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Journal of Molecular Medicine

, Volume 94, Issue 5, pp 523–534 | Cite as

Biological and pathological activities of interleukin-22

  • Mirna Perusina Lanfranca
  • Yanwei Lin
  • Jingyuan Fang
  • Weiping ZouEmail author
  • Timothy FrankelEmail author
Review

Abstract

Interleukin (IL)-22, a member of the IL-10 family, is a cytokine secreted by several types of immune cells including IL-22+CD4+ T cells (Th22) and IL-22 expressing innate leukocytes (ILC22). Recent studies have demonstrated that IL-22 is a key component in mucosal barrier defense, tissue repair, epithelial cell survival, and proliferation. Furthermore, accumulating evidence has defined both protective and pathogenic properties of IL-22 in a number of conditions including autoimmune disease, infection, and malignancy. In this review, we summarize the expression and signaling pathway and functional characteristics of the IL-22 and IL-22 receptor axis in physiological and pathological scenarios and discuss the potential to target IL-22 signaling to treat human diseases.

Keywords

IL-22 Th22 ILC22 Cancer T cell Cancer Autoimmune Infection IL-22R IL-22BP 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no competing interests.

References

  1. 1.
    Sabat R, Ouyang W, Wolk K (2014) Therapeutic opportunities of the IL-22-IL-22R1 system. Nat Rev Drug Discov 13:21–38PubMedCrossRefGoogle Scholar
  2. 2.
    Dumoutier L, Louahed J, Renauld JC (2000) Cloning and characterization of IL-10-related T cell-derived inducible factor (IL-TIF), a novel cytokine structurally related to IL-10 and inducible by IL-9. J Immunol (Baltimore, Md: 1950) 164:1814–1819CrossRefGoogle Scholar
  3. 3.
    Dumoutier L, Van Roost E, Ameye G, Michaux L, Renauld JC (2000) IL-TIF/IL-22: genomic organization and mapping of the human and mouse genes. Genes Immun 1:488–494PubMedCrossRefGoogle Scholar
  4. 4.
    Dumoutier L, Van Roost E, Colau D, Renauld JC (2000) Human interleukin-10-related T cell-derived inducible factor: molecular cloning and functional characterization as an hepatocyte-stimulating factor. Proc Natl Acad Sci U S A 97:10144–10149PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Xie MH et al (2000) Interleukin (IL)-22, a novel human cytokine that signals through the interferon receptor-related proteins CRF2-4 and IL-22R. J Biol Chem 275:31335–31339PubMedCrossRefGoogle Scholar
  6. 6.
    Nagem RA et al (2002) Crystal structure of recombinant human interleukin-22. Structure 10:1051–1062PubMedCrossRefGoogle Scholar
  7. 7.
    Commins S, Steinke JW, Borish L (2008) The extended IL-10 superfamily: IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, and IL-29. J Allergy Clin Immunol 121:1108–1111PubMedCrossRefGoogle Scholar
  8. 8.
    de Oliveira Neto M et al (2008) Interleukin-22 forms dimers that are recognized by two interleukin-22R1 receptor chains. Biophys J 94:1754–1765PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Bleicher L et al (2008) Crystal structure of the IL-22/IL-22R1 complex and its implications for the IL-22 signaling mechanism. FEBS Lett 582:2985–2992PubMedCrossRefGoogle Scholar
  10. 10.
    Aggarwal S, Xie MH, Maruoka M, Foster J, Gurney AL (2001) Acinar cells of the pancreas are a target of interleukin-22. J Interf Cytokine Res Off J Int S Interf Cytokine Res 21:1047–1053CrossRefGoogle Scholar
  11. 11.
    Dumoutier L, Lejeune D, Colau D, Renauld JC (2001) Cloning and characterization of IL-22 binding protein, a natural antagonist of IL-10-related T cell-derived inducible factor/IL-22. J Immunol (Baltimore, Md: 1950) 166:7090–7095CrossRefGoogle Scholar
  12. 12.
    Ciccia F et al (2015) Interleukin (IL)-22 receptor 1 is over-expressed in primary Sjogren's syndrome and Sjogren-associated non-Hodgkin lymphomas and is regulated by IL-18. Clin Exp Immunol 181:219–229PubMedCrossRefGoogle Scholar
  13. 13.
    Li J et al (2004) Temporal associations between interleukin 22 and the extracellular domains of IL-22R and IL-10R2. Int Immunopharmacol 4:693–708PubMedCrossRefGoogle Scholar
  14. 14.
    Lejeune D et al (2002) Interleukin-22 (IL-22) activates the JAK/STAT, ERK, JNK, and p38 MAP kinase pathways in a rat hepatoma cell line. Pathways that are shared with and distinct from IL-10. J Biol Chem 277:33676–33682PubMedCrossRefGoogle Scholar
  15. 15.
    Nagalakshmi ML, Rascle A, Zurawski S, Menon S, de Waal Malefyt R (2004) Interleukin-22 activates STAT3 and induces IL-10 by colon epithelial cells. Int Immunopharmacol 4:679–691PubMedCrossRefGoogle Scholar
  16. 16.
    Hernandez PP, Mahlakoiv T (2015) Interferon-lambda and interleukin 22 act synergistically for the induction of interferon-stimulated genes and control of rotavirus infection. 16, 698–707, doi: 10.1038/ni.3180
  17. 17.
    Naher L et al (2012) STAT3 signal transduction through interleukin-22 in oral squamous cell carcinoma. Int J Oncol 41:1577–1586PubMedPubMedCentralGoogle Scholar
  18. 18.
    Jones BC, Logsdon NJ, Walter MR (2008) Structure of IL-22 bound to its high-affinity IL-22R1 chain. Structure (London, England: 1993) 16:1333–1344CrossRefGoogle Scholar
  19. 19.
    Kotenko SV et al (2001) Identification, cloning, and characterization of a novel soluble receptor that binds IL-22 and neutralizes its activity. J Immunol (Baltimore, Md : 1950) 166:7096–7103CrossRefGoogle Scholar
  20. 20.
    Wei CC, Ho TW, Liang WG, Chen GY, Chang MS (2003) Cloning and characterization of mouse IL-22 binding protein. Genes Immun 4:204–211PubMedCrossRefGoogle Scholar
  21. 21.
    Wu PW et al (2008) IL-22R, IL-10R2, and IL-22BP binding sites are topologically juxtaposed on adjacent and overlapping surfaces of IL-22. J Mol Biol 382:1168–1183PubMedCrossRefGoogle Scholar
  22. 22.
    de Moura PR et al (2009) Crystal structure of a soluble decoy receptor IL-22BP bound to interleukin-22. FEBS Lett 583:1072–1077PubMedCrossRefGoogle Scholar
  23. 23.
    Martin JC et al (2014) Interleukin-22 binding protein (IL-22BP) is constitutively expressed by a subset of conventional dendritic cells and is strongly induced by retinoic acid. Mucosal Immunol 7:101–113PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Huber S et al (2012) IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature 491:259–263PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Gruenberg BH et al (2001) A novel, soluble homologue of the human IL-10 receptor with preferential expression in placenta. Genes Immun 2:329–334PubMedCrossRefGoogle Scholar
  26. 26.
    Weiss B et al (2004) Cloning of murine IL-22 receptor alpha 2 and comparison with its human counterpart. Genes Immun 5:330–336PubMedCrossRefGoogle Scholar
  27. 27.
    Martin JC et al (2015) IL-22BP is produced by eosinophils in human gut and blocks IL-22 protective actions during colitis. Mucosal Immunol. doi: 10.1038/mi.2015.83 PubMedCentralGoogle Scholar
  28. 28.
    Yang X et al (2014) Increased urinary interleukin 22 binding protein levels correlate with lupus nephritis activity. Jo Rheumatol 41:1793–1800CrossRefGoogle Scholar
  29. 29.
    Laaksonen H et al (2014) The multiple sclerosis risk gene IL22RA2 contributes to a more severe murine autoimmune neuroinflammation. Genes Immun 15:457–465PubMedCrossRefGoogle Scholar
  30. 30.
    Wolk K et al (2007) IL-22 induces lipopolysaccharide-binding protein in hepatocytes: a potential systemic role of IL-22 in Crohn's disease. J Immunol (Baltimore, Md: 1950) 178:5973–5981CrossRefGoogle Scholar
  31. 31.
    Liu Y et al (2011) Interleukin-21 induces the differentiation of human Tc22 cells via phosphorylation of signal transducers and activators of transcription. Immunology 132:540–548PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Wolk K, Kunz S, Asadullah K, Sabat R (2002) Cutting edge: immune cells as sources and targets of the IL-10 family members? J Immunol (Baltimore, Md: 1950) 168:5397–5402CrossRefGoogle Scholar
  33. 33.
    Chung Y et al (2006) Expression and regulation of IL-22 in the IL-17-producing CD4+ T lymphocytes. Cell Res 16:902–907PubMedCrossRefGoogle Scholar
  34. 34.
    Nograles KE et al (2009) 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 123:1244–1252.e1242PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Liang SC et al (2006) Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med 203:2271–2279PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Rutz S, Eidenschenk C, Ouyang W (2013) IL-22, not simply a Th17 cytokine. Immunol Rev 252:116–132PubMedCrossRefGoogle Scholar
  37. 37.
    Duhen T, Geiger R, Jarrossay D, Lanzavecchia A, Sallusto F (2009) Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nat Immunol 10:857–863PubMedCrossRefGoogle Scholar
  38. 38.
    Brembilla NC et al (2011) In vivo dioxin favors interleukin-22 production by human CD4+ T cells in an aryl hydrocarbon receptor (AhR)-dependent manner. PLoS One 6, e18741. doi: 10.1371/journal.pone.0018741 PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Ramirez JM et al (2010) Activation of the aryl hydrocarbon receptor reveals distinct requirements for IL-22 and IL-17 production by human T helper cells. Eur J Immunol 40:2450–2459PubMedCrossRefGoogle Scholar
  40. 40.
    Mangan PR et al (2006) Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 441:231–234PubMedCrossRefGoogle Scholar
  41. 41.
    Aliahmadi E et al (2009) TLR2-activated human langerhans cells promote Th17 polarization via IL-1beta, TGF-beta and IL-23. Eur J Immunol 39:1221–1230PubMedCrossRefGoogle Scholar
  42. 42.
    Dubin PJ, Kolls JK (2008) Th17 cytokines and mucosal immunity. Immunol Rev 226:160–171PubMedCrossRefGoogle Scholar
  43. 43.
    Zou W, Restifo NP (2010) T(H)17 cells in tumour immunity and immunotherapy. Nat Rev Immunol 10:248–256PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Trifari S, Kaplan CD, Tran EH, Crellin NK, Spits H (2009) Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from T(H)-17, T(H)1 and T(H)2 cells. Nat Immunol 10:864–871PubMedCrossRefGoogle Scholar
  45. 45.
    Benham H et al (2013) Th17 and Th22 cells in psoriatic arthritis and psoriasis. Arthritis Res Ther 15:R136PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Zhang N, Pan HF, Ye DQ (2011) Th22 in inflammatory and autoimmune disease: prospects for therapeutic intervention. Mol Cell Biochem 353:41–46PubMedCrossRefGoogle Scholar
  47. 47.
    Mabuchi T, Takekoshi T, Hwang ST (2011) Epidermal CCR6+ gammadelta T cells are major producers of IL-22 and IL-17 in a murine model of psoriasiform dermatitis. J Immunol (Baltimore, Md: 1950) 187:5026–5031CrossRefGoogle Scholar
  48. 48.
    Zhou L et al (2008) TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 453:236–240PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Sutton CE et al (2009) Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. Immunity 31:331–341PubMedCrossRefGoogle Scholar
  50. 50.
    Mielke LA et al (2013) Retinoic acid expression associates with enhanced IL-22 production by gammadelta T cells and innate lymphoid cells and attenuation of intestinal inflammation. J Exp Med 210:1117–1124PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Van Maele L et al (2010) TLR5 signaling stimulates the innate production of IL-17 and IL-22 by CD3(neg)CD127+ immune cells in spleen and mucosa. J Immunol (Baltimore, Md: 1950) 185:1177–1185CrossRefGoogle Scholar
  52. 52.
    Tominaga A et al (2013) Autonomous cure of damaged human intestinal epithelial cells by TLR2 and TLR4-dependent production of IL-22 in response to Spirulina polysaccharides. Int Immunopharmacol 17:1009–1019PubMedCrossRefGoogle Scholar
  53. 53.
    Kulkarni OP et al (2014) Toll-like receptor 4-induced IL-22 accelerates kidney regeneration. J Am Soc Nephrol 25:978–989PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Sonnenberg GF, Mjosberg J, Spits H, Artis D (2013) SnapShot: innate lymphoid cells. Immunity 39:622–622.e621PubMedCrossRefGoogle Scholar
  55. 55.
    Hazenberg MD, Spits H (2014) Human innate lymphoid cells. Blood 124:700–709PubMedCrossRefGoogle Scholar
  56. 56.
    Eken A, Singh AK, Treuting PM, Oukka M (2014) IL-23R+ innate lymphoid cells induce colitis via interleukin-22-dependent mechanism. Mucosal Immunol 7:143–154PubMedCrossRefGoogle Scholar
  57. 57.
    Guo X et al (2014) Induction of innate lymphoid cell-derived interleukin-22 by the transcription factor STAT3 mediates protection against intestinal infection. Immunity 40:25–39PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Kirchberger S et al (2013) Innate lymphoid cells sustain colon cancer through production of interleukin-22 in a mouse model. Jo Exp Med 210:917–931CrossRefGoogle Scholar
  59. 59.
    Lee Y et al (2013) Intestinal Lin- c-Kit+ NKp46- CD4- population strongly produces IL-22 upon IL-1beta stimulation. J Immunol (Baltimore, Md: 1950) 190:5296–5305CrossRefGoogle Scholar
  60. 60.
    Longman RS et al (2014) CX(3)CR1(+) mononuclear phagocytes support colitis-associated innate lymphoid cell production of IL-22. J Exp Med 211:1571–1583PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Annunziato F, Romagnani C, Romagnani S (2015) The 3 major types of innate and adaptive cell-mediated effector immunity. Jo Allergy Clin Immunol 135:626–635CrossRefGoogle Scholar
  62. 62.
    Walker JA, Barlow JL, McKenzie AN (2013) Innate lymphoid cells--how did we miss them? Nat Rev Immunol 13:75–87PubMedCrossRefGoogle Scholar
  63. 63.
    Killig M, Glatzer T, Romagnani C (2014) Recognition strategies of group 3 innate lymphoid cells. Front Immunol 5:142PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Satoh-Takayama N et al (2008) Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense. Immunity 29:958–970PubMedCrossRefGoogle Scholar
  65. 65.
    Sanos SL et al (2009) RORgammat and commensal microflora are required for the differentiation of mucosal interleukin 22-producing NKp46+ cells. Nat Immunol 10:83–91PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Spits H, Di Santo JP (2011) The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling. Nat Immunol 12:21–27PubMedCrossRefGoogle Scholar
  67. 67.
    Xu W et al (2015) NFIL3 orchestrates the emergence of common helper innate lymphoid cell precursors. Cell Rep 10:2043–2054PubMedCrossRefGoogle Scholar
  68. 68.
    Yu, X et al (2014) The basic leucine zipper transcription factor NFIL3 directs the development of a common innate lymphoid cell precursor. eLife 3, doi: 10.7554/eLife.04406
  69. 69.
    Geiger TL et al (2014) Nfil3 is crucial for development of innate lymphoid cells and host protection against intestinal pathogens. J Exp Med 211:1723–1731PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Seillet C et al (2014) Nfil3 is required for the development of all innate lymphoid cell subsets. J Exp Med 211:1733–1740PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Constantinides MG et al (2015) PLZF expression maps the early stages of ILC1 lineage development. Proc Natl Acad Sci U S A 112:5123–5128PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Spits H, Cupedo T (2012) Innate lymphoid cells: emerging insights in development, lineage relationships, and function. Annu Rev Immunol 30:647–675PubMedCrossRefGoogle Scholar
  73. 73.
    Cupedo T et al (2009) Human fetal lymphoid tissue-inducer cells are interleukin 17-producing precursors to RORC+ CD127+ natural killer-like cells. Nat Immunol 10:66–74PubMedCrossRefGoogle Scholar
  74. 74.
    Sun, Z et al (2000) Requirement for RORgamma in thymocyte survival and lymphoid organ development. Science 288, 2369–2373, doi:8641Google Scholar
  75. 75.
    Mebius RE, Rennert P, Weissman IL (1997) Developing lymph nodes collect CD4+CD3- LTbeta+ cells that can differentiate to APC, NK cells, and follicular cells but not T or B cells. Immunity 7, 493–504, doi:S1074-7613(00)80371-4Google Scholar
  76. 76.
    Takatori H et al (2009) Lymphoid tissue inducer-like cells are an innate source of IL-17 and IL-22. J Exp Med 206:35–41PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Luci C et al (2009) Influence of the transcription factor RORgammat on the development of NKp46+ cell populations in gut and skin. Nat Immunol 10:75–82PubMedCrossRefGoogle Scholar
  78. 78.
    Cella M et al (2009) A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature 457:722–725PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Ikeuchi H et al (2005) Expression of interleukin-22 in rheumatoid arthritis: potential role as a proinflammatory cytokine. Arthritis Rheum 52:1037–1046PubMedCrossRefGoogle Scholar
  80. 80.
    Mashiko S et al (2015) Human mast cells are major IL-22 producers in patients with psoriasis and atopic dermatitis. J Allergy Clin Immunol 136:351–359.e351PubMedCrossRefGoogle Scholar
  81. 81.
    Hansson M, Silverpil E, Linden A, Glader P et al (2013) Interleukin-22 produced by alveolar macrophages during activation of the innate immune response. Inflamm Res Off J Eur Histamine Res Soc 62:561–569Google Scholar
  82. 82.
    Zindl CL et al (2013) IL-22-producing neutrophils contribute to antimicrobial defense and restitution of colonic epithelial integrity during colitis. Proc Natl Acad Sci U S A 110:12768–12773PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Singh B, Nikoopour E, Huszarik K, Elliott JF, Jevnikar AM (2011) Immunomodulation and regeneration of islet Beta cells by cytokines in autoimmune type 1 diabetes. J Interf Cytokine Res Off J Int Soc Interf Cytokine Res 31:711–719CrossRefGoogle Scholar
  84. 84.
    Hill T et al (2013) The involvement of interleukin-22 in the expression of pancreatic beta cell regenerative Reg genes. Cell Regen (London, England) 2, 2, doi: 10.1186/2045-9769-2-2
  85. 85.
    Dudakov JA et al (2012) Interleukin-22 drives endogenous thymic regeneration in mice. Science (New York, NY) 336:91–95CrossRefGoogle Scholar
  86. 86.
    Mitra A, Raychaudhuri SK, Raychaudhuri SP (2012) IL-22 induced cell proliferation is regulated by PI3K/Akt/mTOR signaling cascade. Cytokine 60:38–42PubMedCrossRefGoogle Scholar
  87. 87.
    Zhu X et al (2012) Participation of Gab1 and Gab2 in IL-22-mediated keratinocyte proliferation, migration, and differentiation. Mol Cell Biochem 369:255–266PubMedCrossRefGoogle Scholar
  88. 88.
    Feng D et al (2012) Interleukin-22 ameliorates cerulein-induced pancreatitis in mice by inhibiting the autophagic pathway. Int J Biol Sci 8:249–257PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Zenewicz LA et al (2007) Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation. Immunity 27:647–659PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Radaeva S, Sun R, Pan HN, Hong F, Gao B (2004) Interleukin 22 (IL-22) plays a protective role in T cell-mediated murine hepatitis: IL-22 is a survival factor for hepatocytes via STAT3 activation. Hepatology (Baltimore, Md) 39:1332–1342CrossRefGoogle Scholar
  91. 91.
    Ki SH et al (2010) Interleukin-22 treatment ameliorates alcoholic liver injury in a murine model of chronic-binge ethanol feeding: role of signal transducer and activator of transcription 3. Hepatology (Baltimore, Md) 52:1291–1300CrossRefGoogle Scholar
  92. 92.
    Brand S et al (2007) IL-22-mediated liver cell regeneration is abrogated by SOCS-1/3 overexpression in vitro. Am J Physiol Gastrointest Liver Physiol 292:G1019–1028PubMedCrossRefGoogle Scholar
  93. 93.
    Aujla SJ et al (2008) IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia. Nat Med 14:275–281PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Zheng Y et al (2008) Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat Med 14:282–289PubMedCrossRefGoogle Scholar
  95. 95.
    Zhao R et al (2014) Elevated peripheral frequencies of Th22 cells: a novel potent participant in obesity and type 2 diabetes. PLoS One 9, e85770. doi: 10.1371/journal.pone.0085770 PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Wang X et al (2014) Interleukin-22 alleviates metabolic disorders and restores mucosal immunity in diabetes. Nature 514:237–241PubMedGoogle Scholar
  97. 97.
    Di Lullo G et al (2015) Th22 cells increase in poor prognosis multiple myeloma and promote tumor cell growth and survival. Oncoimmunology 4, e1005460. doi: 10.1080/2162402x.2015.1005460 PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Huang YH, Cao YF, Jiang ZY, Zhang S, Gao F (2015) Th22 cell accumulation is associated with colorectal cancer development. World J Gastroenterol 21:4216–4224PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Akil H et al (2015) IL22/IL-22R pathway induces cell survival in human glioblastoma cells. PLoS One 10, e0119872. doi: 10.1371/journal.pone.0119872 PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Nardinocchi L et al (2015) Interleukin-17 and interleukin-22 promote tumor progression in human nonmelanoma skin cancer. Eur J Immunol 45:922–931PubMedCrossRefGoogle Scholar
  101. 101.
    Qin SY et al (2015) Association of interleukin 22 polymorphisms with gastric cancer risk. Tumour Biol J Int Soc Oncodev Biol Med 36:2033–2039CrossRefGoogle Scholar
  102. 102.
    Koltsova EK, Grivennikov SI (2014) IL-22 gets to the stem of colorectal cancer. Immunity 40, 639–641, doi: 10.1016/j.cytogfr.2014.04.005  10.1016/j.immuni.2014.04.014
  103. 103.
    Kryczek I et al (2014) IL-22(+)CD4(+) T cells promote colorectal cancer stemness via STAT3 transcription factor activation and induction of the methyltransferase DOT1L. Immunity 40:772–784PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Wolk K et al (2006) 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 36:1309–1323PubMedCrossRefGoogle Scholar
  105. 105.
    Wolk K et al (2009) The Th17 cytokine IL-22 induces IL-20 production in keratinocytes: a novel immunological cascade with potential relevance in psoriasis. Eur J Immunol 39:3570–3581PubMedCrossRefGoogle Scholar
  106. 106.
    Wolk K et al (2009) IL-22 and IL-20 are key mediators of the epidermal alterations in psoriasis while IL-17 and IFN-gamma are not. J Mol Med (Berlin, Germany) 87:523–536CrossRefGoogle Scholar
  107. 107.
    Li W et al (2009) The serine protease marapsin is expressed in stratified squamous epithelia and is up-regulated in the hyperproliferative epidermis of psoriasis and regenerating wounds. J Biol Chem 284:218–228PubMedCrossRefGoogle Scholar
  108. 108.
    Brand S et al (2006) IL-22 is increased in active Crohn's disease and promotes proinflammatory gene expression and intestinal epithelial cell migration. Am J Physiol Gastrointest Liver Physiol 290:G827–838PubMedCrossRefGoogle Scholar
  109. 109.
    Zenewicz LA et al (2008) Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity 29:947–957PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Sugimoto K et al (2008) IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J Clin Invest 118:534–544PubMedPubMedCentralGoogle Scholar
  111. 111.
    Mizuno S et al (2014) Cross-talk between RORgammat+ innate lymphoid cells and intestinal macrophages induces mucosal IL-22 production in Crohn's disease. Inflamm Bowel Dis 20:1426–1434PubMedCrossRefGoogle Scholar
  112. 112.
    Schmechel S et al (2008) Linking genetic susceptibility to Crohn's disease with Th17 cell function: IL-22 serum levels are increased in Crohn's disease and correlate with disease activity and IL23R genotype status. Inflamm Bowel Dis 14:204–212PubMedCrossRefGoogle Scholar
  113. 113.
    Monteleone I, Pallone F, Monteleone G (2013) Aryl hydrocarbon receptor and colitis. Semin Immunopathol 35:671–675PubMedCrossRefGoogle Scholar
  114. 114.
    Sun X, Chalmers L, Fu X, Zhao M (2012) A Molecular Link Between Interleukin 22 and Intestinal Mucosal Wound Healing. Adv Wound Care 1:231–237CrossRefGoogle Scholar
  115. 115.
    Hanash AM et al (2012) Interleukin-22 protects intestinal stem cells from immune-mediated tissue damage and regulates sensitivity to graft versus host disease. Immunity 37:339–350PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Xue J, Nguyen DT, Habtezion A (2012) Aryl hydrocarbon receptor regulates pancreatic IL-22 production and protects mice from acute pancreatitis. Gastroenterology 143:1670–1680PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Pan H, Hong F, Radaeva S, Gao B (2004) Hydrodynamic gene delivery of interleukin-22 protects the mouse liver from concanavalin A-, carbon tetrachloride-, and Fas ligand-induced injury via activation of STAT3. Cell Mol Immunol 1:43–49PubMedGoogle Scholar
  118. 118.
    Xu X et al (2014) Conventional NK cells can produce IL-22 and promote host defense in Klebsiella pneumoniae pneumonia. J Immunol (Baltimore, Md: 1950) 192:1778–1786PubMedCentralCrossRefGoogle Scholar
  119. 119.
    Eidenschenk C, Rutz S, Liesenfeld O, Ouyang W (2014) Role of IL-22 in microbial host defense. Curr Top Microbiol Immunol 380:213–236PubMedGoogle Scholar
  120. 120.
    Van Maele L et al (2014) Activation of Type 3 innate lymphoid cells and interleukin 22 secretion in the lungs during Streptococcus pneumoniae infection. J Infect Dis 210:493–503PubMedCrossRefGoogle Scholar
  121. 121.
    Mear JB et al (2014) Candida albicans airway exposure primes the lung innate immune response against Pseudomonas aeruginosa infection through innate lymphoid cell recruitment and interleukin-22-associated mucosal response. Infect Immun 82:306–315PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Matthews K et al (2011) Predominance of interleukin-22 over interleukin-17 at the site of disease in human tuberculosis. Tuberculosis (Edinburgh, Scotland) 91:587–593CrossRefGoogle Scholar
  123. 123.
    Dhiman R et al (2014) Interleukin 22 inhibits intracellular growth of Mycobacterium tuberculosis by enhancing calgranulin A expression. J Infect Dis 209:578–587PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Dhiman R et al (2009) IL-22 produced by human NK cells inhibits growth of Mycobacterium tuberculosis by enhancing phagolysosomal fusion. J Immunol (Baltimore, Md: 1950) 183:6639–6645CrossRefGoogle Scholar
  125. 125.
    Zhang B et al (2014) Viral infection. Prevention and cure of rotavirus infection via TLR5/NLRC4-mediated production of IL-22 and IL-18. Science (New York, NY) 346:861–865CrossRefGoogle Scholar
  126. 126.
    Guabiraba R et al (2013) IL-22 modulates IL-17A production and controls inflammation and tissue damage in experimental dengue infection. Eur J Immunol 43:1529–1544PubMedCrossRefGoogle Scholar
  127. 127.
    Cobleigh MA, Robek MD (2013) Protective and pathological properties of IL-22 in liver disease: implications for viral hepatitis. Am J Pathol 182:21–28PubMedCrossRefGoogle Scholar
  128. 128.
    Paget C et al (2012) Interleukin-22 is produced by invariant natural killer T lymphocytes during influenza A virus infection: potential role in protection against lung epithelial damages. J Biol Chem 287:8816–8829PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Guo H, Topham DJ (2010) Interleukin-22 (IL-22) production by pulmonary Natural Killer cells and the potential role of IL-22 during primary influenza virus infection. J Virol 84:7750–7759PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Misse D et al (2007) IL-22 participates in an innate anti-HIV-1 host-resistance network through acute-phase protein induction. J Immunol (Baltimore, Md: 1950) 178:407–415CrossRefGoogle Scholar
  131. 131.
    Wang P et al (2012) IL-22 signaling contributes to West Nile encephalitis pathogenesis. PLoS One 7, e44153. doi: 10.1371/journal.pone.0044153 PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Pociask DA et al (2013) IL-22 is essential for lung epithelial repair following influenza infection. Am J Pathol 182:1286–1296PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Kumar P, Thakar MS, Ouyang W, Malarkannan S (2013) IL-22 from conventional NK cells is epithelial regenerative and inflammation protective during influenza infection. Mucosal Immunol 6:69–82PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Zhao J et al (2014) Pathological functions of interleukin-22 in chronic liver inflammation and fibrosis with hepatitis B virus infection by promoting T helper 17 cell recruitment. Hepatology (Baltimore, Md) 59:1331–1342CrossRefGoogle Scholar
  135. 135.
    Wu LY et al (2015) Up-regulation of interleukin-22 mediates liver fibrosis via activating hepatic stellate cells in patients with hepatitis C. Clin Immunol (Orlando, Fla) 158:77–87CrossRefGoogle Scholar
  136. 136.
    Sun D et al (2015) Th22 cells control colon tumorigenesis through STAT3 and Polycomb Repression complex 2 signalling. OncoimmunologyGoogle Scholar
  137. 137.
    Liu F et al (2014) Genetic polymorphisms and plasma levels of interleukin-22 contribute to the development of nonsmall cell lung cancer. DNA Cell Biol 33:705–714PubMedCrossRefGoogle Scholar
  138. 138.
    Kobold S et al (2013) Interleukin-22 is frequently expressed in small- and large-cell lung cancer and promotes growth in chemotherapy-resistant cancer cells. J Thorac Oncol Off Publ Int Assoc Stud Lung Cancer 8:1032–1042Google Scholar
  139. 139.
    Zhang W et al (2008) Antiapoptotic activity of autocrine interleukin-22 and therapeutic effects of interleukin-22-small interfering RNA on human lung cancer xenografts. Clin Cancer Res: an Off J Am Assoc Cancer Res 14:6432–6439CrossRefGoogle Scholar
  140. 140.
    Wen Z et al (2014) High expression of interleukin-22 and its receptor predicts poor prognosis in pancreatic ductal adenocarcinoma. Ann Surg Oncol 21:125–132PubMedCrossRefGoogle Scholar
  141. 141.
    Waidmann O et al (2014) Interleukin-22 serum levels are a negative prognostic indicator in patients with hepatocellular carcinoma. Hepatology (Baltimore, Md) 59:1207CrossRefGoogle Scholar
  142. 142.
    Jiang R et al (2011) Interleukin-22 promotes human hepatocellular carcinoma by activation of STAT3. Hepatology (Baltimore, Md) 54:900–909CrossRefGoogle Scholar
  143. 143.
    Jiang R et al (2013) IL-22 is related to development of human colon cancer by activation of STAT3. BMC Cancer 13:59PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Yu LZ et al (2013) Expression of interleukin-22/STAT3 signaling pathway in ulcerative colitis and related carcinogenesis. World J Gastroenterol 19:2638–2649PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Liu T et al (2012) Increased circulating Th22 and Th17 cells are associated with tumor progression and patient survival in human gastric cancer. J Clin Immunol 32:1332–1339PubMedCrossRefGoogle Scholar
  146. 146.
    Zhuang Y et al (2012) Increased intratumoral IL-22-producing CD4(+) T cells and Th22 cells correlate with gastric cancer progression and predict poor patient survival. Cancer Immunol Immunother 61:1965–1975PubMedCrossRefGoogle Scholar
  147. 147.
    Ji Y et al (2014) IL-22 promotes the migration and invasion of gastric cancer cells via IL-22R1/AKT/MMP-9 signaling. Int J Clin Exp Pathol 7:3694–3703PubMedPubMedCentralGoogle Scholar
  148. 148.
    Qin S et al (2014) Th22 cells are associated with hepatocellular carcinoma development and progression. Chin J Cancer Res = Chung-kuo yen cheng yen chiu 26:135–141PubMedGoogle Scholar
  149. 149.
    Park O et al (2011) In vivo consequences of liver-specific interleukin-22 expression in mice: Implications for human liver disease progression. Hepatology (Baltimore, Md) 54:252–261CrossRefGoogle Scholar
  150. 150.
    Zhao D et al (2015) Metformin decreases IL-22 secretion to suppress tumor growth in an orthotopic mouse model of hepatocellular carcinoma. Int J Cancer J Int du Cancer 136:2556–2565CrossRefGoogle Scholar
  151. 151.
    Hidalgo M et al (2015) Addressing the challenges of pancreatic cancer: future directions for improving outcomes. Pancreatol Off J Int Assoc Pancreatol (IAP) 15:8–18CrossRefGoogle Scholar
  152. 152.
    Xu X et al (2014) Increased intratumoral interleukin 22 levels and frequencies of interleukin 22-producing CD4+ T cells correlate with pancreatic cancer progression. Pancreas 43:470–477PubMedCrossRefGoogle Scholar
  153. 153.
    Curd LM, Favors SE, Gregg RK (2012) Pro-tumour activity of interleukin-22 in HPAFII human pancreatic cancer cells. Clin Exp Immunol 168:192–199PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Jin D et al (2011) Diagnostic value of interleukin 22 and carcinoembryonic antigen in tuberculous and malignant pleural effusions. Exp Ther Med 2:1205–1209PubMedPubMedCentralGoogle Scholar
  155. 155.
    Ye ZJ et al (2012) Interleukin 22-producing CD4+ T cells in malignant pleural effusion. Cancer Lett 326:23–32PubMedCrossRefGoogle Scholar
  156. 156.
    Zhang M et al (2011) B cell infiltration is associated with the increased IL-17 and IL-22 expression in the lungs of patients with tuberculosis. Cell Immunol 270:217–223PubMedCrossRefGoogle Scholar
  157. 157.
    Kim K et al (2014) Interleukin-22 promotes epithelial cell transformation and breast tumorigenesis via MAP3K8 activation. Carcinogenesis 35:1352–1361PubMedCrossRefGoogle Scholar
  158. 158.
    Weber GF et al (2006) IL-22-mediated tumor growth reduction correlates with inhibition of ERK1/2 and AKT phosphorylation and induction of cell cycle arrest in the G2-M phase. J Immunol (Baltimore, Md: 1950) 177:8266–8272CrossRefGoogle Scholar
  159. 159.
    Zhang F, Shang D, Zhang Y, Tian Y (2011) Interleukin-22 suppresses the growth of A498 renal cell carcinoma cells via regulation of STAT1 pathway. PLoS One 6, e20382. doi: 10.1371/journal.pone.0020382 PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Siegel R, Naishadham D, Jemal A (2012) Cancer statistics, 2012. CA: a Cancer J Clin 62:10–29CrossRefGoogle Scholar
  161. 161.
    Zhang S et al (2013) Increased Tc22 and Treg/CD8 ratio contribute to aggressive growth of transplant associated squamous cell carcinoma. PLoS One 8, e62154. doi: 10.1371/journal.pone.0062154 PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    Miyagaki T et al (2011) IL-22, but not IL-17, dominant environment in cutaneous T-cell lymphoma. Clin Cancer Res: an Off J Am Assoc Cancer Res 17:7529–7538CrossRefGoogle Scholar
  163. 163.
    Feng D et al (2012) Interleukin-22 promotes proliferation of liver stem/progenitor cells in mice and patients with chronic hepatitis B virus infection. Gastroenterology 143:188–198.e187PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    McGee HM et al (2013) IL-22 promotes fibroblast-mediated wound repair in the skin. J Investig Dermatol 133:1321–1329PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Pickert G et al (2009) STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J Exp Med 206:1465–1472PubMedPubMedCentralCrossRefGoogle Scholar
  166. 166.
    Li Z, Burns AR, Miller SB, Smith CW (2011) CCL20, gammadelta T cells, and IL-22 in corneal epithelial healing. FASEB J Off Publ Fed Am Soc Exp Biol 25:2659–2668Google Scholar
  167. 167.
    Ren X, Hu B, Colletti LM (2010) IL-22 is involved in liver regeneration after hepatectomy. Am J Physiol Gastrointest Liver Physiol 298:G74–80PubMedPubMedCentralCrossRefGoogle Scholar
  168. 168.
    Simonian PL et al (2010) gammadelta T cells protect against lung fibrosis via IL-22. J Exp Med 207:2239–2253PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Liang M et al (2013) Interleukin-22 inhibits bleomycin-induced pulmonary fibrosis. Mediat Inflamm 2013:209179CrossRefGoogle Scholar
  170. 170.
    Kong X, Feng D, Mathews S, Gao B (2013) Hepatoprotective and anti-fibrotic functions of interleukin-22: therapeutic potential for the treatment of alcoholic liver disease. J Gastroenterol Hepatol 28(Suppl 1):56–60PubMedPubMedCentralCrossRefGoogle Scholar
  171. 171.
    Lu DH et al (2015) Interleukin-22 ameliorates liver fibrogenesis by attenuating hepatic stellate cell activation and downregulating the levels of inflammatory cytokines. World J Gastroenterol 21:1531–1545PubMedPubMedCentralCrossRefGoogle Scholar
  172. 172.
    Kanda N, Watanabe S (2012) Increased serum human beta-defensin-2 levels in atopic dermatitis: relationship to IL-22 and oncostatin M. Immunobiology 217:436–445PubMedCrossRefGoogle Scholar
  173. 173.
    Wolk K et al (2004) IL-22 increases the innate immunity of tissues. Immunity 21:241–254PubMedCrossRefGoogle Scholar
  174. 174.
    Murano T et al (2014) Hes1 promotes the IL-22-mediated antimicrobial response by enhancing STAT3-dependent transcription in human intestinal epithelial cells. Biochem Biophys Res Commun 443:840–846PubMedCrossRefGoogle Scholar
  175. 175.
    Munoz M et al (2015) Interleukin-22 induces interleukin-18 expression from epithelial cells during intestinal infection. Immunity 42:321–331PubMedCrossRefGoogle Scholar
  176. 176.
    Cho KA, Suh JW, Lee KH, Kang JL, Woo SY (2012) IL-17 and IL-22 enhance skin inflammation by stimulating the secretion of IL-1beta by keratinocytes via the ROS-NLRP3-caspase-1 pathway. Int Immunol 24:147–158PubMedCrossRefGoogle Scholar
  177. 177.
    Kong X et al (2012) Interleukin-22 induces hepatic stellate cell senescence and restricts liver fibrosis in mice. Hepatology (Baltimore, Md) 56:1150–1159CrossRefGoogle Scholar
  178. 178.
    Andoh A et al (2005) Interleukin-22, a member of the IL-10 subfamily, induces inflammatory responses in colonic subepithelial myofibroblasts. Gastroenterology 129:969–984PubMedCrossRefGoogle Scholar
  179. 179.
    Liang SC et al (2010) IL-22 induces an acute-phase response. J Immunol (Baltimore, Md: 1950) 185:5531–5538CrossRefGoogle Scholar
  180. 180.
    Zhang Y et al (2011) A proinflammatory role for interleukin-22 in the immune response to hepatitis B virus. Gastroenterology 141:1897–1906PubMedPubMedCentralCrossRefGoogle Scholar
  181. 181.
    Shioya M, Andoh A, Kakinoki S, Nishida A, Fujiyama Y (2008) Interleukin 22 receptor 1 expression in pancreas islets. Pancreas 36:197–199PubMedCrossRefGoogle Scholar
  182. 182.
    Kotenko SV et al (2001) Identification of the functional interleukin-22 (IL-22) receptor complex: the IL-10R2 chain (IL-10Rbeta ) is a common chain of both the IL-10 and IL-22 (IL-10-related T cell-derived inducible factor, IL-TIF) receptor complexes. The J Biol Chem 276:2725–2732PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  1. 1.Department of SurgeryUniversity of Michigan School of MedicineAnn ArborUSA
  2. 2.Division of Gastroenterology and Hepatology, Renji Hospital, School of MedicineShanghai Jiao-Tong UniversityShanghaiChina
  3. 3.The University of Michigan Comprehensive Cancer CenterUniversity of MichiganAnn ArborUSA
  4. 4.Graduate Programs in Immunology and Tumor BiologyUniversity of MichiganAnn ArborUSA

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