Download Gene Section IL23A (interleukin 23, alpha subunit p19)

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in Oncology and Haematology
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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
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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.
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