The IL-20 subfamily of cytokines — from host defence to tissue homeostasis (original) (raw)

• 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).
  CAS PubMed Google Scholar
• Sabat, R., Ouyang, W. & Wolk, K. Therapeutic opportunities of the IL-22–IL-22R1 system. Nature Rev. Drug Discov. 13, 21–38 (2014).
  CAS Google Scholar
• Leng, R.-X., Pan, H.-F., Tao, J.-H. & Ye, D.-Q. IL-19, IL-20 and IL-24: potential therapeutic targets for autoimmune diseases. Expert Opin. Ther. Targets 15, 119–126 (2011).
  CAS PubMed Google Scholar
• Gallagher, G. et al. Cloning, expression and initial characterization of interleukin-19 (IL-19), a novel homologue of human interleukin-10 (IL-10). Genes Immun. 1, 442–450 (2000).
  CAS PubMed Google Scholar
• Blumberg, H. et al. Interleukin 20: discovery, receptor identification, and role in epidermal function. Cell 104, 9–19 (2001).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Jiang, H., Lin, J. J., Su, Z. Z., Goldstein, N. I. & Fisher, P. B. Subtraction hybridization identifies a novel melanoma differentiation associated gene, mda-7, modulated during human melanoma differentiation, growth and progression. Oncogene 11, 2477–2486 (1995).
  CAS PubMed Google Scholar
• Wang, T., Diaz-Rosales, P., Martin, S. A. & Secombes, C. J. Cloning of a novel interleukin (IL)-20-like gene in rainbow trout Oncorhynchus mykiss gives an insight into the evolution of the IL-10 family. Dev. Comp. Immunol. 34, 158–167 (2010).
  CAS PubMed Google Scholar
• Knappe, A., Hor, S., Wittmann, S. & Fickenscher, H. Induction of a novel cellular homolog of interleukin-10, AK155, by transformation of T lymphocytes with herpesvirus saimiri. J. Virol. 74, 3881–3887 (2000).
  CAS PubMed PubMed Central Google Scholar
• Jones, E. A. & Flavell, R. A. Distal enhancer elements transcribe intergenic RNA in the IL-10 family gene cluster. J. Immunol. 175, 7437–7446 (2005).
  CAS PubMed Google Scholar
• Pestka, S. et al. Interleukin-10 and related cytokines and receptors. Annu. Rev. Immunol. 22, 929–979 (2004).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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. 7, 101–113 (2014).
  CAS PubMed Google Scholar
• Huber, S. et al. IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature 491, 259–263 (2012).
  CAS PubMed PubMed Central Google Scholar
• Weathington, N. M. et al. Glycogen synthase kinase-3β stabilizes the interleukin (IL)-22 receptor from proteasomal degradation in murine lung epithelia. J. Biol. Chem. 289, 17610–17619 (2014).
  CAS PubMed PubMed Central Google Scholar
• 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). References 5, 12 and 18 are the first studies to describe the expression of receptors for IL-20 subfamily cytokines on epithelial tissues, which defined this group of cytokines as a means of communication between the immune system and the epithelium.
  CAS PubMed Google Scholar
• Zheng, Y. et al. Interleukin-22, a TH17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature 445, 648–651 (2007).
  CAS PubMed Google Scholar
• Zheng, Y. et al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nature Med. 14, 282–289 (2008).
  CAS PubMed Google Scholar
• de Luca, A. et al. IL-22 defines a novel immune pathway of antifungal resistance. Mucosal Immunol. 3, 361–373 (2010).
  CAS PubMed Google Scholar
• Pickert, G. et al. STAT3 links IL-22 signaling in intestinal epithelial cells to mucosal wound healing. J. Exp. Med. 206, 1465–1472 (2009).
  CAS PubMed PubMed Central Google Scholar
• Zindl, C. L. et al. IL-22-producing neutrophils contribute to antimicrobial defense and restitution of colonic epithelial integrity during colitis. Proc. Natl Acad. Sci. USA 110, 12768–12773 (2013).
  CAS PubMed Google Scholar
• Wang, F. et al. Prominent production of IL-20 by CD68+/CD11c+ myeloid-derived cells in psoriasis: Gene regulation and cellular effects. J. Investigative Dermatol. 126, 1590–1599 (2006).
  CAS Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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). This is the first study to define IL-20 subfamily cytokines on the basis of receptor expression and to carry out a comparative analysis of downstream functions in the skin.
  CAS PubMed Google Scholar
• Yano, S., Banno, T., Walsh, R. & Blumenberg, M. Transcriptional responses of human epidermal keratinocytes to cytokine interleukin-1. J. Cell. Physiol. 214, 1–13 (2008).
  CAS PubMed Google Scholar
• Hunt, D. W. et al. Ultraviolet B light stimulates interleukin-20 expression by human epithelial keratinocytes. Photochem. Photobiol. 82, 1292–1300 (2006).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Aujla, S. J. et al. IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia. Nature Med. 14, 275–281 (2008).
  CAS PubMed Google Scholar
• Huang, F. et al. Potentiation of IL-19 expression in airway epithelia by IL-17A and IL-4/IL-13: important implications in asthma. J. Allergy Clin. Immunol. 121, 1415–1421 (2008).
  CAS PubMed PubMed Central Google Scholar
• Rutz, S., Eidenschenk, C. & Ouyang, W. IL-22, not simply a Th17 cytokine. Immunol. Rev. 252, 116–132 (2013).
  PubMed Google Scholar
• Ouyang, W., Kolls, J. K. & Zheng, Y. The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity 28, 454–467 (2008).
  CAS PubMed PubMed Central Google Scholar
• Colonna, M. Interleukin-22-producing natural killer cells and lymphoid tissue inducer-like cells in mucosal immunity. Immunity 31, 15–23 (2009).
  CAS PubMed Google Scholar
• 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
• Martin, B., Hirota, K., Cua, D. J., Stockinger, B. & Veldhoen, M. Interleukin-17-producing γδ T cells selectively expand in response to pathogen products and environmental signals. Immunity 31, 321–330 (2009).
  CAS PubMed Google Scholar
• Sutton, C. E. et al. Interleukin-1 and IL-23 induce innate IL-17 production from γδ T cells, amplifying Th17 responses and autoimmunity. Immunity 31, 331–341 (2009).
  CAS PubMed Google Scholar
• Takatori, H. et al. Lymphoid tissue inducer-like cells are an innate source of IL-17 and IL-22. J. Exp. Med. 206, 35–41 (2009).
  CAS PubMed PubMed Central Google Scholar
• Spits, H. et al. Innate lymphoid cells — a proposal for uniform nomenclature. Nature Rev. Immunology 13, 145–149 (2013).
  CAS Google Scholar
• 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).
  CAS PubMed Google Scholar
• Luci, C. et al. Influence of the transcription factor RORγt on the development of NKp46+ cell populations in gut and skin. Nature Immunol. 10, 75–82 (2009).
  CAS Google Scholar
• Sanos, S. L. et al. RORγt and commensal microflora are required for the differentiation of mucosal interleukin 22-producing NKp46+ cells. Nature Immunol. 10, 83–91 (2009).
  CAS Google Scholar
• Cella, M. et al. A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature 457, 722–725 (2009).
  CAS PubMed Google Scholar
• Crellin, N. K., Trifari, S., Kaplan, C. D., Cupedo, T. & Spits, H. Human NKp44+IL-22+ cells and LTi-like cells constitute a stable RORC+ lineage distinct from conventional natural killer cells. J. Exp. Med. 207, 281–290 (2010).
  CAS PubMed PubMed Central Google Scholar
• 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). References 19 and 45 identify IL-22 as a T H 17 cell cytokine and pioneer research into IL-22 biology.
  CAS PubMed PubMed Central Google Scholar
• Chung, Y. et al. Expression and regulation of IL-22 in the IL-17-producing CD4+ T lymphocytes. Cell Res. 16, 902–907 (2006).
  CAS PubMed Google Scholar
• Gurney, A. L. IL-22, a Th1 cytokine that targets the pancreas and select other peripheral tissues. Int. Immunopharmacol. 4, 669–677 (2004).
  CAS PubMed Google Scholar
• 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).
  CAS Google Scholar
• Eyerich, S. et al. Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling. J. Clin. Invest. 119, 3573–3585 (2009).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS Google Scholar
• Basu, R. et al. Th22 cells are an important source of IL-22 for host protection against enteropathogenic bacteria. Immunity 37, 1061–1075 (2012).
  CAS PubMed PubMed Central Google Scholar
• McGeachy, M. J. et al. TGF-β and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain TH-17 cell-mediated pathology. Nature Immunol. 8, 1390–1397 (2007).
  CAS Google Scholar
• Nurieva, R. et al. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 448, 480–483 (2007).
  CAS PubMed Google Scholar
• Kreymborg, K. et al. IL-22 is expressed by Th17 cells in an IL-23-dependent fashion, but not required for the development of autoimmune encephalomyelitis. J. Immunol. 179, 8098–8104 (2007).
  CAS PubMed Google Scholar
• Siegemund, S. et al. Differential IL-23 requirement for IL-22 and IL-17A production during innate immunity against Salmonella enterica serovar Enteritidis. Int. Immunol. 21, 555–565 (2009).
  CAS PubMed Google Scholar
• Mus, A. M. C. et al. Interleukin-23 promotes Th17 differentiation by inhibiting T-bet and FoxP3 and is required for elevation of interleukin-22, but not interleukin-21, in autoimmune experimental arthritis. Arthritis Rheum. 62, 1043–1050 (2010).
  CAS PubMed Google Scholar
• Mukherjee, S., Schaller, M. A., Neupane, R., Kunkel, S. L. & Lukacs, N. W. Regulation of T cell activation by Notch ligand, DLL4, promotes IL-17 production and Rorc activation. J. Immunol. 182, 7381–7388 (2009).
  CAS PubMed PubMed Central Google Scholar
• Alam, M. S. et al. Notch signaling drives IL-22 secretion in CD4+ T cells by stimulating the aryl hydrocarbon receptor. Proc. Natl Acad. Sci. USA 107, 5943–5948 (2010).
  PubMed Google Scholar
• Veldhoen, M., Hirota, K., Christensen, J., O'Garra, A. & Stockinger, B. Natural agonists for aryl hydrocarbon receptor in culture medium are essential for optimal differentiation of Th17 T cells. J. Exp. Med. 206, 43–49 (2009).
  CAS PubMed PubMed Central Google Scholar
• Veldhoen, M. et al. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453, 106–109 (2008).
  CAS PubMed Google Scholar
• Schaefer, G., Venkataraman, C. & Schindler, U. Cutting edge: FISP (IL-4-induced secreted protein), a novel cytokine-like molecule secreted by Th2 cells. J. Immunol. 166, 5859–5863 (2001).
  CAS PubMed Google Scholar
• Stevens, L. et al. Involvement of GATA3 in protein kinase C θ-induced Th2 cytokine expression. Eur. J. Immunol. 36, 3305–3314 (2006).
  CAS PubMed Google Scholar
• Sahoo, A. et al. Stat6 and c-Jun mediate Th2 cell-specific IL-24 gene expression. J. Immunol. 186, 4098–4109 (2011).
  CAS PubMed Google Scholar
• Wilson, N. J. et al. Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nature Immunol. 8, 950–957 (2007).
  CAS Google Scholar
• Manel, N., Unutmaz, D. & Littman, D. R. The differentiation of human TH-17 cells requires transforming growth factor-β and induction of the nuclear receptor RORγt. Nature Immunol. 9, 641–649 (2008).
  CAS Google Scholar
• Crellin, N. K. et al. Regulation of cytokine secretion in human CD127+ LTi-like innate lymphoid cells by Toll-like receptor 2. Immunity 33, 752–764 (2010).
  CAS PubMed Google Scholar
• Satpathy, A. T. et al. Notch2-dependent classical dendritic cells orchestrate intestinal immunity to attaching-and-effacing bacterial pathogens. Nature Immunol. 14, 937–948 (2013).
  CAS Google Scholar
• Van Maele, L. et al. TLR5 signaling stimulates the innate production of IL-17 and IL-22 by CD3negCD127+ immune cells in spleen and mucosa. J. Immunol. 185, 1177–1185 (2010).
  CAS PubMed PubMed Central Google Scholar
• Bogunovic, M. et al. Origin of the lamina propria dendritic cell network. Immunity 31, 513–525 (2009).
  CAS PubMed PubMed Central Google Scholar
• Varol, C. et al. Intestinal lamina propria dendritic cell subsets have different origin and functions. Immunity 31, 502–512 (2009).
  CAS PubMed Google Scholar
• Coombes, J. L. & Maloy, K. J. Control of intestinal homeostasis by regulatory T cells and dendritic cells. Semin. Immunol. 19, 116–126 (2007).
  CAS PubMed Google Scholar
• Kinnebrew, M. A. et al. Interleukin 23 production by intestinal CD103+CD11b+ dendritic cells in response to bacterial flagellin enhances mucosal innate immune defense. Immunity 36, 276–287 (2012).
  CAS PubMed PubMed Central Google Scholar
• Kinnebrew, M. A. et al. Bacterial flagellin stimulates Toll-like receptor 5–dependent defense against vancomycin-resistant Enterococcus infection. J. Infect. Dis. 201, 534–543 (2010).
  CAS PubMed PubMed Central Google Scholar
• Ota, N. et al. IL-22 bridges the lymphotoxin pathway with the maintenance of colonic lymphoid structures during infection with Citrobacter rodentium. Nature Immunol. 12, 941–948 (2011).
  CAS Google Scholar
• Tumanov, A. V. et al. Lymphotoxin controls the IL-22 protection pathway in gut innate lymphoid cells during mucosal pathogen challenge. Cell Host Microbe 10, 44–53 (2011).
  CAS PubMed PubMed Central Google Scholar
• Spahn, T. W. et al. The lymphotoxin-β receptor is critical for control of murine _Citrobacter rodentium_-induced colitis. Gastroenterology 127, 1463–1473 (2004).
  CAS PubMed Google Scholar
• Wang, Y. et al. Lymphotoxin β receptor signaling in intestinal epithelial cells orchestrates innate immune responses against mucosal bacterial infection. Immunity 32, 403–413 (2010).
  PubMed PubMed Central Google Scholar
• Manta, C. et al. CX3CR1+ macrophages support IL-22 production by innate lymphoid cells during infection with Citrobacter rodentium. Mucosal Immunol. 6, 177–188 (2013). References 67, 72 and 78 investigate the upstream cell types required for induction of IL-22 during infection.
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Zigmond, E. et al. Ly6Chi monocytes in the inflamed colon give rise to proinflammatory effector cells and migratory antigen-presenting cells. Immunity 37, 1076–1090 (2012).
  CAS PubMed Google Scholar
• Kim, Y.-G. et al. The Nod2 sensor promotes intestinal pathogen eradication via the chemokine CCL2-dependent recruitment of inflammatory monocytes. Immunity 34, 769–780 (2011).
  CAS PubMed PubMed Central Google Scholar
• Colonna, M. Skin function for human CD1a-reactive T cells. Nature Immunol. 11, 1079–1080 (2010).
  CAS Google Scholar
• de Jong, A. et al. CD1a-autoreactive T cells are a normal component of the human αβ T cell repertoire. Nature Immunol. 11, 1102–1109 (2010).
  CAS Google Scholar
• Sonnenberg, G. F., Fouser, L. A. & Artis, D. Border patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22. Nature Immunol. 12, 383–390 (2011).
  CAS Google Scholar
• Hackstein, H. et al. Modulation of respiratory dendritic cells during Klebsiella pneumonia infection. Respir. Res. 14, 91 (2013).
  PubMed PubMed Central Google Scholar
• Ermers, M. J. et al. IL10 family member genes IL19 and IL20 are associated with recurrent wheeze after respiratory syncytial virus bronchiolitis. Pediatr. Res. 70, 518–523 (2011).
  CAS PubMed Google Scholar
• Sonnenberg, G. F. et al. Innate lymphoid cells promote anatomical containment of lymphoid-resident commensal bacteria. Science 336, 1321–1325 (2012).
  CAS PubMed PubMed Central Google Scholar
• Eidenschenk, C., Rutz, S., Liesenfeld, O. & Ouyang, W. Role of IL-22 in microbial host defense. Curr. Top. Microbiol. Immunol. 380, 213–236 (2014).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Dambacher, J. et al. The role of the novel Th17 cytokine IL-26 in intestinal inflammation. Gut 58, 1207–1217 (2009).
  CAS PubMed Google Scholar
• Behnsen, J. et al. The cytokine IL-22 promotes pathogen colonization by suppressing related commensal bacteria. Immunity 40, 262–273 (2014).
  CAS PubMed PubMed Central Google Scholar
• Liu, J. Z. et al. Zinc sequestration by the neutrophil protein calprotectin enhances Salmonella growth in the inflamed gut. Cell Host Microbe 11, 227–239 (2012).
  CAS PubMed PubMed Central Google Scholar
• Raffatellu, M. et al. Lipocalin-2 resistance confers an advantage to Salmonella enterica serotype Typhimurium for growth and survival in the inflamed intestine. Cell Host Microbe 5, 476–486 (2009).
  CAS PubMed PubMed Central Google Scholar
• Stelter, C. et al. Salmonella-induced mucosal lectin RegIIIβ kills competing gut microbiota. PLoS ONE 6, e20749 (2011).
  CAS PubMed PubMed Central Google Scholar
• Winter, S. E., Lopez, C. A. & Baumler, A. J. The dynamics of gut-associated microbial communities during inflammation. EMBO Rep. 14, 319–327 (2013).
  CAS PubMed PubMed Central Google Scholar
• Myles, I. A. et al. Signaling via the IL-20 receptor inhibits cutaneous production of IL-1β and IL-17A to promote infection with methicillin-resistant Staphylococcus aureus. Nature Immunol. 14, 804–811 (2013). This study reports a specific function for IL-19, IL-20 and IL-24 during infection.
  CAS Google Scholar
• Miller, L. S. et al. MyD88 mediates neutrophil recruitment initiated by IL-1R but not TLR2 activation in immunity against Staphylococcus aureus. Immunity 24, 79–91 (2006).
  CAS PubMed Google Scholar
• Cho, J. S. et al. IL-17 is essential for host defense against cutaneous Staphylococcus aureus infection in mice. J. Clin. Invest. 120, 1762–1773 (2010).
  PubMed PubMed Central Google Scholar
• Lowes, M. A., Bowcock, A. M. & Krueger, J. G. Pathogenesis and therapy of psoriasis. Nature 445, 866–873 (2007).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Wolk, K. et al. IL-22 increases the innate immunity of tissues. Immunity 21, 241–254 (2004). References 91 and 104 provide the first description of the downstream functions of IL-22 and define the biology of IL-20 subfamily cytokines.
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Otkjaer, K. et al. The dynamics of gene expression of interleukin-19 and interleukin-20 and their receptors in psoriasis. Br. J. Dermatol. 153, 911–918 (2005).
  CAS PubMed Google Scholar
• Ouyang, W. Distinct roles of IL-22 in human psoriasis and inflammatory bowel disease. Cytokine Growth Factor Rev. 21, 435–441 (2010).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Sugimoto, K. et al. IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J. Clin. Invest. 118, 534–544 (2008).
  CAS PubMed PubMed Central Google Scholar
• Zenewicz, L. A. et al. Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity 29, 947–957 (2008).
  CAS PubMed PubMed Central Google Scholar
• Neufert, C. et al. Activation of epithelial STAT3 regulates intestinal homeostasis. Cell Cycle 9, 652–655 (2010).
  CAS PubMed Google Scholar
• Fonseca-Camarillo, G., Furuzawa-Carballeda, J., Granados, J. & Yamamoto-Furusho, J. K. Expression of interleukin (IL)-19 and IL-24 in inflammatory bowel disease patients: a cross-sectional study. Clin. Exp. Immunol. 177, 64–75 (2014).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Azuma, Y. T. et al. Interleukin-19 protects mice from innate-mediated colonic inflammation. Inflamm. Bowel Dis. 16, 1017–1028 (2010).
  PubMed Google Scholar
• Sakurai, N. et al. Expression of IL-19 and its receptors in RA: potential role for synovial hyperplasia formation. Rheumatol. 47, 815–820 (2008).
  CAS Google Scholar
• Ikeuchi, H. et al. Expression of interleukin-22 in rheumatoid arthritis: potential role as a proinflammatory cytokine. Arthritis Rheum. 52, 1037–1046 (2005).
  CAS PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Corvaisier, M. et al. IL-26 is overexpressed in rheumatoid arthritis and induces proinflammatory cytokine production and Th17 cell generation. PLoS Biol. 10, e1001395 (2012).
  CAS PubMed PubMed Central Google Scholar
• Alanara, T., Karstila, K., Moilanen, T., Silvennoinen, O. & Isomaki, P. Expression of IL-10 family cytokines in rheumatoid arthritis: elevated levels of IL-19 in the joints. Scand. J. Rheumatol 39, 118–126 (2010).
  CAS PubMed Google Scholar
• Hsu, Y.-H. et al. Function of interleukin-20 as a proinflammatory molecule in rheumatoid and experimental arthritis. Arthritis Rheum. 54, 2722–2733 (2006).
  CAS PubMed Google Scholar
• Pène, J. et al. Chronically inflamed human tissues are infiltrated by highly differentiated Th17 lymphocytes. J. Immunol. 180, 7423–7430 (2008).
  PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Leipe, J. et al. Interleukin 22 serum levels are associated with radiographic progression in rheumatoid arthritis. Ann. Rheum. Dis. 70, 1453–1457 (2011).
  CAS PubMed Google Scholar
• Zhang, L. et al. Increased frequencies of Th22 cells as well as Th17 cells in the peripheral blood of patients with ankylosing spondylitis and rheumatoid arthritis. PLoS ONE 7, e31000 (2012).
  CAS PubMed PubMed Central Google Scholar
• Hsu, Y. H., Hsieh, P. P. & Chang, M. S. Interleukin-19 blockade attenuates collagen-induced arthritis in rats. Rheumatol. 51, 434–442 (2012).
  CAS Google Scholar
• Zhang, L. et al. Elevated Th22 cells correlated with Th17 cells in patients with rheumatoid arthritis. J. Clin. Immunol. 31, 606–614 (2011).
  CAS PubMed Google Scholar
• da Rocha, L. F. et al. Increased serum interleukin 22 in patients with rheumatoid arthritis and correlation with disease activity. J. Rheumatol. 39, 1320–1325 (2012).
  PubMed Google Scholar
• 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).
  CAS PubMed Google Scholar
• Justa, S., Zhou, X. & Sarkar, S. Endogenous IL-22 plays a dual role in arthritis: regulation of established arthritis via IFN-γ responses. PLoS ONE 9, e93279 (2014).
  PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed Google Scholar
• Sherlock, J. P. et al. IL-23 induces spondyloarthropathy by acting on ROR-γt+ CD3+CD4−CD8− entheseal resident T cells. Nature Med. 18, 1069–1076 (2012).
  CAS PubMed Google Scholar
• Benham, H. et al. IL-23-mediates the intestinal response to microbial β-glucan and the development of spondyloarthritis pathology in SKG mice. Arthritis Rheumatol. 66, 1755–1767 (2014).
  CAS PubMed Google Scholar
• Benham, H. et al. Th17 and Th22 cells in psoriatic arthritis and psoriasis. Arthritis Res. Ther. 15, R136 (2013).
  PubMed PubMed Central Google Scholar
• Ortonne, J. P. Aetiology and pathogenesis of psoriasis. Br. J. Dermatol. 135 (Suppl. 49), 1–5 (1996).
  PubMed Google Scholar
• Sano, S. et al. Stat3 links activated keratinocytes and immunocytes required for development of psoriasis in a novel transgenic mouse model. Nature Med. 11, 43–49 (2005).
  CAS PubMed Google Scholar
• Sun, D. P. et al. Interleukin (IL)-19 promoted skin wound healing by increasing fibroblast keratinocyte growth factor expression. Cytokine 62, 360–368 (2013).
  CAS PubMed Google Scholar
• McGee, H. M. et al. IL-22 promotes fibroblast-mediated wound repair in the skin. J. Invest. Dermatol. 133, 1321–1329 (2013). References 138 and 139 define the functions of IL-20 subfamily cytokines in wound healing.
  CAS PubMed Google Scholar
• Poindexter, N. J. et al. IL-24 is expressed during wound repair and inhibits TGFα-induced migration and proliferation of keratinocytes. Exp. Dermatol. 19, 714–722 (2010).
  CAS PubMed PubMed Central Google Scholar
• Bao, P. et al. The role of vascular endothelial growth factor in wound healing. J. Surg. Res. 153, 347–358 (2009).
  CAS PubMed Google Scholar
• Perera, G. K. et al. Integrative biology approach identifies cytokine targeting strategies for psoriasis. Sci. Transl. Med. 6, 223ra22 (2014).
  PubMed Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed Google Scholar
• Zenewicz, L. A. et al. Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation. Immunity 27, 647–659 (2007).
  CAS PubMed PubMed Central Google Scholar
• 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
• 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).
  PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Kong, X. et al. Interleukin-22 induces hepatic stellate cell senescence and restricts liver fibrosis in mice. Hepatology 56, 1150–1159 (2012).
  CAS PubMed PubMed Central Google Scholar
• Ren, X. & Colletti, L. M. IL-22 is involved in liver regeneration after hepatectomy. Am. J. Physiol. Gastrointest Liver Physiol. 298, G74–G80 (2009).
  PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Kulkarni, O. P. et al. Toll-like receptor 4-induced IL-22 accelerates kidney regeneration. J. Am. Soc. Nephrol. 25, 978–989 (2014).
  CAS PubMed PubMed Central Google Scholar
• Xu, M. J. et al. IL-22 ameliorates renal ischemia-reperfusion injury by targeting proximal tubule epithelium. J. Am. Soc. Nephrol. 25, 967–977 (2014).
  CAS PubMed PubMed Central Google Scholar
• Dudakov, J. A. et al. Interleukin-22 drives endogenous thymic regeneration in mice. Science 336, 91–95 (2012).
  CAS PubMed PubMed Central Google Scholar
• Hsu, Y. H. et al. Interleukin-19 mediates tissue damage in murine ischemic acute kidney injury. PLoS ONE 8, e56028 (2013).
  CAS PubMed PubMed Central Google Scholar
• Chiu, Y. S., Wei, C. C., Lin, Y. J., Hsu, Y. H. & Chang, M. S. IL-20 and IL-20R1 antibodies protect against liver fibrosis. Hepatology 60, 1003–1014 (2014).
  CAS PubMed Google Scholar
• Hsu, Y. H. et al. Anti-IL-20 monoclonal antibody suppresses breast cancer progression and bone osteolysis in murine models. J. Immunol. 188, 1981–1991 (2012).
  CAS PubMed Google Scholar
• Baird, A. M., Gray, S. G. & O'Byrne, K. J. IL-20 is epigenetically regulated in NSCLC and down regulates the expression of VEGF. Eur. J. Cancer 47, 1908–1918 (2011).
  CAS PubMed Google Scholar
• Hsu, Y. H., Wei, C. C., Shieh, D. B., Chan, C. H. & Chang, M. S. Anti-IL-20 monoclonal antibody alleviates inflammation in oral cancer and suppresses tumor growth. Mol. Cancer Res. 10, 1430–1439 (2012).
  CAS PubMed Google Scholar
• Lee, S. J. et al. Interleukin-20 promotes migration of bladder cancer cells through extracellular signal-regulated kinase (ERK)-mediated MMP-9 protein expression leading to nuclear factor (NF-κB) activation by inducing the up-regulation of p21WAF1 protein expression. J. Biol. Chem. 288, 5539–5552 (2013).
  CAS PubMed Google Scholar
• Lee, S. J. et al. Identification of pro-inflammatory cytokines associated with muscle invasive bladder cancer; the roles of IL-5, IL-20, and IL-28A. PLoS ONE 7, e40267 (2012).
  CAS PubMed PubMed Central Google Scholar
• Nagakawa, H. et al. Expression of interleukin-22 in murine carcinoma cells did not influence tumour growth in vivo but did improve survival of the inoculated hosts. Scand. J. Immunol. 60, 449–454 (2004).
  CAS PubMed Google Scholar
• Wen, Z. et al. High expression of interleukin-22 and its receptor predicts poor prognosis in pancreatic ductal adenocarcinoma. Ann. Surg. Oncol. 21, 125–132 (2014).
  PubMed Google Scholar
• Lim, C. & Savan, R. The role of the IL-22/IL-22R1 axis in cancer. Cytokine Growth Factor Rev. 25, 257–271 (2014).
  CAS PubMed Google Scholar
• Emdad, L. et al. Historical perspective and recent insights into our understanding of the molecular and biochemical basis of the antitumor properties of mda-7/IL-24. Cancer Biol. Ther. 8, 391–400 (2009).
  PubMed Google Scholar
• Whitaker, E. L., Filippov, V. A. & Duerksen-Hughes, P. J. Interleukin 24: mechanisms and therapeutic potential of an anti-cancer gene. Cytokine Growth Factor Rev. 23, 323–331 (2012).
  CAS PubMed Google Scholar
• Kreis, S., Philippidou, D., Margue, C. & Behrmann, I. IL-24: a classic cytokine and/or a potential cure for cancer? J. Cell. Mol. Med. 16, 2505–2510 (2008).
  Google Scholar
• Kreis, S. et al. Recombinant interleukin-24 lacks apoptosis-inducing properties in melanoma cells. PLoS ONE 2, e1300 (2007). This paper investigates whether IL-24 can directly elicit anticancer activity as a cytokine.
  PubMed PubMed Central Google Scholar
• Yu, H., Pardoll, D. & Jove, R. STATs in cancer inflammation and immunity: a leading role for STAT3. Nature Rev. Cancer 9, 798–809 (2009).
  CAS Google Scholar
• Musteanu, M. et al. Stat3 is a negative regulator of intestinal tumor progression in _Apc_Min mice. Gastroenterology 138, 1003–1011. e1-5 (2010).
  CAS PubMed Google Scholar
• You, W. et al. IL-26 promotes the proliferation and survival of human gastric cancer cells by regulating the balance of STAT1 and STAT3 activation. PLoS ONE 8, e63588 (2013).
  PubMed PubMed Central Google Scholar
• Meira, L. B. et al. DNA damage induced by chronic inflammation contributes to colon carcinogenesis in mice. J. Clin. Invest. 118, 2516–2525 (2008).
  CAS PubMed PubMed Central Google Scholar
• 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).
  CAS PubMed PubMed Central Google Scholar
• Yang, L. et al. Amelioration of high fat diet induced liver lipogenesis and hepatic steatosis by interleukin-22. J. Hepatol. 53, 339–347 (2010). This study reports the role of IL-22 in regulating lipid metabolism.
  CAS PubMed Google Scholar
• Kanneganti, T. D. & Dixit, V. D. Immunological complications of obesity. Nature Immunol. 13, 707–712 (2012).
  CAS Google Scholar
• Inoue, H. et al. Role of STAT-3 in regulation of hepatic gluconeogenic genes and carbohydrate metabolism in vivo. Nature Med. 10, 168–174 (2004).
  CAS PubMed Google Scholar
• Vijay-Kumar, M. et al. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 328, 228–231 (2010).
  CAS PubMed PubMed Central Google Scholar
• Wang, X. et al. Interleukin-22 alleviates metabolic disorders and restores mucosal immunity in diabetes. Nature 514, 237–241 (2014). This study demonstrates that IL-22 mediates several essential functions linked to metabolic syndrome, including modulating lipid metabolism in adipose tissue and reducing food consumption.
  CAS PubMed Google Scholar
• Hansson, G. K. Inflammation, atherosclerosis, and coronary artery disease. N. Engl. J. Med. 352, 1685–1695 (2005).
  CAS PubMed Google Scholar
• Prodanovich, S. et al. Association of psoriasis with coronary artery, cerebrovascular, and peripheral vascular diseases and mortality. Arch. Dermatol. 145, 700–703 (2009).
  PubMed Google Scholar
• Ellison, S. et al. Attenuation of experimental atherosclerosis by interleukin-19. Arterioscler Thromb. Vasc. Biol. 33, 2316–2324 (2013).
  CAS PubMed PubMed Central Google Scholar
• Chen, W. Y., Cheng, B. C., Jiang, M. J., Hsieh, M. Y. & Chang, M. S. IL-20 is expressed in atherosclerosis plaques and promotes atherosclerosis in apolipoprotein E-deficient mice. Arteriosclerosis, Thromb. Vascular Biol. 26, 2090–2095 (2006).
  CAS Google Scholar
• Zenewicz, L. A. et al. IL-22 deficiency alters colonic microbiota to be transmissible and colitogenic. J. Immunol. 190, 5306–5312 (2013).
  CAS PubMed PubMed Central Google Scholar
• Gaboriau-Routhiau, V. et al. The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity 31, 677–689 (2009).
  CAS PubMed Google Scholar
• Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).
  CAS PubMed PubMed Central Google Scholar
• Wu, H.-J. et al. Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 32, 815–827 (2010).
  CAS PubMed PubMed Central Google Scholar
• Lee, Y. K., Menezes, J. S., Umesaki, Y. & Mazmanian, S. K. Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 108 (Suppl. 1), 4615–4622 (2011).
  CAS PubMed Google Scholar
• Qiu, J. et al. Group 3 innate lymphoid cells inhibit T-cell-mediated intestinal inflammation through aryl hydrocarbon receptor signaling and regulation of microflora. Immunity 39, 386–399 (2013).
  CAS PubMed Google Scholar
• Upadhyay, V. et al. Lymphotoxin regulates commensal responses to enable diet-induced obesity. Nature Immunol. 13, 947–953 (2012).
  CAS Google Scholar