Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Therapeutic opportunities of the IL-22–IL-22R1 system

Nature Reviews Drug Discovery volume 13, pages 21–38 (2014) Cite this article

View saved research

Key Points

  • Interleukin-22 (IL-22) is a cytokine that is produced during inflammation by activated T cells, including T helper 22 (TH22), TH17 and TH1 cells, and by subsets of innate lymphoid cells (ILCs).

  • Via its transmembrane receptor complex composed of IL-22 receptor 1 (IL-22R1) and IL-10R2, IL-22 mainly influences epithelial cells, hepatocytes, pancreatic acinar cells and related stem cells.

  • In many of its target cells, IL-22 enhances the production of antibacterial proteins, inhibits their differentiation and/or increases their proliferation, and protects them against damage. Furthermore, it potentiates the tumour necrosis factor (TNF)- and IL-17-induced production of pro-inflammatory mediators.

  • Therapeutic strengthening of the IL-22–IL-22R system — for example, through the application of recombinant IL-22 or IL-22-inducing small molecules — might have a beneficial impact in liver and pancreas damage, ulcerative colitis, graft-versus-host disease and transplantation of IL-22R1-expressing organs.

  • Conversely, the regenerative and protective effects mediated via IL-22R1 might have a pathogenetic role in, for example, psoriasis and tumorigenesis of IL-22R1-expressing cancers, which suggests that attenuation of the IL22–IL-22R system might be beneficial in such situations.

  • Targeting IL-22R1 (for example, with antibodies) may produce better clinical results than IL-22 neutralization, because two other cytokines — IL-20 and IL-24 — are often co-produced during inflammation and can mediate IL-22-like effects in an IL-22R1-dependent manner.

  • Owing to the lack of IL-22R1 expression on haematopoietic cells, therapeutic modulation of the IL-22–IL-22R1 system is not expected to be accompanied by severe immunological side effects.

Abstract

Interleukin-22 (IL-22) is a key effector molecule that is produced by activated T cells, including T helper 22 (TH22) cells, TH17 cells and TH1 cells, as well as subsets of innate lymphoid cells. Although IL-22 can act synergistically with IL-17 or tumour necrosis factor, some important functions of IL-22 are unique to this cytokine. Data obtained over the past few years indicate that the IL-22–IL-22 receptor subunit 1 (IL-22R1) system has a high potential clinical relevance in psoriasis, ulcerative colitis, graft-versus-host disease, certain infections and tumours, as well as in liver and pancreas damage. This Review highlights current knowledge of the biology of the IL-22–IL-22R1 system, its role in inflammation, tissue protection, regeneration and antimicrobial defence, as well as the positive and potentially negative consequences of its therapeutic modulation.

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: IL-22–IL-22R1 system and downstream signalling events.
Figure 2: Key effects of IL-22.
Figure 3: Role of the IL-22–IL-22R1 system in psoriasis.
Figure 4: Role of the IL-22–IL-22R1 system in the defence against intestinal infections.
Figure 5: Roles of the IL-22–IL-22R1 system in liver damage.
Figure 6: Options for therapeutic modulation of the IL-22–IL-22R1 system.

Similar content being viewed by others

Explore related subjects

Discover the latest articles and news in related subjects.

References

  1. Dumoutier, L., Louahed, J. & Renauld, J. C. 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. 164, 1814–1819 (2000). This article describes the discovery of IL-22.

    Article  CAS  PubMed  Google Scholar 

  2. Dumoutier, L., Van Roost, E., Colau, D. & Renauld, J. C. Human interleukin-10-related T cell-derived inducible factor: molecular cloning and functional characterization as an hepatocyte-stimulating factor. Proc. Natl Acad. Sci. USA 97, 10144–10149 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Xie, M. H. et al. Interleukin (IL)-22, a novel human cytokine that signals through the interferon receptor-related proteins CRF2-4 and IL-22R. J. Biol. Chem. 275, 31335–31339 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Ouyang, W., Rutz, S., Crellin, N. K., Valdez, P. A. & Hymowitz, S. G. Regulation and functions of the IL-10 family of cytokines in inflammation and disease. Annu. Rev. Immunol. 29, 71–109 (2011).

    Article  CAS  PubMed  Google Scholar 

  5. Sabat, R. IL-10 family of cytokines. Cytokine Growth Factor Rev. 21, 315–324 (2010).

    Article  CAS  PubMed  Google Scholar 

  6. Wolk, K. et al. IL-22 increases the innate immunity of tissues. Immunity 21, 241–254 (2004). This paper shows, for the first time, that IL-22 does not regulate the function of immune cells, identifies keratinocytes as the target cells of IL-22 (in which IL-22 induces antibacterial protein production) and associates IL-22 with chronic inflammatory skin diseases.

    Article  CAS  PubMed  Google Scholar 

  7. Nagem, R. A. et al. Crystal structure of recombinant human interleukin-22. Structure 10, 1051–1062 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Xu, T., Logsdon, N. J. & Walter, M. R. Structure of insect-cell-derived IL-22. Acta Crystallogr. D Biol. Crystallogr. 61, 942–950 (2005).

    Article  CAS  PubMed  Google Scholar 

  9. de Oliveira Neto, M. et al. Interleukin-22 forms dimers that are recognized by two interleukin-22R1 receptor chains. Biophys. J. 94, 1754–1765 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Logsdon, N. J., Jones, B. C., Josephson, K., Cook, J. & Walter, M. R. Comparison of interleukin-22 and interleukin-10 soluble receptor complexes. J. Interferon Cytokine Res. 22, 1099–1112 (2002).

    Article  CAS  PubMed  Google Scholar 

  11. Wolk, K., Kunz, S., Asadullah, K. & Sabat, R. Cutting edge: immune cells as sources and targets of the IL-10 family members? J. Immunol. 168, 5397–5402 (2002).

    Article  CAS  PubMed  Google Scholar 

  12. Liang, S. C. et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J. Exp. Med. 203, 2271–2279 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Chung, Y. et al. Expression and regulation of IL-22 in the IL-17-producing CD4+ T lymphocytes. Cell Res. 16, 902–907 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Zheng, Y. et al. Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature 445, 648–651 (2007).

    Article  CAS  PubMed  Google Scholar 

  15. Rutz, S. et al. Transcription factor c-Maf mediates the TGF-β-dependent suppression of IL-22 production in TH17 cells. Nature Immunol. 12, 1238–1245 (2011).

    Article  CAS  Google Scholar 

  16. Duhen, T., Geiger, R., Jarrossay, D., Lanzavecchia, A. & Sallusto, F. Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nature Immunol. 10, 857–863 (2009).

    Article  CAS  Google Scholar 

  17. Trifari, S., Kaplan, C. D., Tran, E. H., Crellin, N. K. & Spits, H. Identification of a human helper T cell population that has abundant production of interleukin 22 and is distinct from TH-17, TH1 and TH2 cells. Nature Immunol. 10, 864–871 (2009).

    Article  CAS  Google Scholar 

  18. Witte, E., Witte, K., Warszawska, K., Sabat, R. & Wolk, K. Interleukin-22: a cytokine produced by T, NK and NKT cell subsets, with importance in the innate immune defense and tissue protection. Cytokine Growth Factor Rev. 21, 365–379 (2010).

    Article  CAS  PubMed  Google Scholar 

  19. Satoh-Takayama, N. et al. Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense. Immunity 29, 958–970 (2008).

    Article  CAS  PubMed  Google Scholar 

  20. Sonnenberg, G. F., Monticelli, L. A., Elloso, M. M., Fouser, L. A. & Artis, D. CD4+ lymphoid tissue-inducer cells promote innate immunity in the gut. Immunity 34, 122–134 (2011).

    Article  CAS  PubMed  Google Scholar 

  21. Satoh-Takayama, N. et al. IL-7 and IL-15 independently program the differentiation of intestinal CD3-NKp46+ cell subsets from Id2-dependent precursors. J. Exp. Med. 207, 273–280 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Cupedo, T. et al. Human fetal lymphoid tissue-inducer cells are interleukin 17-producing precursors to RORC+ CD127+ natural killer-like cells. Nature Immunol. 10, 66–74 (2009).

    CAS  Google Scholar 

  23. Sciume, G. et al. Distinct requirements for T-bet in gut innate lymphoid cells. J. Exp. Med. 209, 2331–2338 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Lee, J. S. et al. AHR drives the development of gut ILC22 cells and postnatal lymphoid tissues via pathways dependent on and independent of Notch. Nature Immunol. 13, 144–151 (2012).

    Article  CAS  Google Scholar 

  25. Qiu, J. et al. The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells. Immunity 36, 92–104 (2012).

    Article  CAS  PubMed  Google Scholar 

  26. Rankin, L. C. et al. The transcription factor T-bet is essential for the development of NKp46+ innate lymphocytes via the Notch pathway. Nature Immunol. 14, 389–395 (2013).

    Article  CAS  Google Scholar 

  27. Spits, H. et al. Innate lymphoid cells — a proposal for uniform nomenclature. Nature Rev. Immunol. 13, 145–149 (2013).

    Article  CAS  Google Scholar 

  28. Zheng, Y. et al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nature Med. 14, 282–289 (2008). This is the first paper that demonstrates the essential role of IL-22 in the protection against bacterial colitis in mice.

    Article  CAS  PubMed  Google Scholar 

  29. Basu, R. et al. Th22 cells are an important source of IL-22 for host protection against enteropathogenic bacteria. Immunity 37, 1061–1075 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wolk, K. et al. Maturing dendritic cells are an important source of IL-29 and IL-20 that may cooperatively increase the innate immunity of keratinocytes. J. Leukoc. Biol. 83, 1181–1193 (2008).

    Article  CAS  PubMed  Google Scholar 

  31. Monteleone, I. et al. Aryl hydrocarbon receptor-induced signals up-regulate IL-22 production and inhibit inflammation in the gastrointestinal tract. Gastroenterology 141, 237–248 (2011).

    Article  CAS  PubMed  Google Scholar 

  32. Kotenko, S. V. et al. Identification of the functional interleukin-22 (IL-22) receptor complex: the IL-10R2 chain (IL-10Rβ) is a common chain of both the IL-10 and IL-22 (IL-10-related T cell-derived inducible factor, IL-TIF) receptor complexes. J. Biol. Chem. 276, 2725–2732 (2001).

    Article  CAS  PubMed  Google Scholar 

  33. Jones, B. C., Logsdon, N. J. & Walter, M. R. Structure of IL-22 bound to its high-affinity IL-22R1 chain. Structure 16, 1333–1344 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Bleicher, L. et al. Crystal structure of the IL-22/IL-22R1 complex and its implications for the IL-22 signaling mechanism. FEBS Lett. 582, 2985–2992 (2008).

    Article  CAS  PubMed  Google Scholar 

  35. Yoon, S. I. et al. Structure and mechanism of receptor sharing by the IL-10R2 common chain. Structure 18, 638–648 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Logsdon, N. J. et al. The IL-10R2 binding hot spot on IL-22 is located on the N-terminal helix and is dependent on N-linked glycosylation. J. Mol. Biol. 342, 503–514 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Wolk, K. et al. Is there an interaction between interleukin-10 and interleukin-22? Genes Immun. 6, 8–18 (2005).

    Article  CAS  PubMed  Google Scholar 

  38. Wu, P. W. et al. IL-22R, IL-10R2, and IL-22BP binding sites are topologically juxtaposed on adjacent and overlapping surfaces of IL-22. J. Mol. Biol. 382, 1168–1183 (2008).

    Article  CAS  PubMed  Google Scholar 

  39. Dumoutier, L., Leemans, C., Lejeune, D., Kotenko, S. V. & Renauld, J. C. Cutting edge: STAT activation by IL-19, IL-20 and mda-7 through IL-20 receptor complexes of two types. J. Immunol. 167, 3545–3549 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. Wang, M., Tan, Z., Zhang, R., Kotenko, S. V. & Liang, P. Interleukin 24 (MDA-7/MOB-5) signals through two heterodimeric receptors, IL-22R1/IL-20R2 and IL-20R1/IL-20R2. J. Biol. Chem. 277, 7341–7347 (2002).

    Article  CAS  PubMed  Google Scholar 

  41. Lejeune, D. et al. 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, 33676–33682 (2002).

    Article  CAS  PubMed  Google Scholar 

  42. Dumoutier, L., de Meester, C., Tavernier, J. & Renauld, J. C. New activation modus of STAT3: a tyrosine-less region of the interleukin-22 receptor recruits STAT3 by interacting with its coiled-coil domain. J. Biol. Chem. 284, 26377–26384 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Yuan, Z. L., Guan, Y. J., Chatterjee, D. & Chin, Y. E. Stat3 dimerization regulated by reversible acetylation of a single lysine residue. Science 307, 269–273 (2005).

    Article  CAS  PubMed  Google Scholar 

  44. Nie, Y. et al. STAT3 inhibition of gluconeogenesis is downregulated by SirT1. Nature Cell Biol. 11, 492–500 (2009).

    Article  CAS  PubMed  Google Scholar 

  45. Sestito, R. et al. STAT3-dependent effects of IL-22 in human keratinocytes are counterregulated by sirtuin 1 through a direct inhibition of STAT3 acetylation. FASEB J. 25, 916–927 (2011).

    Article  CAS  PubMed  Google Scholar 

  46. Andoh, A. et al. Interleukin-22, a member of the IL-10 subfamily, induces inflammatory responses in colonic subepithelial myofibroblasts. Gastroenterology 129, 969–984 (2005).

    Article  CAS  PubMed  Google Scholar 

  47. Ikeuchi, H. et al. Expression of interleukin-22 in rheumatoid arthritis: potential role as a proinflammatory cytokine. Arthritis Rheum. 52, 1037–1046 (2005).

    Article  CAS  PubMed  Google Scholar 

  48. Wolk, 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. 36, 1309–1323 (2006).

    Article  CAS  PubMed  Google Scholar 

  49. Zhu, X. et al. Participation of Gab1 and Gab2 in IL-22-mediated keratinocyte proliferation, migration, and differentiation. Mol. Cell Biochem. 369, 255–266 (2012).

    Article  CAS  PubMed  Google Scholar 

  50. Mitra, A., Raychaudhuri, S. K. & Raychaudhuri, S. P. IL-22 induced cell proliferation is regulated by PI3K/Akt/mTOR signaling cascade. Cytokine 60, 38–42 (2012).

    Article  CAS  PubMed  Google Scholar 

  51. Whittington, H. A., Armstrong, L., Uppington, K. M. & Millar, A. B. Interleukin-22: a potential immunomodulatory molecule in the lung. Am. J. Respir. Cell. Mol. Biol. 31, 220–226 (2004).

    Article  CAS  PubMed  Google Scholar 

  52. Aujla, S. J. et al. IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia. Nature Med. 14, 275–281 (2008). This paper describes, for the first time, the essential role of IL-22 in the defence against extracellular Gram-negative bacteria in murine lungs and shows the additive action of IL-17 and IL-22 with respect to chemokine induction.

    Article  CAS  PubMed  Google Scholar 

  53. Sugimoto, K. et al. IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J. Clin. Invest. 118, 534–544 (2008). This paper demonstrates, for the first time, the therapeutic potency for IL-22 in a mouse model of ulcerative colitis and describes a new effect of IL-22: the induction of mucus proteins.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Wolk, K. 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. 87, 523–536 (2009). This paper describes the phenotype of transgenic IL-22-overexpressing mice and highlights the effects of IL-22 on keratinocytes in comparison with the effects of IL-17 and IFNγ with respect to psoriasis.

    Article  CAS  PubMed  Google Scholar 

  55. Aggarwal, S., Xie, M. H., Maruoka, M., Foster, J. & Gurney, A. L. Acinar cells of the pancreas are a target of interleukin-22. J. Interferon Cytokine Res. 21, 1047–1053 (2001).

    Article  CAS  PubMed  Google Scholar 

  56. Shioya, M., Andoh, A., Kakinoki, S., Nishida, A. & Fujiyama, Y. Interleukin 22 receptor 1 expression in pancreas islets. Pancreas 36, 197–199 (2008).

    Article  CAS  PubMed  Google Scholar 

  57. Dudakov, J. A. et al. Interleukin-22 drives endogenous thymic regeneration in mice. Science 336, 91–95 (2012). By demonstrating the IL-22-mediated increase in thymic epithelial cell proliferation and survival, this paper suggests regenerative strategies for improving immune competence after thymic insult.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Hanash, A. M. et al. Interleukin-22 protects intestinal stem cells from immune-mediated tissue damage and regulates sensitivity to graft versus host disease. Immunity 37, 339–350 (2012). This paper identifies intestinal stem cells as IL-22 target cells and demonstrates that IL-22 deficiency in recipients increases their mortality and tissue damage during acute GvHD.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Feng, D. et al. Interleukin-22 promotes proliferation of liver stem/progenitor cells in mice and patients with chronic hepatitis B virus infection. Gastroenterology 143, 188–198 (2012).

    Article  CAS  PubMed  Google Scholar 

  60. Dumoutier, L., Lejeune, D., Colau, D. & Renauld, J. C. Cloning and characterization of IL-22 binding protein, a natural antagonist of IL-10-related T cell-derived inducible factor/IL-22. J. Immunol. 166, 7090–7095 (2001).

    Article  CAS  PubMed  Google Scholar 

  61. Gruenberg, B. H. et al. A novel, soluble homologue of the human IL-10 receptor with preferential expression in placenta. Genes Immun. 2, 329–334 (2001).

    Article  CAS  PubMed  Google Scholar 

  62. Kotenko, S. V. et al. Identification, cloning, and characterization of a novel soluble receptor that binds IL-22 and neutralizes its activity. J. Immunol. 166, 7096–7103 (2001).

    Article  CAS  PubMed  Google Scholar 

  63. Xu, W. et al. A soluble class II cytokine receptor, IL-22RA2, is a naturally occurring IL-22 antagonist. Proc. Natl Acad. Sci. USA 98, 9511–9516 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Wei, C. C., Ho, T. W., Liang, W. G., Chen, G. Y. & Chang, M. S. Cloning and characterization of mouse IL-22 binding protein. Genes Immun. 4, 204–211 (2003).

    Article  CAS  PubMed  Google Scholar 

  65. Weiss, B. et al. Cloning of murine IL-22 receptor alpha 2 and comparison with its human counterpart. Genes Immun. 5, 330–336 (2004).

    Article  CAS  PubMed  Google Scholar 

  66. Wolk, K. et al. IL-22 induces lipopolysaccharide-binding protein in hepatocytes: a potential systemic role of IL-22 in Crohn's disease. J. Immunol. 178, 5973–5981 (2007).

    Article  CAS  PubMed  Google Scholar 

  67. de Moura, P. R. et al. Crystal structure of a soluble decoy receptor IL-22BP bound to interleukin-22. FEBS Lett. 583, 1072–1077 (2009).

    Article  CAS  PubMed  Google Scholar 

  68. Huber, S. et al. IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature 491, 259–263 (2012). This article demonstrates the significance of endogenous IL-22BP in vivo and the importance of IL-22 action during inflammation-amplified tumorigenesis in the colon.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Chang, H. et al. Hydrodynamic-based delivery of an interleukin-22-Ig fusion gene ameliorates experimental autoimmune myocarditis in rats. J. Immunol. 177, 3635–3643 (2006).

    Article  CAS  PubMed  Google Scholar 

  70. Martin, J. C. et al. 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. http://dx.doi.org/10.1038/mi.2013.28 (2013).

  71. Wilson, M. S. et al. Redundant and pathogenic roles for IL-22 in mycobacterial, protozoan, and helminth infections. J. Immunol. 184, 4378–4390 (2010).

    Article  CAS  PubMed  Google Scholar 

  72. Gallo, R. L. & Hooper, L. V. Epithelial antimicrobial defence of the skin and intestine. Nature Rev. Immunol. 12, 503–516 (2012).

    Article  CAS  Google Scholar 

  73. Brand, S. et al. 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–G838 (2006).

    Article  CAS  PubMed  Google Scholar 

  74. Sekikawa, A. et al. Involvement of the IL-22/REG Iα axis in ulcerative colitis. Lab Invest. 90, 496–505 (2010).

    Article  CAS  PubMed  Google Scholar 

  75. Wolk, K., Witte, K. & Sabat, R. Interleukin-28 and interleukin-29: novel regulators of skin biology. J. Interferon Cytokine Res. 30, 617–628 (2010).

    Article  CAS  PubMed  Google Scholar 

  76. Boniface, K. et al. IL-22 inhibits epidermal differentiation and induces proinflammatory gene expression and migration of human keratinocytes. J. Immunol. 174, 3695–3702 (2005).

    Article  CAS  PubMed  Google Scholar 

  77. Sa, S. M. 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. 178, 2229–2240 (2007).

    Article  CAS  PubMed  Google Scholar 

  78. Kumar, P., Thakar, M. S., Ouyang, W. & Malarkannan, S. IL-22 from conventional NK cells is epithelial regenerative and inflammation protective during influenza infection. Mucosal Immunol. 6, 69–82 (2013).

    Article  CAS  PubMed  Google Scholar 

  79. Taube, C. et al. IL-22 is produced by innate lymphoid cells and limits inflammation in allergic airway disease. PLoS ONE 6, e21799 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Wolk, K. et al. The Th17 cytokine IL-22 induces IL-20 production in keratinocytes: a novel immunological cascade with potential relevance in psoriasis. Eur. J. Immunol. 39, 3570–3581 (2009).

    Article  CAS  PubMed  Google Scholar 

  81. Xue, J., Nguyen, D. T. & Habtezion, A. Aryl hydrocarbon receptor regulates pancreatic IL-22 production and protects mice from acute pancreatitis. Gastroenterology 143, 1670–1680 (2012).

    Article  CAS  PubMed  Google Scholar 

  82. Feng, D. et al. Interleukin-22 ameliorates cerulein-induced pancreatitis in mice by inhibiting the autophagic pathway. Int. J. Biol. Sci. 8, 249–257 (2012). This is the first study to show that the increase in IL-22 reduces the severity of acute and chronic pancreatitis in mice.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Hill, T. et al. The involvement of interleukin-22 in the expression of pancreatic beta cell regenerative Reg genes. Cell Regener. 2, 2 (2013).

    Article  CAS  Google Scholar 

  84. Zhang, Y. et al. A proinflammatory role for interleukin-22 in the immune response to hepatitis B virus. Gastroenterology 141, 1897–1906 (2011).

    Article  CAS  PubMed  Google Scholar 

  85. Liang, S. C. et al. IL-22 induces an acute-phase response. J. Immunol. 185, 5531–5538 (2010).

    Article  CAS  PubMed  Google Scholar 

  86. Radaeva, S., Sun, R., Pan, H. N., Hong, F. & Gao, B. 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 39, 1332–1342 (2004). This is the first out of many papers showing the protective role of IL-22 in different types of hepatitis.

    Article  CAS  PubMed  Google Scholar 

  87. Park, O. et al. In vivo consequences of liver-specific interleukin-22 expression in mice: implications for human liver disease progression. Hepatology 54, 252–261 (2011).

    Article  CAS  PubMed  Google Scholar 

  88. Wang, B. et al. IL-17A but not IL-22 suppresses the replication of hepatitis B virus mediated by over-expression of MxA and OAS mRNA in the HepG2.2.15 cell line. Antiviral Res. 97, 285–292 (2013).

    Article  CAS  PubMed  Google Scholar 

  89. Ki, S. H. et al. 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 52, 1291–1300 (2010).

    Article  CAS  PubMed  Google Scholar 

  90. Kim, K. W. et al. Interleukin-22 promotes osteoclastogenesis in rheumatoid arthritis through induction of RANKL in human synovial fibroblasts. Arthritis Rheum. 64, 1015–1023 (2012).

    Article  CAS  PubMed  Google Scholar 

  91. Lo Re, S. et al. IL-17A-producing γδ T and Th17 lymphocytes mediate lung inflammation but not fibrosis in experimental silicosis. J. Immunol. 184, 6367–6377 (2010).

    Article  CAS  PubMed  Google Scholar 

  92. McGee, H. M. et al. IL-22 promotes fibroblast-mediated wound repair in the skin. J. Invest. Dermatol. 133, 1321–1329 (2013).

    Article  CAS  PubMed  Google Scholar 

  93. Sabat, R., Sterry, W., Philipp, S. & Wolk, K. Three decades of psoriasis research: where has it led us? Clin. Dermatol. 25, 504–509 (2007).

    Article  PubMed  Google Scholar 

  94. Wolk, K. et al. IL-29 is produced by TH17 cells and mediates the cutaneous antiviral competence in psoriasis. Sci Transl Med. 5, 204ra129 (2013).

    Article  CAS  PubMed  Google Scholar 

  95. Nograles, K. E. 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. 123, 1244–1252 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Wolk, K. et al. Deficiency of IL-22 contributes to a chronic inflammatory disease: pathogenetic mechanisms in acne inversa. J. Immunol. 186, 1228–1239 (2011).

    Article  CAS  PubMed  Google Scholar 

  97. Romer, J. et al. Epidermal overexpression of interleukin-19 and -20 mRNA in psoriatic skin disappears after short-term treatment with cyclosporine A or calcipotriol. J. Invest. Dermatol. 121, 1306–1311 (2003).

    Article  CAS  PubMed  Google Scholar 

  98. Kunz, S. et al. Interleukin (IL)-19, IL-20 and IL-24 are produced by and act on keratinocytes and are distinct from classical ILs. Exp. Dermatol. 15, 991–1004 (2006).

    Article  CAS  PubMed  Google Scholar 

  99. Ma, H. L. et al. IL-22 is required for Th17 cell-mediated pathology in a mouse model of psoriasis-like skin inflammation. J. Clin. Invest. 118, 597–607 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Van Belle, A. B. et al. IL-22 is required for imiquimod-induced psoriasiform skin inflammation in mice. J. Immunol. 188, 462–469 (2012).

    Article  CAS  PubMed  Google Scholar 

  101. Wang, C. et al. The psoriasis-associated D10N variant of the adaptor Act1 with impaired regulation by the molecular chaperone hsp90. Nature Immunol. 14, 72–81 (2013).

    Article  CAS  Google Scholar 

  102. Zaba, L. C. et al. Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses. J. Exp. Med. 204, 3183–3194 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Blumberg, H. et al. Interleukin 20: discovery, receptor identification, and role in epidermal function. Cell 104, 9–19 (2001).

    Article  CAS  PubMedÂ