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

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

Rent or buy this article

Prices vary by article type

from$1.95

to$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

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  PubMed  Google Scholar 

  104. He, M. & Liang, P. IL-24 transgenic mice: in vivo evidence of overlapping functions for IL-20, IL-22, and IL-24 in the epidermis. J. Immunol. 184, 1793–1798 (2010).

    Article  CAS  PubMed  Google Scholar 

  105. Stenderup, K. et al. Interleukin-20 plays a critical role in maintenance and development of psoriasis in the human xenograft transplantation model. Br. J. Dermatol. 160, 284–296 (2009).

    Article  CAS  PubMed  Google Scholar 

  106. Teraki, Y., Sakurai, A. & Izaki, S. IL-13/IL-22-coproducing T cells, a novel subset, are increased in atopic dermatitis. J. Allergy Clin. Immunol. 132, 971–974 (2013).

    Article  CAS  PubMed  Google Scholar 

  107. Ong, P. Y. et al. Endogenous antimicrobial peptides and skin infections in atopic dermatitis. N. Engl. J. Med. 347, 1151–1160 (2002).

    Article  CAS  PubMed  Google Scholar 

  108. Jemec, G. B. Clinical practice. Hidradenitis suppurativa. N. Engl. J. Med. 366, 158–164 (2012).

    Article  CAS  PubMed  Google Scholar 

  109. Geremia, A. et al. IL-23-responsive innate lymphoid cells are increased in inflammatory bowel disease. J. Exp. Med. 208, 1127–1133 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Andoh, A. et al. Expression of IL-24, an activator of the JAK1/STAT3/SOCS3 cascade, is enhanced in inflammatory bowel disease. J. Immunol. 183, 687–695 (2009).

    Article  CAS  PubMed  Google Scholar 

  111. Fonseca-Camarillo, G., Furuzawa-Carballeda, J., Llorente, L. & Yamamoto-Furusho, J. K. IL-10- and IL-20-expressing epithelial and inflammatory cells are increased in patients with ulcerative colitis. J. Clin. Immunol. 33, 640–648 (2013).

    Article  CAS  PubMed  Google Scholar 

  112. Dige, A. et al. Increased levels of circulating Th17 cells in quiescent versus active Crohn's disease. J. Crohns Colitis 7, 248–255 (2013).

    Article  PubMed  Google Scholar 

  113. Zenewicz, L. A. et al. Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity 29, 947–957 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Zenewicz, L. A. et al. IL-22 deficiency alters colonic microbiota to be transmissible and colitogenic. J. Immunol. 190, 5306–5312 (2013).

    Article  CAS  PubMed  Google Scholar 

  115. Pickert, G. et al. STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J. Exp. Med. 206, 1465–1472 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Munoz, M. et al. Interleukin (IL)-23 mediates Toxoplasma gondii-induced immunopathology in the gut via matrixmetalloproteinase-2 and IL-22 but independent of IL-17. J. Exp. Med. 206, 3047–3059 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Kamanaka, M. et al. Memory/effector (CD45RBlo) CD4 T cells are controlled directly by IL-10 and cause IL-22-dependent intestinal pathology. J. Exp. Med. 208, 1027–1040 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Broadhurst, M. J. et al. IL-22+ CD4+ T cells are associated with therapeutic trichuris trichiura infection in an ulcerative colitis patient. Sci Transl Med. 2, 60ra88 (2010).

    Article  CAS  PubMed  Google Scholar 

  119. Besnard, A. G. et al. Dual Role of IL-22 in allergic airway inflammation and its cross-talk with IL-17A. Am. J. Respir. Crit. Care Med. 183, 1153–1163 (2011).

    Article  CAS  PubMed  Google Scholar 

  120. Farfariello, V. et al. IL-22 mRNA in peripheral blood mononuclear cells from allergic rhinitic and asthmatic pediatric patients. Pediatr. Allergy Immunol. 22, 419–423 (2011).

    Article  PubMed  Google Scholar 

  121. Takahashi, K. et al. IL-22 attenuates IL-25 production by lung epithelial cells and inhibits antigen-induced eosinophilic airway inflammation. J. Allergy Clin. Immunol. 128, 1067–1076 (2011).

    Article  CAS  PubMed  Google Scholar 

  122. Nakagome, K. et al. High expression of IL-22 suppresses antigen-induced immune responses and eosinophilic airway inflammation via an IL-10-associated mechanism. J. Immunol. 187, 5077–5089 (2011).

    Article  CAS  PubMed  Google Scholar 

  123. Paget, C. et al. 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, 8816–8829 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Kudo, M. et al. IL-17A produced by αβ T cells drives airway hyper-responsiveness in mice and enhances mouse and human airway smooth muscle contraction. Nature Med. 18, 547–554 (2012).

    Article  CAS  PubMed  Google Scholar 

  125. Simonian, P. L. et al. γδ T cells protect against lung fibrosis via IL-22. J. Exp. Med. 207, 2239–2253 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Hoegl, S. et al. Protective properties of inhaled IL-22 in a model of ventilator-induced lung injury. Am. J. Respir. Cell. Mol. Biol. 44, 369–376 (2011).

    Article  CAS  PubMed  Google Scholar 

  127. Sonnenberg, G. F. et al. Pathological versus protective functions of IL-22 in airway inflammation are regulated by IL-17A. J. Exp. Med. 207, 1293–1305 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Graham, A. C. et al. IL-22 production is regulated by IL-23 during Listeria monocytogenes infection but is not required for bacterial clearance or tissue protection. PLoS ONE 6, e17171 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Schulz, S. M. et al. Protective immunity to systemic infection with attenuated Salmonella enterica serovar enteritidis in the absence of IL-12 is associated with IL-23-dependent IL-22, but not IL-17. J. Immunol. 181, 7891–7901 (2008).

    Article  CAS  PubMed  Google Scholar 

  130. Lin, Y. et al. Interleukin-17 is required for T helper 1 cell immunity and host resistance to the intracellular pathogen Francisella tularensis. Immunity 31, 799–810 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Sonnenberg, G. F. et al. Innate lymphoid cells promote anatomical containment of lymphoid-resident commensal bacteria. Science 336, 1321–1325 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Berer, K. et al. Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature 479, 538–541 (2011).

    Article  CAS  PubMed  Google Scholar 

  133. Markle, J. G. et al. Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science 339, 1084–1088 (2013).

    Article  CAS  PubMed  Google Scholar 

  134. Gessner, M. A. et al. Dectin-1-dependent interleukin-22 contributes to early innate lung defense against Aspergillus fumigatus. Infect. Immun. 80, 410–417 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. De Luca, A. et al. IL-22 defines a novel immune pathway of antifungal resistance. Mucosal Immunol. 3, 361–373 (2010).

    Article  CAS  PubMed  Google Scholar 

  136. Kagami, S., Rizzo, H. L., Kurtz, S. E., Miller, L. S. & Blauvelt, A. IL-23 and IL-17A, but not IL-12 and IL-22, are required for optimal skin host defense against Candida albicans. J. Immunol. 185, 5453–5462 (2010).

    Article  CAS  PubMed  Google Scholar 

  137. Kisand, K. et al. Chronic mucocutaneous candidiasis in APECED or thymoma patients correlates with autoimmunity to Th17-associated cytokines. J. Exp. Med. 207, 299–308 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Pociask, D. A. et al. IL-22 is essential for lung epithelial repair following influenza infection. Am. J. Pathol. 182, 1286–1296 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Ivanov, S. et al. Interleukin-22 reduces lung inflammation during influenza A virus infection and protects against secondary bacterial infection. J. Virol. 87, 6911–6924 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Klatt, N. R. et al. Loss of mucosal CD103+ DCs and IL-17+ and IL-22+ lymphocytes is associated with mucosal damage in SIV infection. Mucosal Immunol. 5, 646–657 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Kim, C. J. et al. A role for mucosal IL-22 production and Th22 cells in HIV-associated mucosal immunopathogenesis. Mucosal Immunol. 5, 670–680 (2012).

    Article  CAS  PubMed  Google Scholar 

  142. Dambacher, J. et al. The role of interleukin-22 in hepatitis C virus infection. Cytokine 41, 209–216 (2008).

    Article  CAS  PubMed  Google Scholar 

  143. Pan, H., Hong, F., Radaeva, S. & Gao, B. 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, 43–49 (2004).

    CAS  PubMed  Google Scholar 

  144. Zenewicz, L. A. et al. Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation. Immunity 27, 647–659 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Xing, W. W. et al. Interleukin-22 protects against acute alcohol-induced hepatotoxicity in mice. Biosci. Biotechnol. Biochem. 75, 1290–1294 (2011).

    Article  CAS  PubMed  Google Scholar 

  146. Chestovich, P. J. et al. Interleukin-22: implications for liver ischemia-reperfusion injury. Transplantation 93, 485–492 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Mastelic, B. et al. IL-22 protects against liver pathology and lethality of an experimental blood-stage malaria infection. Front. Immunol. 3, 85 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  148. Ren, X., Hu, B. & Colletti, L. M. IL-22 is involved in liver regeneration after hepatectomy. Am. J. Physiol. Gastrointest. Liver Physiol. 298, G74–G80 (2010).

    Article  CAS  PubMed  Google Scholar 

  149. Shen, H., Goodall, J. C. & Hill Gaston, J. S. Frequency and phenotype of peripheral blood Th17 cells in ankylosing spondylitis and rheumatoid arthritis. Arthritis Rheum. 60, 1647–1656 (2009).

    Article  CAS  PubMed  Google Scholar 

  150. Cascao, R. et al. Identification of a cytokine network sustaining neutrophil and Th17 activation in untreated early rheumatoid arthritis. Arthritis Res. Ther. 12, R196 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Leipe, J. et al. Interleukin 22 serum levels are associated with radiographic progression in rheumatoid arthritis. Ann. Rheum. Dis. 70, 1453–1457 (2011).

    Article  CAS  PubMed  Google Scholar 

  152. Zhang, L. et al. Elevated Th22 cells correlated with Th17 cells in patients with rheumatoid arthritis. J. Clin. Immunol. 31, 606–614 (2011).

    Article  CAS  PubMed  Google Scholar 

  153. da Rocha, L. F. Jr et al. Increased serum interleukin 22 in patients with rheumatoid arthritis and correlation with disease activity. J. Rheumatol 39, 1320–1325 (2012).

    Article  CAS  PubMed  Google Scholar 

  154. Geboes, L. et al. Proinflammatory role of the Th17 cytokine interleukin-22 in collagen-induced arthritis in C57BL/6 mice. Arthritis Rheum. 60, 390–395 (2009).

    Article  CAS  PubMed  Google Scholar 

  155. Marijnissen, R. J. et al. Increased expression of interleukin-22 by synovial Th17 cells during late stages of murine experimental arthritis is controlled by interleukin-1 and enhances bone degradation. Arthritis Rheum. 63, 2939–2948 (2011).

    Article  CAS  PubMed  Google Scholar 

  156. van Hamburg, J. P. et al. IL-17/Th17 mediated synovial inflammation is IL-22 independent. Ann. Rheum. Dis. (2013).

  157. Sarkar, S., Zhou, X., Justa, S. & Bommireddy, S. R. Interleukin-22 reduces the severity of collagen-induced arthritis in association with increased levels of interleukin-10. Arthritis Rheum. 65, 960–971 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Kragstrup, T. W. et al. The expression of IL-20 and IL-24 and their shared receptors are increased in rheumatoid arthritis and spondyloarthropathy. Cytokine 41, 16–23 (2008).

    Article  CAS  PubMed  Google Scholar 

  159. Hsu, Y. H. & Chang, M. S. Interleukin-20 antibody is a potential therapeutic agent for experimental arthritis. Arthritis Rheum. 62, 3311–3321 (2010).

    Article  CAS  PubMed  Google Scholar 

  160. Hsu, Y. H. et al. Anti-IL-20 monoclonal antibody inhibits the differentiation of osteoclasts and protects against osteoporotic bone loss. J. Exp. Med. 208, 1849–1861 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Sherlock, J. P. et al. IL-23 induces spondyloarthropathy by acting on ROR-gammat+ CD3+CD4CD8 entheseal resident T cells. Nature Med. 18, 1069–1076 (2012). This is the first description of an important role of IL-22 in enthesis.

    Article  CAS  PubMed  Google Scholar 

  162. Jiang, R. et al. IL-22 is related to development of human colon cancer by activation of STAT3. BMC Cancer 13, 59 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Zhuang, Y. et al. 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, 1965–1975 (2012).

    Article  CAS  PubMed  Google Scholar 

  164. Jiang, R. et al. Interleukin-22 promotes human hepatocellular carcinoma by activation of STAT3. Hepatology 54, 900–909 (2011).

    Article  CAS  PubMed  Google Scholar 

  165. Kobold, S. et al. Interleukin-22 Is frequently expressed in small- and large-cell lung cancer and promotes growth in chemotherapy-resistant cancer cells. J. Thorac. Oncol. 8, 1032–1042 (2013).

    Article  CAS  PubMed  Google Scholar 

  166. Wang, Z. et al. High fat diet induces formation of spontaneous liposarcoma in mouse adipose tissue with overexpression of interleukin 22. PLoS ONE 6, e23737 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Kirchberger, S. et al. Innate lymphoid cells sustain colon cancer through production of interleukin-22 in a mouse model. J. Exp. Med. 210, 917–931 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Croft, M., Benedict, C. A. & Ware, C. F. Clinical targeting of the TNF and TNFR superfamilies. Nature Rev. Drug Discov. 12, 147–168 (2013).

    Article  CAS  Google Scholar 

  169. Papp, K. A. et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet 371, 1675–1684 (2008).

    Article  CAS  PubMed  Google Scholar 

  170. Leonardi, C. L. et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 371, 1665–1674 (2008).

    Article  CAS  PubMed  Google Scholar 

  171. Leonardi, C. et al. Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. N. Engl. J. Med. 366, 1190–1199 (2012).

    Article  CAS  PubMed  Google Scholar 

  172. Miossec, P. & Kolls, J. K. Targeting IL-17 and TH17 cells in chronic inflammation. Nature Rev. Drug Discov. 11, 763–776 (2012). This review highlights the biology of IL-17 and T H 17 cells, their role in disease and clinical trials using IL-17 and IL-17R inhibitors.

    Article  CAS  Google Scholar 

  173. Förster, R., Braun, A. & Worbs T. Lymph node homing of T cells and dendritic cells via afferent lymphatics. Trends Immunol. 33, 271–280 (2012).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Robert Sabat.

Ethics declarations

Competing interests

W.O. is an employee of Genentech.

Related links

PowerPoint slides

Glossary

IL-10 cytokine family

A group of cytokines that, in humans, comprises interleukin-10 (IL-10), IL-19, IL-20, IL-22, IL-24, IL-26 and the interferon-λ (IFNλ) species (IL-28α, IL-28β and IL-29).

Antibacterial proteins

Small proteins that are mainly produced by epithelial cells and phagocytes; these proteins kill or inhibit the growth of bacteria using different mechanisms, including pore formation in the bacterial membrane and sequestration of metal ions that are essential for bacterial growth.

Psoriasis

A chronic disease that is characterized by red, raised, sharply demarcated, scaling skin lesions that frequently occur on the scalp, the back and the extension side of the limbs. Lesions have infiltration of immune cells in the dermis and epidermis, and a massively altered epidermis structure.

Innate lymphoid cells

(ILCs). Immune cells that are characterized by lymphoid morphology, the absence of T cell and B cell receptors and a lack of myeloid cell surface markers. Based on their cytokine production profile, they are divided into three groups: group 1 cells (which have a profile similar to T helper 1 (TH1) cells), group 2 cells (which have a profile similar to TH2 cells) and group 3 cells (which have a profile similar to TH17 and TH22 cells).

Class 2 cytokine receptor family

A group of transmembrane receptor chains with extracellular domains composed of two tandem fibronectin type III domains that have conserved cysteine residues but that do not contain the Trp-Ser-X-Trp-Ser motif that is typical of the class 1cytokine receptor family.

Janus kinases

A group of tyrosine kinases (JAK1, JAK2, JAK3 and TYK2) that are associated with the intracellular domains of the class I and class II family of cytokine receptors. By initiating phosphorylation steps, they transduce the signal that is generated from a receptor complex (following the binding of the cytokine to the receptor) to intracellular signal transducer and activator of transcription (STAT) molecules.

Mucus-associated proteins

A family of macromolecules composed of a central protein that is highly glycosylated. Glycosylation is associated with a very high water-binding capacity and protection from proteolysis. These molecules are produced by cells of the respiratory and intestinal tracts, where they form the mucus that protects the epithelial layer.

Acanthosis

Thickening of the stratum spinosum layer of the epidermis.

Parakeratosis

The presence of remnants of the cell nucleus in the epidermal stratum corneum, caused by dysfunction of the keratinocyte cornification process.

Acute-phase proteins

Plasma proteins, levels of which increase (positive acute-phase proteins) or decrease (negative acute-phase proteins) during infection or inflammation owing to altered secretion — mostly by hepatocytes — in response to circulating cytokines.

Rheumatoid arthritis

A systemic autoimmune disease with a relapsing progressive course that begins with synovitis and leads to arthritis, tendovaginitis and substantial loss of function of affected joints.

Hepatitis

A group of liver disorders characterized by inflammation and the presence of immune cells within the organ. The persistent inflammation and immune cell attack on hepatocytes leads to hepatocyte injury, fibrosis and consequent loss of liver function.

Pancreatitis

A disorder of the pancreas that is characterized by intrapancreatic activation of digestive enzymes, immune cell infiltration and progressive destruction of the exocrine — and eventually also endocrine — tissue of this organ.

Atopic dermatitis

A chronic skin disease that is characterized by itchy, red and flaky lesions that often occur on bending sides of the limbs. The lesions have infiltration of immune cells in the dermis and epidermis as well as acanthosis, fibrosis and collagen deposition in the chronic stage.

Acne inversa

A chronic inflammatory disease that affects axillary, inguinal and perianal skin areas, leads to the development of inflamed nodules, abscesses and fistula, and is associated with painful tissue destruction, malodorous purulence and extensive scarring.

Crohn's disease

A chronic bowel disease — often located in the terminal ileum and proximal colon — that is characterized by an inflammation of all layers of the intestinal wall. Typical characteristics include ulcerations, crypt abscesses that have neutrophilic granulocytes, granuloma-containing macrophages and subserous lymphocyte aggregates.

Ulcerative colitis

A chronic bowel disease that mostly begins from the rectum and continuously spreads proximally. It usually affects the mucosa, which is infiltrated with lymphocytes and macrophages.

Asthma

The most common form of chronic inflammatory airway disease that is characterized by bronchial hyperresponsiveness and variable, recurring and reversible airflow obstructions.

Ovalbumin-induced asthma

A mouse model of human asthma. The repeated application of ovalbumin during the sensitization phase leads to the generation of ovalbumin-specific T helper cells. Lung inflammation is induced by subsequent intranasal application of ovalbumin (effector phase).

Citrobacter rodentium

A bacterium that induces acute colitis in mice. This infectious colitis is used as a murine model of human infection produced by attaching and effacing bacterial pathogens such as enterohaemorrhagic Escherichia coli and enteropathogenic E. coli, which cause diarrhoea, morbidity and mortality, especially among infants and children.

Rheumatoid factor

Autoantibodies against the Fc portion of an organism's own immunoglobulin G. Around 80% of patients suffering from rheumatoid arthritis have high levels of rheumatoid factor, whereas only 5% of healthy people have rheumatoid factor, and mostly at a low level.

Enthesitis

Inflammation at the sites where tendons or ligaments insert into the bone. Enthesitis is often associated with ankylosing spondylitis and psoriatic arthritis.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sabat, R., Ouyang, W. & Wolk, K. Therapeutic opportunities of the IL-22–IL-22R1 system. Nat Rev Drug Discov 13, 21–38 (2014). https://doi.org/10.1038/nrd4176

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd4176

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer