Cytokine Network

  • Kenji IzuharaEmail author
  • Satoshi Nunomura
  • Shoichiro Ohta
  • Masahiro Ogawa
  • Yasuhiro Nanri


Immune dysregulation, barrier defects, and increased skin infections combine to lead to the onset of atopic dermatitis (AD). It was previously thought that type 2 inflammation was dominant in the acute phase of AD, and then in the chronic phase, it became type 1 inflammation. However, it is now widely accepted that both type 2 inflammation and inflammation induced by TH22 cells are dominant in both the acute and chronic phases of AD. In type 2 inflammation, IL-4, IL-13, and IL-5, which are signature type 2 cytokines, are highly expressed and are involved in forming the characteristic features of AD. Epithelial cell-derived cytokines—thymic stromal lymphopoietin, IL-33, and IL-25—initiate type 2 inflammation by controlling various cells, including group 2 innate lymphoid cells. Moreover, IL-31, a newly identified type 2 cytokine, induces itch by acting on sensory neurons. IL-22, a signature cytokine derived from TH22 cells, is significantly expressed in AD skin and is believed to contribute to the pathogenesis of AD as well as type 2 cytokines by acting on keratinocytes. Based on both basic and clinical findings, several antibodies targeting cytokines have been developed as therapeutic agents against AD, among which dupilumab, targeting the IL-4 receptor α chain shared with IL-4R and IL-13R, has become the first molecularly targeted drug for the treatment of AD.


Cytokine Type 2 inflammation TH22 cell Epithelial cell-derived cytokine Dupilumab 



We thank Dr. Dovie R. Wylie for her critical review of this manuscript.


  1. 1.
    Czarnowicki T, Krueger JG, Guttman-Yassky E. Skin barrier and immune dysregulation in atopic dermatitis: an evolving story with important clinical implications. J Allergy Clin Immunol Pract. 2014;2:371–379.; quiz 80-1. doi: 10.1016/j.jaip.2014.03.006.CrossRefPubMedGoogle Scholar
  2. 2.
    Leung DY. Atopic dermatitis: the skin as a window into the pathogenesis of chronic allergic diseases. J Allergy Clin Immunol. 1995;96:302–18. quiz 19CrossRefPubMedGoogle Scholar
  3. 3.
    Izuhara K, Arima K, Kanaji S, Ohta S, Kanaji T. IL-13: a promising therapeutic target for bronchial asthma. Curr Med Chem. 2006;13:2291–8.CrossRefPubMedGoogle Scholar
  4. 4.
    Moro K, Yamada T, Tanabe M, Takeuchi T, Ikawa T, Kawamoto H, et al. Innate production of TH2 cytokines by adipose tissue-associated c-Kit+Sca-1+ lymphoid cells. Nature. 2010;463:540–544. doi:nature08636 [pii]. doi: 10.1038/nature08636.CrossRefPubMedGoogle Scholar
  5. 5.
    Neill DR, Wong SH, Bellosi A, Flynn RJ, Daly M, Langford TK, et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature. 2010;464:1367–1370. nature08900 [pii]. doi: 10.1038/nature08900.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Price AE, Liang HE, Sullivan BM, Reinhardt RL, Eisley CJ, Erle DJ, et al. Systemically dispersed innate IL-13-expressing cells in type 2 immunity. Proc Natl Acad Sci U S A. 2010;107:11489–11494. 1003988107 [pii]. doi: 10.1073/pnas.1003988107.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Doherty TA, Khorram N, Lund S, Mehta AK, Croft M, Broide DH. Lung type 2 innate lymphoid cells express cysteinyl leukotriene receptor 1, which regulates TH2 cytokine production. J Allergy Clin Immunol. 2013;132:205–13. doi: 10.1016/j.jaci.2013.03.048.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Mjosberg J, Bernink J, Golebski K, Karrich JJ, Peters CP, Blom B, et al. The transcription factor GATA3 is essential for the function of human type 2 innate lymphoid cells. Immunity. 2012;37:649–59. doi: 10.1016/j.immuni.2012.08.015.CrossRefPubMedGoogle Scholar
  9. 9.
    Izuhara K, Ohta S, Shiraishi H, Suzuki S. Interleukin 4, interleukin 13, and interleukin 9. In: Izuhara K, Holgate ST, Wills-Karp M, editors. Inflammation and allergy drug design. London: Wiley-Blackwell; 2011. p. 175–85.CrossRefGoogle Scholar
  10. 10.
    Chan LS, Robinson N, Xu L. Expression of interleukin-4 in the epidermis of transgenic mice results in a pruritic inflammatory skin disease: an experimental animal model to study atopic dermatitis. J Invest Dermatol. 2001;117:977–83. doi: 10.1046/j.0022-202x.2001.01484. x. jid1484 [pii]CrossRefPubMedGoogle Scholar
  11. 11.
    Chen L, Martinez O, Overbergh L, Mathieu C, Prabhakar BS, Chan LS. Early up-regulation of Th2 cytokines and late surge of Th1 cytokines in an atopic dermatitis model. Clin Exp Immunol. 2004;138:375–87. doi: 10.1111/j.1365-2249.2004.02649.x. CEI2649 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Zheng T, Oh MH, Oh SY, Schroeder JT, Glick AB, Zhu Z. Transgenic expression of interleukin-13 in the skin induces a pruritic dermatitis and skin remodeling. J Invest Dermatol. 2009;129:742–51.CrossRefPubMedGoogle Scholar
  13. 13.
    Kagami S, Kakinuma T, Saeki H, Tsunemi Y, Fujita H, Nakamura K, et al. Significant elevation of serum levels of eotaxin-3/CCL26, but not of eotaxin-2/CCL24, in patients with atopic dermatitis: serum eotaxin-3/CCL26 levels reflect the disease activity of atopic dermatitis. Clin Exp Immunol. 2003;134:309–13.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Kagami S, Saeki H, Komine M, Kakinuma T, Tsunemi Y, Nakamura K, et al. Interleukin-4 and interleukin-13 enhance CCL26 production in a human keratinocyte cell line, HaCaT cells. Clin Exp Immunol. 2005;141:459–66. doi: 10.1111/j.1365-2249.2005.02875.x.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Kakinuma T, Nakamura K, Wakugawa M, Mitsui H, Tada Y, Saeki H, et al. Thymus and activation-regulated chemokine in atopic dermatitis: serum thymus and activation-regulated chemokine level is closely related with disease activity. J Allergy Clin Immunol. 2001;107:535–541. doi:S0091-6749(01)90455-5 [pii]. doi: 10.1067/mai.2001.113237.CrossRefPubMedGoogle Scholar
  16. 16.
    Kakinuma T, Nakamura K, Wakugawa M, Yano S, Saeki H, Torii H, et al. IL-4, but not IL-13, modulates TARC (thymus and activation-regulated chemokine)/CCL17 and IP-10 (interferon-induced protein of 10kDA)/CXCL10 release by TNFα and IFN-γ in HaCaT cell line. Cytokine. 2002;20:1–6.CrossRefPubMedGoogle Scholar
  17. 17.
    Howell MD, Kim BE, Gao P, Grant AV, Boguniewicz M, Debenedetto A, et al. Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol. 2007;120:150–5.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Kim BE, Leung DY, Boguniewicz M, Howell MD. Loricrin and involucrin expression is down-regulated by Th2 cytokines through STAT-6. Clin Immunol. 2008;126:332–7. doi: 10.1016/j.clim.2007.11.006.CrossRefPubMedGoogle Scholar
  19. 19.
    Nomura I, Goleva E, Howell MD, Hamid QA, Ong PY, Hall CF, et al. Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes. J Immunol. 2003;171:3262–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Ong PY, Ohtake T, Brandt C, Strickland I, Boguniewicz M, Ganz T, et al. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N Engl J Med. 2002;347:1151–60. doi: 10.1056/NEJMoa021481.CrossRefPubMedGoogle Scholar
  21. 21.
    Masuoka M, Shiraishi H, Ohta S, Suzuki S, Arima K, Aoki S, et al. Periostin promotes chronic allergic inflammation in response to Th2 cytokines. J Clin Invest. 2012;122:2590–2600. 58978 [pii]. doi: 10.1172/JCI58978.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Llop-Guevara A, Marcinko J, Fattoub R, Jordana M. Interleukin 3, interleukin 5, and granulocyte-macrophage colony-stimulating factor. In: Izuhara K, Holgate ST, Wills-Karp M, editors. Inflammation and allergy drug design. London: Wiley-Blackwell; 2011. p. 187–96.CrossRefGoogle Scholar
  23. 23.
    Foster EL, Simpson EL, Fredrikson LJ, Lee JJ, Lee NA, Fryer AD, et al. Eosinophils increase neuron branching in human and murine skin and in vitro. PLoS One. 2011;6:e22029. doi: 10.1371/journal.pone.0022029.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Kimura M, Tsuruta S, Yoshida T. Correlation of house dust mite-specific lymphocyte proliferation with IL-5 production, eosinophilia, and the severity of symptoms in infants with atopic dermatitis. J Allergy Clin Immunol. 1998;101:84–9. doi: 10.1016/s0091-6749(98)70197-6.CrossRefPubMedGoogle Scholar
  25. 25.
    Oldhoff JM, Darsow U, Werfel T, Katzer K, Wulf A, Laifaoui J, et al. Anti-IL-5 recombinant humanized monoclonal antibody (mepolizumab) for the treatment of atopic dermatitis. Allergy. 2005;60:693–6. doi: 10.1111/j.1398-9995.2005.00791.x. ALL791 [pii]CrossRefPubMedGoogle Scholar
  26. 26.
    Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey SW, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371:1189–97. doi: 10.1056/NEJMoa1403291.CrossRefPubMedGoogle Scholar
  27. 27.
    Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371:1198–207. doi: 10.1056/NEJMoa1403290.CrossRefPubMedGoogle Scholar
  28. 28.
    Hammad H, Lambrecht BN. Barrier epithelial cells and the control of type 2 immunity. Immunity. 2015;43:29–40. doi: 10.1016/j.immuni.2015.07.007.CrossRefPubMedGoogle Scholar
  29. 29.
    He R, Geha RS. Thymic stromal lymphopoietin. Ann N Y Acad Sci. 2010;1183:13–24. doi: 10.1111/j.1749-6632.2009.05128.x.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Soumelis V, Reche PA, Kanzler H, Yuan W, Edward G, Homey B, et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol. 2002;3:673–80.CrossRefPubMedGoogle Scholar
  31. 31.
    Mu Z, Zhao Y, Liu X, Chang C, Zhang J. Molecular biology of atopic dermatitis. Clin Rev Allergy Immunol. 2014;47:193–218. doi: 10.1007/s12016-014-8415-1.CrossRefPubMedGoogle Scholar
  32. 32.
    Bogiatzi SI, Fernandez I, Bichet JC, Marloie-Provost MA, Volpe E, Sastre X, et al. Proinflammatory and Th2 cytokines synergize to induce thymic stromal lymphopoietin production by human skin keratinocytes. J Immunol. 2007;178:3373–7.CrossRefPubMedGoogle Scholar
  33. 33.
    Kinoshita H, Takai T, Le TA, Kamijo S, Wang XL, Ushio H, et al. Cytokine milieu modulates release of thymic stromal lymphopoietin from human keratinocytes stimulated with double-stranded RNA. J Allergy Clin Immunol. 2009;123:179–86.CrossRefPubMedGoogle Scholar
  34. 34.
    Sokol CL, Barton GM, Farr AG, Medzhitov R. A mechanism for the initiation of allergen-induced T helper type 2 responses. Nat Immunol. 2008;9:310–8. doi: 10.1038/ni1558.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Miyata M, Hatsushika K, Ando T, Shimokawa N, Ohnuma Y, Katoh R, et al. Mast cell regulation of epithelial TSLP expression plays an important role in the development of allergic rhinitis. Eur J Immunol. 2008;38:1487–92. doi: 10.1002/eji.200737809.CrossRefPubMedGoogle Scholar
  36. 36.
    Arima K, Liu Y-J. Thymic stromal lymphopoietin. In: Izuhara K, Holgate ST, Wills-Karp M, editors. Inflammation and allergy. London: Wiley-Blackwell; 2011. p. 205–14.CrossRefGoogle Scholar
  37. 37.
    Ito T, Wang YH, Duramad O, Hori T, Delespesse GJ, Watanabe N, et al. TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand. J Exp Med. 2005;202:1213–23. doi: 10.1084/jem.20051135.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Seshasayee D, Lee WP, Zhou M, Shu J, Suto E, Zhang J, et al. In vivo blockade of OX40 ligand inhibits thymic stromal lymphopoietin driven atopic inflammation. J Clin Invest. 2007;117:3868–78. doi: 10.1172/JCI33559.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Omori M, Ziegler S. Induction of IL-4 expression in CD4+ T cells by thymic stromal lymphopoietin. J Immunol. 2007;178:1396–404.CrossRefPubMedGoogle Scholar
  40. 40.
    Kim BS, Siracusa MC, Saenz SA, Noti M, Monticelli LA, Sonnenberg GF, et al. TSLP elicits IL-33-independent innate lymphoid cell responses to promote skin inflammation. Sci Transl Med. 2013;5:170ra16. doi: 10.1126/scitranslmed.3005374.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Wilson SR, The L, Batia LM, Beattie K, Katibah GE, McClain SP, et al. The epithelial cell-derived atopic dermatitis cytokine TSLP activates neurons to induce itch. Cell. 2013;155:285–95. doi: 10.1016/j.cell.2013.08.057.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Yoo J, Omori M, Gyarmati D, Zhou B, Aye T, Brewer A, et al. Spontaneous atopic dermatitis in mice expressing an inducible thymic stromal lymphopoietin transgene specifically in the skin. J Exp Med. 2005;202:541–9.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    He R, Oyoshi MK, Garibyan L, Kumar L, Ziegler SF, Geha RS. TSLP acts on infiltrating effector T cells to drive allergic skin inflammation. Proc Natl Acad Sci U S A. 2008;105:11875–80.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Liew FY, Pitman NI, McInnes IB. Disease-associated functions of IL-33: the new kid in the IL-1 family. Nat Rev Immunol. 2010;10:103–10. doi: 10.1038/nri2692.CrossRefPubMedGoogle Scholar
  45. 45.
    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;37:2779–86. doi: 10.1002/eji.200737547.CrossRefPubMedGoogle Scholar
  46. 46.
    Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, 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. 2005;23:479–90. doi: 10.1016/j.immuni.2005.09.015.CrossRefPubMedGoogle Scholar
  47. 47.
    Ali S, Huber M, Kollewe C, Bischoff SC, Falk W, Martin MU. IL-1 receptor accessory protein is essential for IL-33-induced activation of T lymphocytes and mast cells. Proc Natl Acad Sci U S A. 2007;104:18660–5. doi: 10.1073/pnas.0705939104.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Allakhverdi Z, Smith DE, Comeau MR, Delespesse G. The ST2 ligand IL-33 potently activates and drives maturation of human mast cells. J Immunol. 2007;179:2051–4.CrossRefPubMedGoogle Scholar
  49. 49.
    Suzukawa M, Iikura M, Koketsu R, Nagase H, Tamura C, Komiya A, et al. An IL-1 cytokine member, IL-33, induces human basophil activation via its ST2 receptor. J Immunol. 2008a;181:5981–9.CrossRefPubMedGoogle Scholar
  50. 50.
    Cherry WB, Yoon J, Bartemes KR, Iijima K, Kita H. A novel IL-1 family cytokine, IL-33, potently activates human eosinophils. J Allergy Clin Immunol. 2008;121:1484–90. doi: 10.1016/j.jaci.2008.04.005.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Suzukawa M, Koketsu R, Iikura M, Nakae S, Matsumoto K, Nagase H, et al. Interleukin-33 enhances adhesion, CD11b expression and survival in human eosinophils. Lab Investig. 2008b;88:1245–53. doi: 10.1038/labinvest.2008.82.CrossRefPubMedGoogle Scholar
  52. 52.
    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. doi: 10.4049/jimmunol.0901575.CrossRefPubMedGoogle Scholar
  53. 53.
    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;123:1047–54. doi: 10.1016/j.jaci.2009.02.026.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Savinko T, Matikainen S, Saarialho-Kere U, Lehto M, Wang G, Lehtimaki S, et al. IL-33 and ST2 in atopic dermatitis: expression profiles and modulation by triggering factors. J Invest Dermatol. 2012;132:1392–400. doi: 10.1038/jid.2011.446.CrossRefPubMedGoogle Scholar
  55. 55.
    Imai Y, Yasuda K, Sakaguchi Y, Haneda T, Mizutani H, Yoshimoto T, et al. Skin-specific expression of IL-33 activates group 2 innate lymphoid cells and elicits atopic dermatitis-like inflammation in mice. Proc Natl Acad Sci U S A. 2013;110:13921–6. doi: 10.1073/pnas.1307321110.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Hvid M, Vestergaard C, Kemp K, Christensen GB, Deleuran B, Deleuran M. IL-25 in atopic dermatitis: a possible link between inflammation and skin barrier dysfunction? J Invest Dermatol. 2011;131:150–7. doi: 10.1038/jid.2010.277.CrossRefPubMedGoogle Scholar
  57. 57.
    Wang YH, Angkasekwinai P, Lu N, Voo KS, Arima K, Hanabuchi S, et al. IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLP-DC-activated Th2 memory cells. J Exp Med. 2007;204:1837–47. doi: 10.1084/jem.20070406. jem.20070406 [pii]CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Dillon SR, Sprecher C, Hammond A, Bilsborough J, Rosenfeld-Franklin M, Presnell SR, et al. Interleukin 31, a cytokine produced by activated T cells, induces dermatitis in mice. Nat Immunol. 2004;5:752–60. doi: 10.1038/ni1084.CrossRefPubMedGoogle Scholar
  59. 59.
    Cornelissen C, Luscher-Firzlaff J, Baron JM, Luscher B. Signaling by IL-31 and functional consequences. Eur J Cell Biol. 2012;91:552–66. doi: 10.1016/j.ejcb.2011.07.006.CrossRefPubMedGoogle Scholar
  60. 60.
    Sonkoly E, Muller A, Lauerma AI, Pivarcsi A, Soto H, Kemeny L, et al. IL-31: a new link between T cells and pruritus in atopic skin inflammation. J Allergy Clin Immunol. 2006;117:411–7. doi: 10.1016/j.jaci.2005.10.033.CrossRefPubMedGoogle Scholar
  61. 61.
    Neis MM, Peters B, Dreuw A, Wenzel J, Bieber T, Mauch C, et al. Enhanced expression levels of IL-31 correlate with IL-4 and IL-13 in atopic and allergic contact dermatitis. J Allergy Clin Immunol. 2006;118:930–7. doi: 10.1016/j.jaci.2006.07.015.CrossRefPubMedGoogle Scholar
  62. 62.
    Raap U, Weissmantel S, Gehring M, Eisenberg AM, Kapp A, Folster-Holst R. IL-31 significantly correlates with disease activity and Th2 cytokine levels in children with atopic dermatitis. Pediatr Allergy Immunol. 2012;23:285–8. doi: 10.1111/j.1399-3038.2011.01241.x.CrossRefPubMedGoogle Scholar
  63. 63.
    Raap U, Wichmann K, Bruder M, Stander S, Wedi B, Kapp A, et al. Correlation of IL-31 serum levels with severity of atopic dermatitis. J Allergy Clin Immunol. 2008;122:421–3. doi: 10.1016/j.jaci.2008.05.047.CrossRefPubMedGoogle Scholar
  64. 64.
    Singh B, Jegga AG, Shanmukhappa KS, Edukulla R, Khurana GH, Medvedovic M, et al. IL-31-driven skin remodeling involves epidermal cell proliferation and thickening that lead to impaired skin-barrier function. PLoS One. 2016;11:e0161877. doi: 10.1371/journal.pone.0161877.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Cevikbas F, Wang X, Akiyama T, Kempkes C, Savinko T, Antal A, et al. A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch: involvement of TRPV1 and TRPA1. J Allergy Clin Immunol. 2014;133:448–60. doi: 10.1016/j.jaci.2013.10.048.CrossRefPubMedGoogle Scholar
  66. 66.
    Kittaka H, Tominaga M. The molecular and cellular mechanisms of itch and the involvement of TRP channels in the peripheral sensory nerve system and skin. Allergol Int. 2017;66:22–30. doi: 10.1016/j.alit.2016.10.003
  67. 67.
    Feld M, Garcia R, Buddenkotte J, Katayama S, Lewis K, Muirhead G, et al. The pruritus- and TH2-associated cytokine IL-31 promotes growth of sensory nerves. J Allergy Clin Immunol. 2016;138:500–8.e24. doi: 10.1016/j.jaci.2016.02.020.CrossRefPubMedGoogle Scholar
  68. 68.
    Eyerich K, Eyerich S. Th22 cells in allergic disease. Allergo J Int. 2015;24:1–7. doi: 10.1007/s40629-015-0039-3.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Mirshafiey A, Simhag A, El Rouby NM, Azizi G. T-helper 22 cells as a new player in chronic inflammatory skin disorders. Int J Dermatol. 2015;54:880–8. doi: 10.1111/ijd.12883.CrossRefPubMedGoogle Scholar
  70. 70.
    Niebuhr M, Scharonow H, Gathmann M, Mamerow D, Werfel T. Staphylococcal exotoxins are strong inducers of IL-22: A potential role in atopic dermatitis. J Allergy Clin Immunol. 2010;126:1176–83.e4. doi: 10.1016/j.jaci.2010.07.041.CrossRefPubMedGoogle Scholar
  71. 71.
    Nograles KE, Zaba LC, Shemer A, Fuentes-Duculan J, Cardinale I, Kikuchi T, et al. IL-22-producing "T22" T cells account for upregulated IL-22 in atopic dermatitis despite reduced IL-17-producing TH17 T cells. J Allergy Clin Immunol. 2009;123:1244–52.e2. doi: 10.1016/j.jaci.2009.03.041.CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Simon D, Aeberhard C, Erdemoglu Y, Simon HU. Th17 cells and tissue remodeling in atopic and contact dermatitis. Allergy. 2014;69:125–31. doi: 10.1111/all.12351.CrossRefPubMedGoogle Scholar
  73. 73.
    Gittler JK, Shemer A, Suarez-Farinas M, Fuentes-Duculan J, Gulewicz KJ, Wang CQ, et al. Progressive activation of TH2/TH22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis. J Allergy Clin Immunol. 2012;130:1344–54. doi: 10.1016/j.jaci.2012.07.012.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Boniface K, Bernard FX, Garcia M, Gurney AL, Lecron JC, Morel F. IL-22 inhibits epidermal differentiation and induces proinflammatory gene expression and migration of human keratinocytes. J Immunol. 2005;174:3695–702.CrossRefPubMedGoogle Scholar
  75. 75.
    Nograles KE, Zaba LC, Guttman-Yassky E, Fuentes-Duculan J, Suarez-Farinas M, Cardinale I, et al. Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways. Br J Dermatol. 2008;159:1092–102. doi: 10.1111/j.1365-2133.2008.08769.x.PubMedPubMedCentralGoogle Scholar
  76. 76.
    Sa SM, Valdez PA, Wu J, Jung K, Zhong F, Hall L, et al. The effects of IL-20 subfamily cytokines on reconstituted human epidermis suggest potential roles in cutaneous innate defense and pathogenic adaptive immunity in psoriasis. J Immunol. 2007;178:2229–40.CrossRefPubMedGoogle Scholar
  77. 77.
    Wolk K, Haugen HS, Xu W, Witte E, Waggie K, Anderson M, et al. IL-22 and IL-20 are key mediators of the epidermal alterations in psoriasis while IL-17 and IFN-γ are not. J Mol Med. 2009;87:523–36. doi: 10.1007/s00109-009-0457-0.CrossRefPubMedGoogle Scholar
  78. 78.
    Wolk K, Witte E, Wallace E, Docke WD, Kunz S, Asadullah K, et al. IL-22 regulates the expression of genes responsible for antimicrobial defense, cellular differentiation, and mobility in keratinocytes: a potential role in psoriasis. Eur J Immunol. 2006;36:1309–23. doi: 10.1002/eji.200535503.CrossRefPubMedGoogle Scholar
  79. 79.
    Gutowska-Owsiak D, Schaupp AL, Salimi M, Taylor S, Ogg GS. Interleukin-22 downregulates filaggrin expression and affects expression of profilaggrin processing enzymes. Br J Dermatol. 2011;165:492–8. doi: 10.1111/j.1365-2133.2011.10400.x.CrossRefPubMedGoogle Scholar
  80. 80.
    Guilloteau K, Paris I, Pedretti N, Boniface K, Juchaux F, Huguier V et al. Skin inflammation induced by the synergistic action of IL-17A, IL-22, oncostatin M, IL-1α, and TNFα recapitulates some features of psoriasis. J Immunol. 2010. doi: 10.4049/jimmunol.0902464.
  81. 81.
    Ma HL, Liang S, Li J, Napierata L, Brown T, Benoit S, et al. IL-22 is required for Th17 cell-mediated pathology in a mouse model of psoriasis-like skin inflammation. J Clin Invest. 2008;118:597–607. doi: 10.1172/jci33263.PubMedPubMedCentralGoogle Scholar
  82. 82.
    Pantelyushin S, Haak S, Ingold B, Kulig P, Heppner FL, Navarini AA, et al. Rorγt+ innate lymphocytes and γδ T cells initiate psoriasiform plaque formation in mice. J Clin Invest. 2012;122:2252–6. doi: 10.1172/jci61862.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Van Belle AB, de Heusch M, Lemaire MM, Hendrickx E, Warnier G, Dunussi-Joannopoulos K, et al. IL-22 is required for imiquimod-induced psoriasiform skin inflammation in mice. J Immunol. 2012;188:462–9. doi: 10.4049/jimmunol.1102224.CrossRefPubMedGoogle Scholar
  84. 84.
    Grewe M, Bruijnzeel-Koomen CA, Schopf E, Thepen T, Langeveld-Wildschut AG, Ruzicka T, et al. A role for Th1 and Th2 cells in the immunopathogenesis of atopic dermatitis. Immunol Today. 1998;19:359–61.CrossRefPubMedGoogle Scholar
  85. 85.
    Koga C, Kabashima K, Shiraishi N, Kobayashi M, Tokura Y. Possible pathogenic role of Th17 cells for atopic dermatitis. J Invest Dermatol. 2008;128:2625–30.CrossRefPubMedGoogle Scholar
  86. 86.
    Toda M, Leung DY, Molet S, Boguniewicz M, Taha R, Christodoulopoulos P, et al. Polarized in vivo expression of IL-11 and IL-17 between acute and chronic skin lesions. J Allergy Clin Immunol. 2003;111:875–81.CrossRefPubMedGoogle Scholar
  87. 87.
    Huang F, Wachi S, Thai P, Loukoianov A, Tan KH, Forteza RM, et al. Potentiation of IL-19 expression in airway epithelia by IL-17A and IL-4/IL-13: important implications in asthma. J Allergy Clin Immunol. 2008;121:1415–21.e1–3. doi: 10.1016/j.jaci.2008.04.016.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Witte E, Kokolakis G, Witte K, Philipp S, Doecke WD, Babel N, et al. IL-19 is a component of the pathogenetic IL-23/IL-17 cascade in psoriasis. J Invest Dermatol. 2014;134:2757–67. doi: 10.1038/jid.2014.308.CrossRefPubMedGoogle Scholar
  89. 89.
    Esaki H, Brunner PM, Renert-Yuval Y, Czarnowicki T, Huynh T, Tran G, et al. Early-onset pediatric atopic dermatitis is TH2 but also TH17 polarized in skin. J Allergy Clin Immunol. 2016;138:1639–51. doi: 10.1016/j.jaci.2016.07.013.CrossRefPubMedGoogle Scholar
  90. 90.
    Noda S, Suarez-Farinas M, Ungar B, Kim SJ, de Guzman SC, Xu H, et al. The Asian atopic dermatitis phenotype combines features of atopic dermatitis and psoriasis with increased TH17 polarization. J Allergy Clin Immunol. 2015;136:1254–64. doi: 10.1016/j.jaci.2015.08.015.CrossRefPubMedGoogle Scholar
  91. 91.
    Beck LA, Thaci D, Hamilton JD, Graham NM, Bieber T, Rocklin R, et al. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N Engl J Med. 2014;371:130–9. doi: 10.1056/NEJMoa1314768.CrossRefPubMedGoogle Scholar
  92. 92.
    Hamilton JD, Suarez-Farinas M, Dhingra N, Cardinale I, Li X, Kostic A, et al. Dupilumab improves the molecular signature in skin of patients with moderate-to-severe atopic dermatitis. J Allergy Clin Immunol. 2014;134:1293–300. doi: 10.1016/j.jaci.2014.10.013.CrossRefPubMedGoogle Scholar
  93. 93.
    Thaci D, Simpson EL, Beck LA, Bieber T, Blauvelt A, Papp K, et al. Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial. Lancet. 2016;387:40–52. doi: 10.1016/s0140-6736(15)00388-8.CrossRefPubMedGoogle Scholar
  94. 94.
    Simpson EL, Bieber T, Guttman-Yassky E, Beck LA, Blauvelt A, Cork MJ, et al. Two phase 3 trials of Dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016;375:2335–48. doi: 10.1056/NEJMoa1610020.CrossRefPubMedGoogle Scholar
  95. 95.
    Nemoto O, Furue M, Nakagawa H, Shiramoto M, Hanada R, Matsuki S, et al. The first trial of CIM331, a humanized antihuman interleukin-31 receptor a antibody, in healthy volunteers and patients with atopic dermatitis to evaluate safety, tolerability and pharmacokinetics of a single dose in a randomized, double-blind, placebo-controlled study. Br J Dermatol. 2016;174:296–304. doi: 10.1111/bjd.14207.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • Kenji Izuhara
    • 1
    Email author
  • Satoshi Nunomura
    • 1
  • Shoichiro Ohta
    • 1
  • Masahiro Ogawa
    • 1
  • Yasuhiro Nanri
    • 1
  1. 1.Division of Medical Biochemistry, Department of Biomolecular Sciences, Saga Medical SchoolSagaJapan

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