macrophage polarization, promoting resistance against Pseudomonas aeruginosa keratitis. Invest. Ophthalmol. Vis. Sci. 51, 1524–1532 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  82. 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).

    Article  CAS  PubMed  Google Scholar 

  83. Kondo, Y. et al. Administration of IL-33 induces airway hyperresponsiveness and goblet cell hyperplasia in the lungs in the absence of adaptive immune system. Int. Immunol. 20, 791–800 (2008).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  85. Verri, W. A. Jr. et al. IL-33 mediates antigen-induced cutaneous and articular hypernociception in mice. Proc. Natl Acad. Sci. USA 105, 2723–2728 (2008).

    Article  PubMed  Google Scholar 

  86. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  88. Masamune, A. et al. Nuclear expression of interleukin-33 in pancreatic stellate cells. Am. J. Physiol. Gastrointest. Liver Physiol. 299, G821–G832 (2010).

    Article  CAS  PubMed  Google Scholar 

  89. Lohning, M. et al. T1/ST2 is preferentially expressed on murine TH2 cells, independent of interleukin 4, interleukin 5, and interleukin 10, and important for TH2 effector function. Proc. Natl Acad. Sci. USA 95, 6930–6935 (1998).

    Article  CAS  PubMed  Google Scholar 

  90. Coyle, A. J. et al. Crucial role of the interleukin 1 receptor family member T1/ST2 in T helper cell type 2-mediated lung mucosal immune responses. J. Exp. Med. 190, 895–902 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Hoshino, K. et al. The absence of interleukin 1 receptor-related T1/ST2 does not affect T helper cell type 2 development and its effector function. J. Exp. Med. 190, 1541–1548 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Townsend, M. J., Fallon, P. G., Matthews, D. J., Jolin, H. E. & McKenzie, A. N. T1/ST2-deficient mice demonstrate the importance of T1/ST2 in developing primary T helper cell type 2 responses. J. Exp. Med. 191, 1069–1076 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Senn, K. A. et al. T1-deficient and T1-Fc-transgenic mice develop a normal protective TH2-type immune response following infection with Nippostrongylus brasiliensis. Eur. J. Immunol. 30, 1929–1938 (2000).

    Article  CAS  PubMed  Google Scholar 

  94. Mangan, N. E., Dasvarma, A., McKenzie, A. N. & Fallon, P. G. T1/ST2 expression on TH2 cells negatively regulates allergic pulmonary inflammation. Eur. J. Immunol. 37, 1302–1312 (2007).

    Article  CAS  PubMed  Google Scholar 

  95. Zhiguang, X. et al. Over-expression of IL-33 leads to spontaneous pulmonary inflammation in mIL-33 transgenic mice. Immunol. Lett. 131, 159–165 (2010).

    Article  CAS  PubMed  Google Scholar 

  96. Leung, B. P., Xu, D., Culshaw, S., McInnes, I. B. & Liew, F. Y. A novel therapy of murine collagen-induced arthritis with soluble T1/ST2. J. Immunol. 173, 145–150 (2004).

    Article  CAS  PubMed  Google Scholar 

  97. Saleh, H. et al. Interleukin-33, a target of parathyroid hormone and oncostatin M, increases osteoblastic matrix mineral deposition and inhibits osteoclast formation in vitro. Endocrinology doi:10.1210/en.2010–1268.

  98. Saidi, S. et al. IL-33 is expressed in human osteoblasts, but has no direct effect on bone remodeling. Cytokine 53, 347–354 (2011).

    Article  CAS  PubMed  Google Scholar 

  99. Jones, L. A. et al. IL-33 receptor (T1/ST2) signalling is necessary to prevent the development of encephalitis in mice infected with Toxoplasma gondii. Eur. J. Immunol. 40, 426–436 (2010).

    Article  CAS  PubMed  Google Scholar 

  100. Wieland, C. W., van der Windt, G. J., Florquin, S., McKenzie, A. N. & van der Poll, T. ST2 deficient mice display a normal host defense against pulmonary infection with Mycobacterium tuberculosis. Microbes Infect. 11, 524–530 (2009).

    Article  CAS  PubMed  Google Scholar 

  101. Alves-Filho, J. C. et al. Interleukin-33 attenuates sepsis by enhancing neutrophil influx to the site of infection. Nat. Med. 16, 708–712 (2010).

    Article  CAS  PubMed  Google Scholar 

  102. Choi, Y. S. et al. Interleukin-33 induces angiogenesis and vascular permeability through ST2/TRAF6-mediated endothelial nitric oxide production. Blood 114, 3117–3126 (2009).

    Article  CAS  PubMed  Google Scholar 

  103. Miller, A. M. et al. IL-33 reduces the development of atherosclerosis. J. Exp. Med. 205, 339–346 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. McLaren, J. E. et al. IL-33 reduces macrophage foam cell formation. J. Immunol. 185, 1222–1229 (2010).

    Article  CAS  PubMed  Google Scholar 

  105. Seki, K. et al. Interleukin-33 prevents apoptosis and improves survival after experimental myocardial infarction through ST2 signaling. Circ. Heart Fail. 2, 684–691 (2009).

    Article  CAS  PubMed  Google Scholar 

  106. Sakashita, M. et al. Association of serum interleukin-33 level and the interleukin-33 genetic variant with Japanese cedar pollinosis. Clin. Exp. Allergy 38, 1875–1881 (2008).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  108. Talabot-Ayer, D. et al. Distinct serum and synovial fluid interleukin (IL)-33 levels in rheumatoid arthritis, psoriatic arthritis and osteoarthritis. Joint Bone Spine doi:10.1016/j.jbspin.2011.02.011.

  109. Mok, M. Y. et al. Serum levels of IL-33 and soluble ST2 and their association with disease activity in systemic lupus erythematosus. Rheumatology (Oxford) 49, 520–527 (2010).

    Article  CAS  Google Scholar 

  110. Yang, Z., Liang, Y., Xi, W., Li, C. & Zhong, R. Association of increased serum IL-33 levels with clinical and laboratory characteristics of systemic lupus erythematosus in Chinese population. Clin. Exp. Med. doi:10.1007/s10238-010-0115–4.

  111. Manetti, M. et al. The IL1-like cytokine IL33 and its receptor ST2 are abnormally expressed in the affected skin and visceral organs of patients with systemic sclerosis. Ann. Rheum. Dis. 69, 598–605 (2010).

    Article  CAS  PubMed  Google Scholar 

  112. Sahlander, K., Larsson, K. & Palmberg, L. Increased serum levels of soluble ST2 in birch pollen atopics and individuals working in laboratory animal facilities. J. Occup. Environ. Med. 52, 214–218 (2010).

    Article  CAS  PubMed  Google Scholar 

  113. Oshikawa, K. et al. Elevated soluble ST2 protein levels in sera of patients with asthma with an acute exacerbation. Am. J. Respir. Crit. Care Med. 164, 277–281 (2001).

    Article  CAS  PubMed  Google Scholar 

  114. Brunner, M. et al. Increased levels of soluble ST2 protein and IgG1 production in patients with sepsis and trauma. Intensive Care Med. 30, 1468–1473 (2004).

    Article  PubMed  Google Scholar 

  115. Shimpo, M. et al. Serum levels of the interleukin-1 receptor family member ST2 predict mortality and clinical outcome in acute myocardial infarction. Circulation 109, 2186–2190 (2004).

    Article  CAS  PubMed  Google Scholar 

  116. Shah, R. V. & Januzzi, J. L. Jr. ST2: a novel remodeling biomarker in acute and chronic heart failure. Curr. Heart Fail. Rep. 7, 9–14 (2010).

    Article  CAS  PubMed  Google Scholar 

  117. Hoogerwerf, J. J. et al. Soluble ST2 plasma concentrations predict mortality in severe sepsis. Intensive Care Med. 36, 630–637 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Oppenheim, J. J. & Yang, D. Alarmins: chemotactic activators of immune responses. Curr. Opin. Immunol. 17, 359–365 (2005).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the Swiss National Science Foundation grants 320000-120319 (to G. Palmer) and 320000-119728 (to C. Gabay), the Rheumasearch Foundation, the de Reuter Foundation and the Institute of Arthritis Research.

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Authors and Affiliations

  1. Division of Rheumatology, University Hospitals of Geneva & Department of Pathology-Immunology, University of Geneva School of Medicine, 26 avenue Beau-Séjour, 1211, Geneva 14, Switzerland

    Gaby Palmer & Cem Gabay

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  1. Gaby Palmer
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  2. Cem Gabay
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G. Palmer and C. Gabay contributed equally to all aspects of the preparation of this manuscript.

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Correspondence to Cem Gabay.

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Palmer, G., Gabay, C. Interleukin-33 biology with potential insights into human diseases. Nat Rev Rheumatol 7, 321–329 (2011). https://doi.org/10.1038/nrrheum.2011.53

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