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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Gene Section Review IL23A (interleukin 23, alpha subunit p19) Norimitsu Inoue Department of Molecular Genetics, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Osaka 537-8511, Japan (NI) Published in Atlas Database: May 2010 Online updated version : http://AtlasGeneticsOncology.org/Genes/IL23AID44517ch12q13.html DOI: 10.4267/2042/44965 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2011 Atlas of Genetics and Cytogenetics in Oncology and Haematology Identity Protein Other names: IL-23, IL-23A, IL23P19, MGC79388, P19, SGRF HGNC (Hugo): IL23A Location: 12q13.3 Local order: Centromere-CNPY2-PAN2-IL23ASTAT2-APOF-Telomere. 4 exons. Note The IL23A protein (IL-23p19 subunit) is covalently linked to a p40 subunit (IL12B, IL-12p40), which is shared with IL-12, to form IL-23 (Oppmann et al., 2000). The IL23A protein requires IL12B for secretion. The receptor for IL-23 is formed by the association of a specific IL-23 receptor (IL23R) and IL-12Rbeta1 (IL12RB1), which is shared with the receptor for IL-12 (Parham et al., 2002). The receptor for IL-23 is constitutively associated with Jak2 (Janus kinase 2) and predominantly activates Stat3, with less Stat4 activation than IL-12. Transcription Description The transcript is 1041 bp, with a 166 bp 5' untranslated region (UTR), a 570 bp coding sequence, and a 305 bp 3' UTR. The protein consists of 189 amino acids and is 20.7 kD, comprising a 19 amino acid signal peptide and a mature peptide (170 amino acids, 18.7 kD). DNA/RNA Description Pseudogene No pseudogene. IL23A gene. The IL23A gene spans a region of 1531 bp composed of 4 exons [untranslated region (UTR), light blue; coding region, dark blue] with 328 bp, 99 bp, 147 bp and 467 bp in length, and 3 introns (brown) with 219 bp, 166 bp and 105 bp in length. Atlas Genet Cytogenet Oncol Haematol. 2011; 15(2) 191 IL23A (interleukin 23, alpha subunit p19) Inoue N Homology IL23A has homology with four-helix bundle cytokine family members such as IL12A (IL-12p35), IL-6, and G-CSF. IL23A and IL12A have the highest homology, with approximately 40% of sequence identity among this family. Implicated in Various cancers IL23A protein. The IL23A protein is composed of a signal peptide (light green) and a mature peptide (dark green) with four alpha-helices (dark yellow). Note Promotion of tumor incidence and growth The expression of IL-23A mRNA is significantly elevated in various human cancers, such as melanoma, colon, ovarian, head and neck, lung, breast, and stomach cancers, when compared with adjacent normal tissues (Langowski et al., 2006). IL-23 upregulation is also observed in sera from multiple myeloma patients (Prabhala et al., 2010). A deficiency of IL23A promotes increased infiltration of cytotoxic T cells into the transformed tissue and mediates resistance to chemically induced tumors. IL-23 facilitates the induction of inflammation and angiogenesis in the tumor microenvironment and inhibits CD8+ T cells infiltration, thereby promoting tumor incidence and growth (Langowski et al., 2006; Langowski et al., 2007; Martin-Orozco and Dong, 2009). It has been suggested that IL-23 also suppresses carcinogenesis and metastasis in mouse models, where it acts independently of IL-17A (Teng et al., 2010). Stat3 signaling shifts the balance between IL-23 and IL-12 toward IL-23 in the tumor microenvironment (Kortylewski et al., 2009). In tumor-associated regulatory T cells, IL-23-activated Stat3 induces the upregulation of Foxp3 and IL-10. Anti-tumor effects In several mouse tumor models, IL-23 overexpression in tumors (Overwijk et al., 2006) or intratumoral injection of IL-23-introduced DCs (Hu et al., 2006) has been shown to induce tumoral infiltration of CD8+ T cells and to inhibit tumor growth. Systemic administration of IL-23 also suppresses the growth of a pre-existing tumor in mice (Kaiga et al., 2007). Expression IL-23 is secreted by dendritic cells (DCs) and phagocytic cells activated with pathogens and pathogen-associated molecular patterns that act through toll-like receptors (TLRs) (Hunter, 2005; Kastelein et al., 2007; Goriely et al., 2008). The TLR2 ligand peptidoglycan, a cell wall component of Gram-positive bacteria, preferentially promotes the expression of IL23A but not IL12A through activation of a cytosolic receptor, nucleotide-binding oligomerization domain 2 (NOD2), with TLR2. Activation of the C-type lectinsSyc-CARD9 signaling pathway by the beta-glucan curdlan also induces IL-23 production by DCs (LeibundGut-Landmann et al., 2007). Prostaglandin E2 (PGE2) and ATP act on their G-protein-coupled receptors, EP2 and EP4 (PGE2) and P2Y (ATP), to enhance IL-23 production via an increase in cAMP concentration (Sheibanie et al., 2004; Yao et al., 2009; Schnurr et al., 2005). Lactic acid also facilitates IL-23 production (Shime et al., 2008). Although these factors themselves do not induce IL-23 production, they can shift the balance between IL-12 and IL-23 secretion by activated DCs or macrophages toward IL-23. Polarized Th1 and Th2 cells highly express IL23A mRNA but not IL12B mRNA (Oppmann et al., 2000). The roles of IL23A mRNA expression in T cells are unknown. Function IL-23 receptor is mainly expressed on activated/memory T cells and natural killer (NK) cells. Monocytes, macrophage and DCs also express IL-23 receptor at low levels (Parham et al., 2002). Although IL-23 does not directly stimulate the initial differentiation of naive T cells to Th17 cells, it is essential for the full differentiation of Th17 cells and promotes their expansion and maintenance to induce IL-17A production (Korn et al., 2009). NKT cells (Rachitskaya et al., 2008) and innate lymphoid cells such as lymphoid tissue induce (LTi)-like cells (Takatori et al., 2009; Buonocore et al., 2010) express IL-23 receptor and retinoic-acid-related orphan receptor (ROR) gammat and produce IL-17 in response to IL-23. IL-1beta and IL-23 also costimulate gammadelta T cells to induce IL-17 production without T cell receptor engagement (Sutton et al., 2009). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(2) Ovarian cancer Note The occurrence of specific single nucleotide polymorphisms (SNPs) in the IL23R gene is increased in ovarian cancer patients compared with controls (dbSNPs: rs10889677) and in advanced ovarian cancer stage (dbSNPs: rs11465817) (Zhang et al., 2010). Inflammation and inflammatory diseases Note IL23A and IL23R knockout mice are resistant to the development of experimental autoimmune 192 IL23A (interleukin 23, alpha subunit p19) Inoue N Overwijk WW, de Visser KE, Tirion FH, de Jong LA, Pols TW, van der Velden YU, van den Boorn JG, Keller AM, Buurman WA, Theoret MR, Blom B, Restifo NP, Kruisbeek AM, Kastelein RA, Haanen JB. Immunological and antitumor effects of IL-23 as a cancer vaccine adjuvant. J Immunol. 2006 May 1;176(9):5213-22 encephalomyelitis and collagen-induced arthritis (Hunter, 2005; Kastelein et al., 2007; Abraham and Cho, 2009; Korn et al., 2009). IL-23A deficiency or treatment with anti-IL-23A blocking antibodies suppresses intestinal inflammation induced in IL-10deficient mice. Ubiquitous overexpression of IL-23A in mice results in multi-organ inflammation. Therefore, IL-23 upregulation is thought to promote many inflammatory and autoimmune diseases. Many SNPs in the IL23R gene are reported to be significantly associated with Crohn's disease, ulcerative colitis, psoriasis, and ankylosing spondylitis. In particular, an uncommon allele at Arg381Gln (dbSNP: rs11209026) in the IL23R gene is associated with protection from Crohn's diseases, ulcerative colitis, and psoriasis. Kaiga T, Sato M, Kaneda H, Iwakura Y, Takayama T, Tahara H. Systemic administration of IL-23 induces potent antitumor immunity primarily mediated through Th1-type response in association with the endogenously expressed IL-12. J Immunol. 2007 Jun 15;178(12):7571-80 Kastelein RA, Hunter CA, Cua DJ. Discovery and biology of IL23 and IL-27: related but functionally distinct regulators of inflammation. Annu Rev Immunol. 2007;25:221-42 Langowski JL, Kastelein RA, Oft M. Swords into plowshares: IL-23 repurposes tumor immune surveillance. Trends Immunol. 2007 May;28(5):207-12 T-cell-independent colitis LeibundGut-Landmann S, Gross O, Robinson MJ, Osorio F, Slack EC, Tsoni SV, Schweighoffer E, Tybulewicz V, Brown GD, Ruland J, Reis e Sousa C. Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17. Nat Immunol. 2007 Jun;8(6):630-8 Note IL-23 is involved in bacteria-driven innate immune colitis in Rag-/- mice. Recently, Buonocore et al. reported that IL-23 induces IL-17 and IFN-gamma expression by innate lymphoid cells expressing Thy-1, Stem cell antigen 1 (Sca-1), RORgammat and IL23R to mediate acute and chronic innate immune colitis (Buonocore et al., 2010). Goriely S, Neurath MF, Goldman M. How microorganisms tip the balance between interleukin-12 family members. Nat Rev Immunol. 2008 Jan;8(1):81-6 Rachitskaya AV, Hansen AM, Horai R, Li Z, Villasmil R, Luger D, Nussenblatt RB, Caspi RR. Cutting edge: NKT cells constitutively express IL-23 receptor and RORgammat and rapidly produce IL-17 upon receptor ligation in an IL-6independent fashion. J Immunol. 2008 Apr 15;180(8):5167-71 References Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, Vega F, Yu N, Wang J, Singh K, Zonin F, Vaisberg E, Churakova T, Liu M, Gorman D, Wagner J, Zurawski S, Liu Y, Abrams JS, Moore KW, Rennick D, de Waal-Malefyt R, Hannum C, Bazan JF, Kastelein RA. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity. 2000 Nov;13(5):715-25 Shime H, Yabu M, Akazawa T, Kodama K, Matsumoto M, Seya T, Inoue N. Tumor-secreted lactic acid promotes IL-23/IL17 proinflammatory pathway. J Immunol. 2008 Jun 1;180(11):7175-83 Parham C, Chirica M, Timans J, Vaisberg E, Travis M, Cheung J, Pflanz S, Zhang R, Singh KP, Vega F, To W, Wagner J, O'Farrell AM, McClanahan T, Zurawski S, Hannum C, Gorman D, Rennick DM, Kastelein RA, de Waal Malefyt R, Moore KW. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R. J Immunol. 2002 Jun 1;168(11):5699-708 Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 Cells. Annu Rev Immunol. 2009;27:485-517 Abraham C, Cho JH. IL-23 and autoimmunity: new insights into the pathogenesis of inflammatory bowel disease. Annu Rev Med. 2009;60:97-110 Kortylewski M, Xin H, Kujawski M, Lee H, Liu Y, Harris T, Drake C, Pardoll D, Yu H. Regulation of the IL-23 and IL-12 balance by Stat3 signaling in the tumor microenvironment. Cancer Cell. 2009 Feb 3;15(2):114-23 Martin-Orozco N, Dong C. The IL-17/IL-23 axis of inflammation in cancer: friend or foe? Curr Opin Investig Drugs. 2009 Jun;10(6):543-9 Sheibanie AF, Tadmori I, Jing H, Vassiliou E, Ganea D. Prostaglandin E2 induces IL-23 production in bone marrowderived dendritic cells. FASEB J. 2004 Aug;18(11):1318-20 Hunter CA. New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions. Nat Rev Immunol. 2005 Jul;5(7):521-31 Sutton CE, Lalor SJ, Sweeney CM, Brereton CF, Lavelle EC, Mills KH. Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. Immunity. 2009 Aug 21;31(2):331-41 Schnurr M, Toy T, Shin A, Wagner M, Cebon J, Maraskovsky E. Extracellular nucleotide signaling by P2 receptors inhibits IL12 and enhances IL-23 expression in human dendritic cells: a novel role for the cAMP pathway. Blood. 2005 Feb 15;105(4):1582-9 Takatori H, Kanno Y, Watford WT, Tato CM, Weiss G, Ivanov II, Littman DR, O'Shea JJ. Lymphoid tissue inducer-like cells are an innate source of IL-17 and IL-22. J Exp Med. 2009 Jan 16;206(1):35-41 Yao C, Sakata D, Esaki Y, Li Y, Matsuoka T, Kuroiwa K, Sugimoto Y, Narumiya S. Prostaglandin E2-EP4 signaling promotes immune inflammation through Th1 cell differentiation and Th17 cell expansion. Nat Med. 2009 Jun;15(6):633-40 Hu J, Yuan X, Belladonna ML, Ong JM, Wachsmann-Hogiu S, Farkas DL, Black KL, Yu JS. Induction of potent antitumor immunity by intratumoral injection of interleukin 23-transduced dendritic cells. Cancer Res. 2006 Sep 1;66(17):8887-96 Buonocore S, Ahern PP, Uhlig HH, Ivanov II, Littman DR, Maloy KJ, Powrie F. Innate lymphoid cells drive interleukin-23dependent innate intestinal pathology. Nature. 2010 Apr 29;464(7293):1371-5 Langowski JL, Zhang X, Wu L, Mattson JD, Chen T, Smith K, Basham B, McClanahan T, Kastelein RA, Oft M. IL-23 promotes tumour incidence and growth. Nature. 2006 Jul 27;442(7101):461-5 Atlas Genet Cytogenet Oncol Haematol. 2011; 15(2) 193 IL23A (interleukin 23, alpha subunit p19) Inoue N Prabhala RH, Pelluru D, Fulciniti M, Prabhala HK, Nanjappa P, Song W, Pai C, Amin S, Tai YT, Richardson PG, Ghobrial IM, Treon SP, Daley JF, Anderson KC, Kutok JL, Munshi NC. Elevated IL-17 produced by TH17 cells promotes myeloma cell growth and inhibits immune function in multiple myeloma. Blood. 2010 Jul 1;115(26):5385-92 Zhang Z, Zhou B, Zhang J, Chen Y, Lai T, Yan L, Liang A, Li Y, Wang Y, Chen Y, Zhang L, Xi MR. Association of interleukin-23 receptor gene polymorphisms with risk of ovarian cancer. Cancer Genet Cytogenet. 2010 Jan 15;196(2):146-52 This article should be referenced as such: Teng MW, Andrews DM, McLaughlin N, von Scheidt B, Ngiow SF, Möller A, Hill GR, Iwakura Y, Oft M, Smyth MJ. IL-23 suppresses innate immune response independently of IL-17A during carcinogenesis and metastasis. Proc Natl Acad Sci U S A. 2010 May 4;107(18):8328-33 Atlas Genet Cytogenet Oncol Haematol. 2011; 15(2) Inoue N. IL23A (interleukin 23, alpha subunit p19). Atlas Genet Cytogenet Oncol Haematol. 2011; 15(2):191-194. 194