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Interleukin-33: increasing role in dermatological conditions

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Abstract

Interleukin-33 is a novel and an unconventional member of IL-1 family. It is an inflammation-induced factor with dual function exercising its role as an intracellular regulator of gene expression, as well as, an extracellular alarm mediator. It is a ligand for ST2, a heterodimeric membrane-bound receptor of the orphan IL-1 family receptor. Interleukin-33/ST2 signaling has been studied in a wide range of inflammatory skin conditions for its crucial role in immune responses and tissue homeostasis. In this review, we report the current knowledge regarding the complex biology of interleukin-33 and its function in the skin and in clinical settings.

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References

  1. Ali S, Mohs A, Thomas M (2011) The dual function cytokine IL-33 interacts with the transcription factor NF-κB to dampen NF-κB-stimulated gene transcription. J Immunol 187:1609–1616

    Article  CAS  PubMed  Google Scholar 

  2. Bae S, Kang T, Hong J et al (2012) Contradictory functions (activation/termination) of neutrophil proteinase 3 enzyme (PR3) in interleukin-33 biological activity. J Biol Chem 287:8205–8213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Baekkevold ES, Roussigne M, Yamanaka T et al (2003) Molecular characterization of NF-HEV, a nuclear factor preferentially expressed in human high endothelial venules. Am J Pathol 163:69–79

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Balato A, Lembo S, Mattii M et al (2012) IL-33 is secreted by psoriatic keratinocytes and induces pro-inflammatory cytokines via keratinocyte and mast cell activation. Exp Dermatol 21:892–894

    Article  CAS  PubMed  Google Scholar 

  5. Balato A, Di Caprio R, Canta L et al (2014) IL-33 is regulated by TNF-α in normal and psoriatic skin. Arch Dermatol Res 306:299–304

    Article  CAS  PubMed  Google Scholar 

  6. Batista MD, Ho EL, Kuebler PJ et al (2013) Skewed distribution of natural killer cells in psoriasis skin lesions. Exp Dermatol 22:64–66

    Article  PubMed  PubMed Central  Google Scholar 

  7. Bourgeois E, Van LP, Samson M et al (2009) The pro-Th2 cytokine IL-33 directly interacts with invariant NKT and NK cells to induce IFN-gamma production. Eur J Immunol 39:1046–1055

    Article  CAS  PubMed  Google Scholar 

  8. Bulek K, Swaidani S, Qin J et al (2011) 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

    Article  Google Scholar 

  9. Byrne SN, Beaugie C, O’Sullivan C et al (2011) The immune-modulating cytokine and endogenous alarmin interleukin-33 is upregulated in skin exposed to inflammatory UVB radiation. Am J Pathol 179:211–222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Carmi-Levy I, Homey B, Soumelis V (2011) A modular view of cytokine networks in atopic dermatitis. Clin Rev Allergy Immunol 41:245–253

    Article  CAS  PubMed  Google Scholar 

  11. Carriere V, Roussel L, Ortega N et al (2007) 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

    Article  CAS  PubMed  Google Scholar 

  12. Cevikbas F, Steinhoff M (2012) IL-33: a novel danger signal system in atopic dermatitis. J Invest Dermatol 132:1326–1329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Chan WL, Pejnovic N, Lee CA et al (2001) Human IL-18 receptor and ST2L are stable and selective markers for the respective type 1 and type 2 circulating lymphocytes. J Immunol 167:1238–1244

    Article  CAS  PubMed  Google Scholar 

  14. Choi YS, Park JA, Kim J et al (2012) Nuclear IL-33 is a transcriptional regulator of NF-κB p65 and induces endothelial cell activation. Biochem Biophys Res Commun 421:305–311

    Article  CAS  PubMed  Google Scholar 

  15. Dinarello CA (2009) Immunological and inflammatory functions of the interleukin-1 family. Annu Rev Immunol 27:519–550

    Article  CAS  PubMed  Google Scholar 

  16. Dinarello CA, Simon A, van der Meer JW (2012) Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nature Rev Drug Discov 11:633–652

    Article  CAS  Google Scholar 

  17. Espinassous Q, Garcia-de-Paco E, Garcia-Verdugo I et al (2009) IL-33 enhances lipopolysaccharide-induced inflammatory cytokine production from mouse macrophages by regulating lipopolysaccharide receptor complex. J Immunol 183:1446–1455

    Article  CAS  PubMed  Google Scholar 

  18. Garlanda C, Riva F, Polentarutti N et al (2004) Intestinal inflammation in mice deficient in Tir8, an inhibitory member of the IL-1 receptor family. Proc Natl Acad Sci USA 101:3522–3526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Garlanda C, Anders HJ, Mantovani A (2009) TIR8_SIGIRR: an IL-1R_TLR family member with regulatory functions in inflammation and T cell polarization. Trends Immunol 30:439–446

    Article  CAS  PubMed  Google Scholar 

  20. Garlanda C, Dinarello CA, Mantovani A (2013) The interleukin-1 family: back to the future. Immunity 39:1003–1018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Greaves M (2000) Chronic urticaria. J Allergy Clin Immunol 105:664–672

    Article  CAS  PubMed  Google Scholar 

  22. Guarneri F, Minciullo PL, Mannucci C et al (2015) IL-31 and IL-33 circulating levels in allergic contact dermatitis. Eur Ann Allergy Clin Immunol 47:156–158

    CAS  PubMed  Google Scholar 

  23. Guo L, Wei G, Zhu J et al (2009) IL-1 family members and STAT activators induce cytokine production by Th2, Th17, and Th1 cells. Proc Natl Acad Sci USA 106:13463–13468

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Homey B, Steinhoff M, Ruzicka T, Leung DY (2006) Cytokines and chemokines orchestrate atopic skin inflammation. J Allergy Clin Immunol 118:178–189

    Article  CAS  PubMed  Google Scholar 

  25. Hueber AJ, Alves-Filho JC, Asquith DL et al (2011) IL-33 induces skin inflammation with mast cell and neutrophil activation. Eur J Immunol 41:2229–2237

    Article  CAS  PubMed  Google Scholar 

  26. Imai Y, Yasuda K, Sakaguchi Y et al (2013) Skin-specific expression of IL-33 activates group 2 innate lymphoid cells and elicits atopic dermatitis-like inflammation in mice. Proc Natl Acad Sci USA 110:13921–13926

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Iwahana H, Yanagisawa K, Ito-Kosaka A et al (1999) Different promoter usage and multiple transcription initiation sites of the interleukin-1 receptor-related human ST2 gene in UT-7 and TM12 cells. Eur J Biochem 264:397–406

    Article  CAS  PubMed  Google Scholar 

  28. Kakinuma T, Wakugawa M, Nakamura K et al (2003) High level of thymus and activation-regulated chemokine in blister fluid and sera of patients with bullous pemphigoid. Br J Dermatol 148:203–210

    Article  CAS  PubMed  Google Scholar 

  29. Kakkar R, Hei H, Dobner S, Lee RT (2012) Interleukin 33 as a mechanically responsive cytokine secreted by living cells. J Biol Chem 287:6941–6948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kasperkiewicz M, Zillikens D (2007) The pathophysiology of bullous pemphigoid. Clin Rev Allergy Immunol 33:67–77

    Article  CAS  PubMed  Google Scholar 

  31. Kay AB, Clark P, Maurer M et al (2015) Elevations in T-helper-2-initiating cytokines (interleukin-33, interleukin-25 and thymic stromal lymphopoietin) in lesional skin from chronic spontaneous (‘idiopathic’) urticaria. Br J Dermatol 172:1294–1302

    Article  CAS  PubMed  Google Scholar 

  32. Komai-Koma M, Gilchrist DS, McKenzie ANJ et al (2011) IL-33 activates B1 cells and exacerbates contact sensitivity. J Immunol 186:2584–2591

    Article  CAS  PubMed  Google Scholar 

  33. Kondo Y, Yoshimoto T, Yasuda K et al (2008) 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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  35. Langley NJ (1906) On nerve endings and on special excitable substances in cells. Proc R Soc Lond Ser B 78:170

    Article  CAS  Google Scholar 

  36. Lefrancais E, Roga S, Gautier V et al (2012) IL-33 is processed into mature bioactive forms by neutrophil elastase and cathepsin G. Proc Natl Acad Sci USA 109:1673–1678

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Li P, Ma H, Han D, Mou K (2015) Interleukin-33 affects cytokine production by keratinocytes in Vitiligo. Clin Exp Dermatol 40:163–170

    Article  CAS  PubMed  Google Scholar 

  38. Liu Q, Turnquist HR (2013) Implications for Interleukin-33 in solid organ transplantation. Cytokine 62:183–194

    Article  PubMed  PubMed Central  Google Scholar 

  39. Lowes MA, Kikuchi T, Fuentes-Duculan J et al (2008) Psoriasis vulgaris lesions contain discrete populations of Th1 and Th17 T cells. J Invest Dermatol 128:1207–1211

    Article  CAS  PubMed  Google Scholar 

  40. Luthi AU, Cullen SP, McNeela EA et al (2009) Suppression of interleukin-33 bioactivity through proteolysis by apoptotic caspases. Immunity 31:84–98

    Article  CAS  PubMed  Google Scholar 

  41. Manetti M, Ibba-Manneschi L, Liakouli V et al (2010) 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

    Article  CAS  PubMed  Google Scholar 

  42. Manetti M, Guiducci S, Ceccarelli C et al (2011) Increased circulating levels of interleukin 33 in systemic sclerosis correlate with early disease stage and microvascular involvement. Ann Rheum Dis 70:1876–1878

    Article  CAS  PubMed  Google Scholar 

  43. Mantovani A, Sica A, Sozzani S et al (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25:677–686

    Article  CAS  PubMed  Google Scholar 

  44. Mattii M, Ayala F, Balato N et al (2013) The balance between pro- and anti-inflammatory cytokines is crucial in human allergic contact dermatitis pathogenesis: the role of IL-1 family members. Exp Dermatol 22:813–819

    Article  CAS  PubMed  Google Scholar 

  45. Mayuzumi N, Matsushima H, Takashima A (2009) IL-33 promotes DC development in BM culture by triggering GMCSF production. Eur J Immunol 39:3331–3342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. McGuirk P, McCann C, Mills KH (2002) Pathogen-specific T regulatory 1 cells induced in the respiratory tract by a bacterial molecule that stimulates interleukin 10 production by dendritic cells: a novel strategy for evasion of protective T helper type 1 responses by Bordetella pertussis. J Exp Med 195:221–231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Meephansan J, Tsuda H, Komine M et al (2012) Regulation of IL-33 expression by IFN-γ and tumor necrosis factor-α in normal human epidermal keratinocytes. J Invest Dermatol 132:2593–2600

    Article  CAS  PubMed  Google Scholar 

  48. Meephansan J, Komine M, Tsuda H et al (2013) Expression of IL-33 in the epidermis: the mechanism of induction by IL-17. J Dermatol Sci 71:107–114

    Article  CAS  PubMed  Google Scholar 

  49. Miniati A, Weng Z, Zhang B et al (2012) Neuro-immuno-endocrine processes in vitiligo pathogenesis. Int J Immunopathol Pharmacol 25:1–7

    CAS  PubMed  Google Scholar 

  50. Mitsui A, Tada Y, Takahashi T et al (2015) Serum IL-33 levels are increased in patients with psoriasis. Clin Exp Dermatol (epub ahead of print)

  51. Moussion C, Ortega N, Girard JP (2008) 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

    Article  PubMed  PubMed Central  Google Scholar 

  52. O’Neill LA (2008) The interleukin-1 receptor Toll-like receptor superfamily: 10 years of progress. Immunol Rev 226:10–18

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  54. Onda H, Kasuya H, Takakura K et al (1999) Identification of genes differentially expressed in canine vasospastic cerebral arteries after subarachnoid hemorrhage. J Cereb Blood Flow Metab 19:1279–1288

    Article  CAS  PubMed  Google Scholar 

  55. Oshikawa K, Yanagisawa K, Tominaga S, Sugiyama Y (2002) ST2 protein induced by inflammatory stimuli can modulate acute lung inflammation. Biochem Biophys Res Commun 299:18–24

    Article  CAS  PubMed  Google Scholar 

  56. Palmer G, Gabay C (2011) Interleukin-33 biology with potential insights into human diseases. Nat Rev Rheumatol 7:321–329

    Article  CAS  PubMed  Google Scholar 

  57. Pecaric-Petkovic T, Didichenko SA, Kaempfer S et al (2009) Human basophils and eosinophils are the direct target leukocytes of the novel IL-1 family member IL-33. Blood 113:1526–1534

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Puxeddu I, Italiani P, Giungato P et al (2013) Free IL-18 and IL-33 cytokines in chronic spontaneous urticaria. Cytokine 61:741–743

    Article  CAS  PubMed  Google Scholar 

  59. Rank MA, Kobayashi T, Kozaki H et al (2009) IL-33-activated dendritic cells induce an atypical TH2-type response. J Allergy Clin Immunol 123:1047–1054

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Rankin AL, Mumm JB, Murphy E et al (2010) IL-33 induces IL-13-dependent cutaneous fibrosis. J Immunol 184:1526–1535

    Article  CAS  PubMed  Google Scholar 

  61. Rho SS, Park H, Kim YM, Kwon YG, Colotta F, Re F, Muzio M et al (1993) Interleukin-1 type II receptor: a decoy target for IL-1 that is regulated by IL-4. Science 261:472–475

    Article  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Ryu WI, Lee H, Kim JH et al (2015) IL-33 induces Egr-1-dependent TSLP expression via the MAPK pathways in human keratinocytes. Exp Dermatol (epub ahead of print)

  64. Saint-Mezard P, Berard F, Dubois B et al (2004) The role of CD4+ and CD8+ T cells in contact hypersensitivity and allergic contact dermatitis. Eur J Dermatol 14:131–138

    PubMed  Google Scholar 

  65. Salimi M, Barlow JL, Saunders SP et al (2013) A role for IL-25 and IL-33-driven type-2 innate lymphoid cells in atopic dermatitis. J Exp Med 210:2939–2950

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Savinko T, Matikainen S, Saarialho-Kere U et al (2012) IL-33 and ST2 in atopic dermatitis: expression profiles and modulation by triggering factors. J Invest Dermatol 132:1392–1400

    Article  CAS  PubMed  Google Scholar 

  67. Savinko T, Karisola P, Lehtimäki S et al (2013) ST2 regulates allergic airway inflammation and T-cell polarization in epicutaneously sensitized mice. J Invest Dermatol 133:2522–2529

    Article  CAS  PubMed  Google Scholar 

  68. Schmitz J, Owyang A, Oldham E et al (2005) 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

    Article  CAS  PubMed  Google Scholar 

  69. Seltmann J, Roesner LM, von Hesler FW et al (2015) IL-33 impacts on the skin barrier by downregulating the expression of filaggrin. J Allergy Clin Immunol 135:1659–1661

    Article  CAS  PubMed  Google Scholar 

  70. Silver MR, Margulis A, Wood N et al (2010) IL-33 synergizes with IgE-dependent and IgE-independent agents to promote mast cell and basophil activation. Inflamm Res 59:207–218

    Article  CAS  PubMed  Google Scholar 

  71. Smithgall MD, Comeau MR, Yoon BR et al (2008) 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

    Article  CAS  PubMed  Google Scholar 

  72. Sundnes O, Pietka W, Loos T et al (2015) Epidermal expression and regulation of interleukin-33 during homeostasis and inflammation: strong species differences. J Invest Dermatol 135:1771–1780

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Talabot-Ayer D, McKee T, Gindre P 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

    Article  CAS  PubMed  Google Scholar 

  75. Tamagawa-Mineoka R, Okuzawa Y, Masuda K, Katoh N (2014) Increased serum levels of interleukin 33 in patients with atopic dermatitis. J Am Acad Dermatol 70:882–888

    Article  CAS  PubMed  Google Scholar 

  76. Taniguchi K, Yamamoto S, Hitomi E et al (2013) Interleukin 33 is induced by tumor necrosis factor alpha and interferon gamma in keratinocytes and contributes to allergic contact dermatitis. J Investig Allergol Clin Immunol 23:428–434

    CAS  PubMed  Google Scholar 

  77. Theoharides TC, Zhang B, Kempuraj D et al (2010) IL-33 augments substance P-induced VEGF secretion from human mast cells and is increased in psoriatic skin. Proc Natl Acad Sci USA 107:4448–4453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. van der Meer JW, Barza M, Wolff SM, Dinarello CA (1988) A low dose of recombinant interleukin 1 protects granulocytopenic mice from lethal gram-negative infection. Proc Natl Acad Sci USA 85:1620–1623

    Article  PubMed  PubMed Central  Google Scholar 

  79. Wakatabi K, Mayumi K, Meephansan J et al (2012) The levels of soluble ST2 in sera and bullous fluid from patients with bullous pemphigoid. Eur J Dermatol 22:333–336

    CAS  PubMed  Google Scholar 

  80. Wollheim FA (2005) Classification of systemic sclerosis. Visions and reality. Rheumatology 44:1212–1216

    Article  CAS  PubMed  Google Scholar 

  81. Yanaba K, Yoshizaki A, Asano Y et al (2011) Serum IL-33 levels are raised in patients with systemic sclerosis: association with extent of skin sclerosis and severity of pulmonary fibrosis. Clin Rheumatol 30:825–830

    Article  PubMed  Google Scholar 

  82. Yang Q, Yu C, Yang Z et al (2014) Deregulated NLRP3 and NLRP1 inflammasomes and their correlations with disease activity in systemic lupus erythematosus. J Rheumatol 41:444–452

    Article  CAS  PubMed  Google Scholar 

  83. Yuan L, Yao L, Zhao L et al (2013) Serum levels of soluble ST2 and interleukin-33 in patients with dermatomyositis and polymyositis. Clin Exp Rheumatol 31:428–432

    PubMed  Google Scholar 

  84. Zhao Q, Chen G (2014) Role of IL-33 and its receptor in T cell-mediated autoimmune diseases. Biomed Res Int 2014:587376

    PubMed  PubMed Central  Google Scholar 

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  1. Section of Dermatology, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, 80131, Italy

    Anna Balato, Annunziata Raimondo, Nicola Balato, Fabio Ayala & Serena Lembo

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  1. Anna Balato
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  2. Annunziata Raimondo
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Correspondence to Anna Balato.

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Balato, A., Raimondo, A., Balato, N. et al. Interleukin-33: increasing role in dermatological conditions. Arch Dermatol Res 308, 287–296 (2016). https://doi.org/10.1007/s00403-016-1638-7

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