Immunologic Research

, Volume 52, Issue 1–2, pp 89–99

IL-33/ST2 axis in inflammation and immunopathology

  • Marija Milovanovic
  • Vladislav Volarevic
  • Gordana Radosavljevic
  • Ivan Jovanovic
  • Nada Pejnovic
  • Nebojsa Arsenijevic
  • Miodrag L. Lukic
Immunology in Serbia

Abstract

Interleukin-33 (IL-33), a member of the IL-1 family of cytokines, binds to its plasma membrane receptor, heterodimeric complex consisted of membrane-bound ST2L and IL-1R accessory protein, inducing NFkB and MAPK activation. IL-33 exists as a nuclear precursor and may act as an alarmin, when it is released after cell damage or as negative regulator of NFκB gene transcription, when acts in an intracrine manner. ST2L is expressed on several immune cells: Th2 lymphocytes, NK, NKT and mast cells and on cells of myeloid lineage: monocytes, dendritic cells and granulocytes. IL-33/ST2 axis can promote both Th1 and Th2 immune responses depending on the type of activated cell and microenvironment and cytokine network in damaged tissue. We previously described and discuss here the important role of IL-33/ST2 axis in experimental models of type 1 diabetes, experimental autoimmune encephalomyelitis, fulminant hepatitis and breast cancer. We found that ST2 deletion enhance the development of T cell-mediated autoimmune disorders, EAE and diabetes mellitus type I. Disease development was accompanied by dominantly Th1/Th17 immune response but also higher IL-33 production, which suggest that IL-33 in receptor independent manner could promote the development of inflammatory autoreactive T cells. IL-33/ST2 axis has protective role in Con A hepatitis. ST2-deficient mice had more severe hepatitis with higher influx of inflammatory cells in liver and dominant Th1/Th17 systemic response. Pretreatment of mice with IL-33 prevented Con A-induced liver damage through prevention of apoptosis of hepatocytes and Th2 amplification. Deletion of IL-33/ST2 axis enhances cytotoxicity of NK cells, production of IFN-γ in these cells and systemic production of IFN-γ, IL-17 and TNF-α, which leads to attenuated tumor growth. IL-33 treatment of tumor-bearing mice suppresses activity of NK cells, dendritic cell maturation and enhances alternative activation of macrophages. In conclusion, we observed that IL-33 has attenuated anti-inflammatory effects in T cell-mediated responses and that both IL-33 and ST2 could be further explored as potential therapeutic targets in treatment of immune-mediated diseases.

Keywords

IL-33/ST2 axis Con A hepatitis EAE MLD-STZ diabetes Mouse breast cancer 

References

  1. 1.
    Onda H, Kasuya H, Takakura K, Hori T, Imaizumi T, Takeuchi T, Inoue I, Takeda J. Identification of genes differentially expressed in canine vasospastic cerebral arteries after subarachnoid hemorrhage. J Cereb Blood Flow Metab. 1999;19(11):1279–88.PubMedCrossRefGoogle Scholar
  2. 2.
    Baekkevold ES, Roussigné M, Yamanaka T, Johansen FE, Jahnsen FL, Amalric F, Brandtzaeg P, Erard M, Haraldsen G, Girard JP. Molecular characterization of NF-HEV, a nuclear factor preferentially expressed in human high endothelial venules. Am J Pathol. 2003;163(1):69–79.PubMedCrossRefGoogle Scholar
  3. 3.
    Tominaga S, Jenkins NA, Gilbert DJ, Copeland NG, Tetsuka T. Molecular cloning of the murine ST2 gene: characterization and chromosomal mapping. Biochim Biophys Acta. 1991;1090:1–8.PubMedGoogle Scholar
  4. 4.
    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. 1994;13:1176–88.PubMedGoogle Scholar
  5. 5.
    Oshikawa K, Yanagisawa K, Tominaga S, Sugiyama Y. Expression and function of the ST2 gene in a murine model of allergic airway inflammation. Clin Exp Allergy. 2002;32(10):1520–6.PubMedCrossRefGoogle Scholar
  6. 6.
    Kuroiwa K, Arai T, Okazaki H, Minota S, Tominaga S. Identification of human ST2 protein in the sera of patients with autoimmune diseases. Biochem Biophys Res Commun. 2001;284(5):1104–8.PubMedCrossRefGoogle Scholar
  7. 7.
    Oshikawa K, Kuroiwa K, Tago K, Iwahana H, Yanagisawa K, Ohno S, Tominaga SI, Sugiyama Y. Elevated soluble ST2 protein levels in sera of patients with asthma with an acute exacerbation. Am J Respir Crit Care Med. 2001;164(2):277–81.PubMedGoogle Scholar
  8. 8.
    Tajima S, Oshikawa K, Tominaga S, Sugiyama Y. The increase in serum soluble ST2 protein upon acute exacerbation of idiopathic pulmonary fibrosis. Chest. 2003;124(4):1206–14.PubMedCrossRefGoogle Scholar
  9. 9.
    Weinberg EO, Shimpo M, Hurwitz S, Tominaga S, Rouleau JL, Lee RT. Identification of serum soluble ST2 receptor as a novel heart failure biomarker. Circulation. 2003;107(5):721–6.PubMedCrossRefGoogle Scholar
  10. 10.
    Xu D, Chan WL, Leung BP, Huang F, Wheeler R, Piedrafita D, Robinson JH, Liew FY. Selective expression of a stable cell surface molecule on type 2 but not type 1 helper T cells. J Exp Med. 1998;187(5):787–94.PubMedCrossRefGoogle Scholar
  11. 11.
    Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, Zurawski G, Moshrefi M, Qin J, Li X, Gorman DM, Bazan JF, Kastelein RA. 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. 2005;23(5):479–90.PubMedCrossRefGoogle Scholar
  12. 12.
    Palmer G, Lipsky BP, Smithgall MD, Meininger D, Siu S, Talabot-Ayer D, Gabay C, Smith DE. 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. 2008;42(3):358–64.PubMedCrossRefGoogle Scholar
  13. 13.
    Bulek K, Swaidani S, Qin J, Lu Y, Gulen MF, Herjan T, Min B, Kastelein RA, Aronica M, Kosz-Vnenchak M, Li X. The essential role of single Ig IL-1 receptor-related molecule/Toll IL-1R8 in regulation of Th2 immune response. J Immunol. 2009;182(5):2601–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Pushparaj PN, Tay HK, H’ng SC, Pitman N, Xu D, McKenzie A, Liew FY, Melendez AJ. The cytokine interleukin-33 mediates anaphylactic shock. Proc Natl Acad Sci USA. 2009;106(24):9773–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Allakhverdi Z, Smith DE, Comeau MR, Delespesse G. Cutting edge: The ST2 ligand IL-33 potently activates and drives maturation of human mast cells. J Immunol. 2007;179(4):2051–4.PubMedGoogle Scholar
  16. 16.
    Moulin D, Donzé O, Talabot-Ayer D, Mézin F, Palmer G, Gabay C. Interleukin (IL)-33 induces the release of pro-inflammatory mediators by mast cells. Cytokine. 2007;40(3):216–25.PubMedCrossRefGoogle Scholar
  17. 17.
    Moussion C, Ortega N, Girard JP. 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. 2008;3(10):e3331.PubMedCrossRefGoogle Scholar
  18. 18.
    Ohno T, Oboki K, Morita H, Kajiwara N, Arae K, Tanaka S, Ikeda M, Iikura M, Akiyama T, Inoue J, Matsumoto K, Sudo K, Azuma M, Okumura K, Kamradt T, Saito H, Nakae S. Paracrine IL-33 stimulation enhances lipopolysaccharide-mediated macrophage activation. PLoS ONE. 2011;6(4):e18404.PubMedCrossRefGoogle Scholar
  19. 19.
    Liu J, Buckley JM, Redmond HP, Wang JH. ST2 negatively regulates TLR2 signaling, but is not required for bacterial lipoprotein-induced tolerance. J Immunol. 2010;184(10):5802–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Sweet MJ, Leung BP, Kang D, Sogaard M, Schulz K, Trajkovic V, Campbell CC, Xu D, Liew FY. A novel pathway regulating lipopolysaccharide-induced shock by ST2/T1 via inhibition of Toll-like receptor 4 expression. J Immunol. 2001;166:6633–9.PubMedGoogle Scholar
  21. 21.
    Kumar S, Tzimas MN, Griswold DE, Young PR. Expression of ST2, an interleukin-1 receptor homologue, is induced by proinflammatory stimuli. Biochem Biophys Res Commun. 1997;235(3):474–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Talabot-Ayer D, Lamacchia C, Gabay C, Palmer G. Interleukin-33 is biologically active independently of caspase-1 cleavage. J Biol Chem. 2009;284(29):19420–6.PubMedCrossRefGoogle Scholar
  23. 23.
    Lüthi AU, Cullen SP, McNeela EA, Duriez PJ, Afonina IS, Sheridan C, Brumatti G, Taylor RC, Kersse K, Vandenabeele P, Lavelle EC, Martin SJ. Suppression of interleukin-33 bioactivity through proteolysis by apoptotic caspases. Immunity. 2009;31(1):84–98.PubMedCrossRefGoogle Scholar
  24. 24.
    Ali S, Nguyen DQ, Falk W, Martin MU. Caspase 3 inactivates biologically active full length interleukin-33 as a classical cytokine but does not prohibit nuclear translocation. Biochem Biophys Res Commun. 2010;391(3):1512–6.PubMedCrossRefGoogle Scholar
  25. 25.
    Zhao W, Hu Z. The enigmatic processing and secretion of interleukin-33. Cell Mol Immunol. 2010;7(4):260–2.PubMedCrossRefGoogle Scholar
  26. 26.
    Haraldsen G, Balogh J, Pollheimer J, Sponheim J, Küchler AM. Interleukin-33 - cytokine of dual function or novel alarmin? Trends Immunol. 2009;30(5):227–33.PubMedCrossRefGoogle Scholar
  27. 27.
    Carriere V, Roussel L, Ortega N, Lacorre DA, Americh L, Aguilar L, Bouche G, Girard JP. IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo. Proc Natl Acad Sci USA. 2007;104(1):282–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Ali S, Mohs A, Thomas M, Klare J, Ross R, Schmitz ML, Martin MU. The dual function cytokine IL-33 interacts with the transcription factor NF-κB to dampen NF-κB-stimulated gene transcription. J Immunol. 2011;187(4):1609–16.PubMedCrossRefGoogle Scholar
  29. 29.
    Enoksson M, Lyberg K, Möller-Westerberg C, Fallon PG, Nilsson G, Lunderius-Andersson C. Mast cells as sensors of cell injury through IL-33 recognition. J Immunol. 2011;186(4):2523–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Komai-Koma M, Xu D, Li Y, McKenzie AN, McInnes IB, Liew FY. IL-33 is a chemoattractant for human Th2 cells. Eur J Immunol. 2007;37(10):2779–86.PubMedCrossRefGoogle Scholar
  31. 31.
    Smithgall MD, Comeau MR, Yoon BR, Kaufman D, Armitage R, Smith DE. 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. 2008;20(8):1019–30.PubMedCrossRefGoogle Scholar
  32. 32.
    Bourgeois E, Van LP, Samson M, Diem S, Barra A, Roga S, Gombert JM, Schneider E, Dy M, Gourdy P, Girard JP, Herbelin A. The pro-Th2 cytokine IL-33 directly interacts with invariant NKT and NK cells to induce IFN-gamma production. Eur J Immunol. 2009;39(4):1046–55.PubMedCrossRefGoogle Scholar
  33. 33.
    Kurowska-Stolarska M, Stolarski B, Kewin P, Murphy G, Corrigan CJ, Ying S, et al. IL-33 amplifies the polarization of alternatively activated macrophages that contribute to airway inflammation. J Immunol. 2009;183:6469–77.PubMedCrossRefGoogle Scholar
  34. 34.
    Rank MA, Kobayashi T, Kozaki H, Bartemes KR, Squillace DL, Kita H. IL-33-activated dendritic cells induce an atypical TH2-type response. J Allergy Clin Immunol. 2009;123(5):1047–54.PubMedCrossRefGoogle Scholar
  35. 35.
    Yang Q, Li G, Zhu Y, Liu L, Chen E, Turnquist H, Zhang X, Finn OJ, Chen X, Lu B. IL-33 synergizes with TCR and IL-12 signaling to promote the effector function of CD8(+) T cells. Eur J Immunol. 2011;41(11):3351–60.PubMedCrossRefGoogle Scholar
  36. 36.
    Miller AM, et al. IL-33 reduces the development of atherosclerosis. J Exp Med. 2008;205:339–46.PubMedCrossRefGoogle Scholar
  37. 37.
    Humphreys NE, Xu D, Hepworth MR, Liew FY, Grencis RK. IL-33, a potent inducer of adaptive immunity to intestinal nematodes. J Immunol. 2008;180(4):2443–9.PubMedGoogle Scholar
  38. 38.
    Jones LA, Roberts F, Nickdel MB, Brombacher F, McKenzie AN, Henriquez FL, Alexander J, Roberts CW. IL-33 receptor (T1/ST2) signalling is necessary to prevent the development of encephalitis in mice infected with Toxoplasma gondii. Eur J Immunol. 2010;40(2):426–36.PubMedCrossRefGoogle Scholar
  39. 39.
    Becerra A, Warke RV, de Bosch N, Rothman AL, Bosch I. Elevated levels of soluble ST2 protein in dengue virus infected patients. Cytokine. 2008;41(2):114–20.PubMedCrossRefGoogle Scholar
  40. 40.
    Hudson CA, Christophi GP, Gruber RC, Wilmore JR, Lawrence DA, Massa PT. Induction of IL-33 expression and activity in central nervous system glia. J Leukoc Biol. 2008;84(3):631–43.PubMedCrossRefGoogle Scholar
  41. 41.
    Roth GA, Zimmermann M, Lubsczyk BA, Pilz J, Faybik P, Hetz H, Hacker S, Mangold A, Bacher A, Krenn CG, Ankersmit HJ. Up-regulation of interleukin 33 and soluble ST2 serum levels in liver failure. J Surg Res. 2010;163(2):79–83.CrossRefGoogle Scholar
  42. 42.
    Xiao X, Zhao P, Rodriguez-Pinto D, Qi D, Henegariu O, Alexopoulou L, Flavell A, Wong S, Wen L. Inflammatory regulation by TLR3 in acute hepatitis. J Immunol. 2009;183:3712–9.PubMedCrossRefGoogle Scholar
  43. 43.
    Itoh A, Isoda K, Kondoh M, Kawase M, Kobayashi M, Tamesada M, Yagi K. Hepatoprotective effect of syringic acid and vanillic acid on concanavalin a-induced liver injury. Biol Pharm Bull. 2009;32:1215–9.PubMedCrossRefGoogle Scholar
  44. 44.
    Wolf AM, Wolf D, Avila MA, Moschen AR, Berasain C, Enrich B, Rumpold H, Tilg H. Up-regulation of the anti-inflammatory adipokine adiponectin in acute liver failure in mice. J Hepatol. 2006;44:537–43.PubMedCrossRefGoogle Scholar
  45. 45.
    Hanson JC, Bostick MK, Campe CB, Kodali P, Lee G, Yan J, Maher JJ. Transgenic overexpression of interleukin-8 in mouse liver protects against galactosamine/endotoxin toxicity. J Hepatol. 2006;44:359–567.PubMedCrossRefGoogle Scholar
  46. 46.
    Tiegs G, Hentschel J, Wendel A. A T cell-dependent experimental liver injury in mice inducible by concanavalin A. J Clin Invest. 1992;90:196–203.PubMedCrossRefGoogle Scholar
  47. 47.
    Volarevic V, Mitrovic M, Milovanovic M, Zelen I, Nikolic I, Mitrovic S, Pejnovic N, Arsenijevic N, Lukic ML. Protective role of IL-33/ST2 axis in Con A-induced hepatitis. J Hepatol. 2012;56(1):26–33.Google Scholar
  48. 48.
    Erhardt A, Biburger M, Papadopoulos T, Tiegs G. IL-10, regulatory T cells, and Kupffer cells mediate tolerance in concanavalin A-induced liver injury in mice. Hepatology. 2007;45(2):475–85.PubMedCrossRefGoogle Scholar
  49. 49.
    Wei HX, Chuang YH, Li B, Wei H, Sun R, Moritoki Y, Gershwin ME, Lian ZX, Tian Z. CD4 + CD25 + Foxp3 + regulatory T cells protect against T cell-mediated fulminant hepatitis in a TGF-beta-dependent manner in mice. J Immunol. 2008;181(10):7221–9.PubMedGoogle Scholar
  50. 50.
    Nagata T, Mckinley L, Peschon J, Alcorn J, Aujla S, Kolls J. Requirement of IL-17RA in Con A induced hepatitis and negative regulation of IL-17 production in mouse T cells. J Immunol. 2008;181:7473–9.PubMedGoogle Scholar
  51. 51.
    Suzuki M, Maghni K, Molet S, Shimbara A, Hamid QA, Martin JG. IFN-gamma secretion by CD8T cells inhibits allergen-induced airway eosinophilia but not late airway responses. J Allergy Clin Immunol. 2002;109:803–9.PubMedCrossRefGoogle Scholar
  52. 52.
    Dong Z, Wei H, Sun R, Tian Z. The roles of innate immune cells in liver injury and regeneration. Cell Mol Immunol. 2007;4:241–52.PubMedGoogle Scholar
  53. 53.
    Takeda K, Hayakawa Y, Van Kaer L, Matsuda H, Yagita H, Okumura K. Critical contribution of liver natural killer T cells to a murine model of hepatitis. Proc Natl Acad Sci USA. 2000;97:5498–503.PubMedCrossRefGoogle Scholar
  54. 54.
    Küsters S, Gantner F, Kunstle G, Tiegs G. Interferon gamma plays a critical role in T cell dependent liver injury in mice initiated by concanavalin A. Gastroenterology. 1996;111:462–71.PubMedCrossRefGoogle Scholar
  55. 55.
    Robinson R, Wang J, Cripps J, Milks M, English K, Pearson T, Gorham J. End-organ damage in a mouse model of fulminant liver inflammation requires CD4 + T cell production of IFN-γ but is independent of Fas. J Immunol. 2009;182:3278–84.PubMedCrossRefGoogle Scholar
  56. 56.
    Tagawa Y, Sekikawa K, Iwakura Y. Suppression of concanavalin A-induced hepatitis in IFN-γ −/− mice, but not in TNF-α −/− mice: role for IFN-γ in activating apoptosis of hepatocytes. J Immunol. 1997;159:1418–28.PubMedGoogle Scholar
  57. 57.
    Zenewicz LA, Yancopoulos GD, Valenzuela DM, Murphy A, Karow M, Flavell RA. Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation. Immunity. 2007;27:647–59.PubMedCrossRefGoogle Scholar
  58. 58.
    Wondimu Z, Santodomingo-Garzon T, Le T, Swain MG. Protective role of interleukin-17 in murine NKT cell-driven acute experimental hepatitis. Am J Pathol. 2010;177:2334–46.PubMedCrossRefGoogle Scholar
  59. 59.
    Xu M, Morishima N, Mizoguchi I, Chiba Y, Fujita K, Kuroda M, Iwakura Y, Cua DJ, Yasutomo K, Mizuguchi J, Yoshimoto T. Regulation of the development of acute hepatitis by IL-23 through IL-22 and IL-17 production. Eur J Immunol. 2011;41(10):2828–39.PubMedCrossRefGoogle Scholar
  60. 60.
    Erhardt A, Tiegs G. IL-33—a cytokine which balances on a knife’s edge? J Hepatol. 2012;56(1):7–10.Google Scholar
  61. 61.
    Liew FY, Pitman NI, McInnes IB. Disease-associated functions of IL-33: the new kid in the IL-1 family. Nat Rev Immunol. 2010;10(2):103–10.PubMedCrossRefGoogle Scholar
  62. 62.
    Oboki K, Nakae S, Matsumoto K, Saito H. IL-33 and airway inflammation. Allergy Asthma Immunol Res. 2011;3(2):81–8.PubMedCrossRefGoogle Scholar
  63. 63.
    Préfontaine D, Lajoie-Kadoch S, Foley S, Audusseau S, Olivenstein R, Halayko AJ, Lemière C, Martin JG, Hamid Q. Increased expression of IL-33 in severe asthma: evidence of expression by airway smooth muscle cells. J Immunol. 2009;183(8):5094–103.PubMedCrossRefGoogle Scholar
  64. 64.
    Kearley J, Buckland KF, Mathie SA, Lloyd CM. Resolution of allergic inflammation and airway hyperreactivity is dependent upon disruption of the T1/ST2-IL-33 pathway. Am J Respir Crit Care Med. 2009;179(9):772–81.PubMedCrossRefGoogle Scholar
  65. 65.
    Hayakawa H, Hayakawa M, Kume A, Tominaga S. Soluble ST2 blocks interleukin-33 signaling in allergic airway inflammation. J Biol Chem. 2007;282:26369–80.PubMedCrossRefGoogle Scholar
  66. 66.
    Préfontaine D, Nadigel J, Chouiali F, Audusseau S, Semlali A, Chakir J, Martin JG, Hamid Q. Increased IL-33 expression by epithelial cells in bronchial asthma. J Allergy Clin Immunol. 2010;125(3):752–4.PubMedCrossRefGoogle Scholar
  67. 67.
    Kondo Y, Yoshimoto T, Yasuda K, Futatsugi-Yumikura S, Morimoto M, Hayashi N, Hoshino T, Fujimoto J, Nakanishi K. Administration of IL-33 induces airway hyperresponsiveness and goblet cell hyperplasia in the lungs in the absence of adaptive immune system. Int Immunol. 2008;20(6):791–800.PubMedCrossRefGoogle Scholar
  68. 68.
    Stolarski B, Kurowska-Stolarska M, Kewin P, Xu D, Liew FY. IL-33 exacerbates eosinophil-mediated airway inflammation. J Immunol. 2010;185(6):3472–80.PubMedCrossRefGoogle Scholar
  69. 69.
    Zhiguang X, Wei C, Steven R, Wei D, Wei Z, Rong M, Zhanguo L, Lianfeng Z. Over-expression of IL-33 leads to spontaneous pulmonary inflammation in mIL-33 transgenic mice. Immunol Lett. 2010;131(2):159–65.PubMedCrossRefGoogle Scholar
  70. 70.
    Besnard AG, Togbe D, Guillou N, Erard F, Quesniaux V, Ryffel B. IL-33-activated dendritic cells are critical for allergic airway inflammation. Eur J Immunol. 2011;41(6):1675–86.PubMedCrossRefGoogle Scholar
  71. 71.
    Oboki K, Ohno T, Kajiwara N, Arae K, Morita H, Ishii A, Nambu A, Abe T, Kiyonari H, Matsumoto K, Sudo K, Okumura K, Saito H, Nakae S. IL-33 is a crucial amplifier of innate rather than acquired immunity. Proc Natl Acad Sci USA. 2010;107(43):18581–6.PubMedCrossRefGoogle Scholar
  72. 72.
    Coyle AJ, Lloyd C, Tian J, Nguyen T, Erikkson C, Wang L, Ottoson P, Persson P, Delaney T, Lehar S, Lin S, Poisson L, Meisel C, Kamradt T, Bjerke T, Levinson D, Gutierrez-Ramos JC. 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. 1999;190(7):895–902.PubMedCrossRefGoogle Scholar
  73. 73.
    Kurowska-Stolarska M, Kewin P, Murphy G, Russo RC, Stolarski B, Garcia CC, Komai-Koma M, Pitman N, Li Y, Niedbala W, McKenzie AN, Teixeira MM, Liew FY, Xu D. IL-33 induces antigen-specific IL-5 + T cells and promotes allergic-induced airway inflammation independent of IL-4. J Immunol. 2008;181(7):4780–90.PubMedGoogle Scholar
  74. 74.
    Mangan NE, Dasvarma A, McKenzie AN, Fallon PG. T1/ST2 expression on Th2 cells negatively regulates allergic pulmonary inflammation. Eur J Immunol. 2007;37(5):1302–12.PubMedCrossRefGoogle Scholar
  75. 75.
    Wesche H, Korherr C, Kracht M, Falk W, Resch K, Martin MU. The interleukin-1 receptor accessory protein (IL-1RAcP) is essential for IL-1-induced activation of interleukin-1 receptor-associated kinase (IRAK) and stress-activated protein kinases (SAP kinases). J Biol Chem. 1997;272(12):7727–31.PubMedCrossRefGoogle Scholar
  76. 76.
    Zdravkovic N, Shahin A, Arsenijevic N, Lukic ML, Mensah-Brown EP. Regulatory T cells and ST2 signaling control diabetes induction with multiple low doses of streptozotocin. Mol Immunol. 2009;47(1):28–36.PubMedCrossRefGoogle Scholar
  77. 77.
    Jiang HR, Al Rasebi Z, Mensah-Brown E, et al. Galectin-3 deficiency reduces the severity of experimental autoimmune encephalomyelitis. J Immunol. 2009;182(2):1167–73.PubMedGoogle Scholar
  78. 78.
    Nakano H, Lin KL, Yanagita M, Charbonneau C, Cook DN, Kakiuchi T, Gunn MD. Blood-derived inflammatory dendritic cells in lymph nodes stimulate acute T helper type 1 immune responses. Nat Immunol. 2009;10(4):394–402.PubMedCrossRefGoogle Scholar
  79. 79.
    Vinay DS, Kim CH, Choi BK, Kwon BS. Origins and functional basis of regulatory CD11c + CD8 + T cells. Eur J Immunol. 2009;39(6):1552–63.PubMedCrossRefGoogle Scholar
  80. 80.
    Jovanovic I, Radosavljevic G, Mitrovic M, Juranic VL, McKenzie AN, Arsenijevic N, Jonjic S, Lukic ML. ST2 deletion enhances innate and acquired immunity to murine mammary carcinoma. Eur J Immunol. 2011;41(7):1902–12.PubMedCrossRefGoogle Scholar
  81. 81.
    Foti M, Granucci F, Ricciardi-Castagnoli P. A central role for tissue-resident dendritic cells in innate responses. Trends Immunol. 2004;25(12):650–4.PubMedCrossRefGoogle Scholar
  82. 82.
    Mayuzumi N, Matsushima H, Takashima A. IL-33 promotes DC development in BM culture by triggering GM-CSF production. Eur J Immunol. 2009;39(12):3331–42.PubMedCrossRefGoogle Scholar
  83. 83.
    Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23:549–55.PubMedCrossRefGoogle Scholar
  84. 84.
    Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol. 2005;5:953–64.PubMedCrossRefGoogle Scholar
  85. 85.
    Mantovani A, Sica A, Locati M. Macrophage polarization comes of age. Immunity. 2005;23:344–6.PubMedCrossRefGoogle Scholar
  86. 86.
    Martinez FO, Helming L, Gordon S. Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol. 2009;27:451–83.PubMedCrossRefGoogle Scholar
  87. 87.
    Verreck FA, de Boer T, Langenberg DM, Hoeve MA, Kramer M, Vaisberg E, Kastelein R, Kolk A, de Waal-Malefyt R, Ottenhoff TH. Human IL-23-producing type 1 macrophages promote but IL-10-producing type 2 macrophages subvert immunity to (myco)bacteria. Proc Natl Acad Sci USA. 2004;101:4560–5.PubMedCrossRefGoogle Scholar
  88. 88.
    Mantovani A, Sica A, Locati M. New vistas on macrophage differentiation and activation. Eur J Immunol. 2007;37:14–6.PubMedCrossRefGoogle Scholar
  89. 89.
    Solinas G, Germano G, Mantovani A, Allavena P. Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J Leukoc Biol. 2009;86:1065–73.PubMedCrossRefGoogle Scholar
  90. 90.
    Stout RD, Watkins SK, Suttles J. Functional plasticity of macrophages: in situ reprogramming of tumor-associated macrophages. J Leukoc Biol. 2009;86:1105–9.PubMedCrossRefGoogle Scholar
  91. 91.
    Pollard JW. Trophic macrophages in development and disease. Nat Rev Immunol. 2009;9:259–70.PubMedCrossRefGoogle Scholar
  92. 92.
    Mantovani A, Allavena P, Sica A. Tumor-associated macrophages as a prototypic type II polarized phagocyte population: role in tumor progression. Eur J Cancer. 2004;40:1660–7.PubMedCrossRefGoogle Scholar
  93. 93.
    Jovanovic I, Pejnovic N, Radosavljevic G, Arsenijevic N, Lukic ML. IL-33/ST2 Axis in innate and acquired immunity to tumors. Oncoimmunology. 2012;1:229–31.Google Scholar
  94. 94.
    Palmer G, Talabot-Ayer D, Lamacchia C, Toy D, Seemayer CA, Viatte S, Finckh A, Smith DE, Gabay C. Inhibition of interleukin-33 signaling attenuates the severity of experimental arthritis. Arthritis Rheum. 2009;60(3):738–49.PubMedCrossRefGoogle Scholar
  95. 95.
    Ohto-Ozaki H, Kuroiwa K, Mato N, Matsuyama Y, Hayakawa M, Tamemoto H, Tominaga S. Characterization of ST2 transgenic mice with resistance to IL-33. Eur J Immunol. 2010;40(9):2632–42.PubMedCrossRefGoogle Scholar
  96. 96.
    Pastorelli L, Garg RR, Hoang SB, Spina L, Mattioli B, Scarpa M, Fiocchi C, Vecchi M, Pizarro TT. 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. 2010;107(17):8017–22.PubMedCrossRefGoogle Scholar
  97. 97.
    Yin H, Li XY, Yuan BH, Zhang BB, Hu SL, Gu HB, Jin XB, Zhu JY. Adenovirus-mediated overexpression of soluble ST2 provides a protective effect on lipopolysaccharide-induced acute lung injury in mice. Clin Exp Immunol. 2011;164(2):248–55.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Marija Milovanovic
    • 1
  • Vladislav Volarevic
    • 1
  • Gordana Radosavljevic
    • 1
  • Ivan Jovanovic
    • 1
  • Nada Pejnovic
    • 1
  • Nebojsa Arsenijevic
    • 1
  • Miodrag L. Lukic
    • 1
  1. 1.Faculty of Medicine, Center for Molecular Medicine and Stem Cell ResearchUniversity of KragujevacKragujevacSerbia

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