Entry - *605580 - INTERLEUKIN 23-ALPHA; IL23A - OMIM - (OMIM.ORG)

 
 
* 605580

INTERLEUKIN 23-ALPHA; IL23A


Alternative titles; symbols

INTERLEUKIN 23, p19 SUBUNIT
p19
SGRF


HGNC Approved Gene Symbol: IL23A

Cytogenetic location: 12q13.3   Genomic coordinates (GRCh38) : 12:56,338,884-56,340,410 (from NCBI)


TEXT

▼ Description

Cytokines are soluble protein factors that regulate the proliferation, differentiation, and effector functions of immune cells. Based on sequence and structural analysis, cytokines can be classified into discrete families and subfamilies, such as the interleukin-6 (IL6; 147620)-like cytokines, which include the p35 subunit of IL12 (IL12A; 161560). IL12A is only active in cell-mediated immunity when associated with the IL12 p40 subunit (IL12B; 161561) as a composite molecule. IL23 is composed of the IL12 p40 subunit and the p19 subunit (IL23A) (Oppmann et al., 2000).


▼ Cloning and Expression

By computationally screening databases for sequences similar to IL6 subfamily members, Oppmann et al. (2000) identified a cDNA encoding a calculated 19-kD cytokine, p19. The deduced 189-amino acid protein, which is 70% identical to the 196-residue mouse sequence, contains 4 alpha helices, 5 cysteine residues, and no N-linked glycosylation sites.


▼ Gene Function

Functional analysis by Oppmann et al. (2000) indicated that cells transfected with p19 were unable to efficiently secrete the protein, and p19 was inactive in the absence of expression of IL12B but not other IL6 subfamily members. Immunoprecipitation analysis determined that IL12B and p19 form a soluble cytokine/receptor complex, which the authors termed IL23. RT-PCR analysis showed that high levels of p19 are expressed by dendritic cells. Immunoprecipitation and 2-dimensional SDS-PAGE analysis detected expression of high levels of IL23 in activated dendritic cells. Functional analysis determined that IL23 enhanced the secretion of gamma-interferon (IFNG; 147570) by memory (CD45RO) but not naive (CD45RA) T cells in an IL2 (147680)-dependent manner; however, this occurred at lower levels than in IL12-stimulated cells. Receptor-binding analysis established that IL23 and IL12 share IL12RB1 (601604), but that only IL12 binds to IL12RB2 (601642). However, IL23 stimulation did result in STAT4 (600558) activation at lower levels than those observed with IL12/IL12RB2 signaling, suggesting that IL23 has a unique receptor as well. Oppmann et al. (2000) pointed out that anti-IL12B antibodies used to evaluate IL12 in immunity and immunopathology do not discriminate between IL12 and IL23.

Psoriasis (see 177900) is characterized by the presence of IFNG and multiple IFN-related inflammatory genes in lesions. Because IL23 is involved in the recruitment of inflammatory cells in Th1-mediated diseases, Lee et al. (2004) examined psoriatic lesions for IL23 production. Quantitative RT-PCR detected significantly increased levels of IL23A and IL12B, but not IL12A, in psoriatic lesions compared with nonlesional skin. IL23 expression was found mainly in dermal cells of psoriatic lesions, particularly monocytes and mature dendritic cells, suggesting that IL23 plays a more dominant role than IL12 in psoriasis.

By RT-PCR, immunoblot, ELISA, and functional analyses, Piskin et al. (2006) found that culture supernatants and cell lysates of keratinocytes from normal and lesional psoriatic skin had low levels of IL23 sufficient to enhance IFNG production by memory T cells. Immunohistochemical analysis showed expression of both IL23 subunits in keratinocytes, and IL23 p19 was detected in dermal dendritic cells, macrophages, and epidermal Langerhans cells. Piskin et al. (2006) proposed that the ability of keratinocyte-expressed IL23 to enhance IFNG expression may contribute to the perpetuation of inflammation in psoriasis.

Langowski et al. (2006) demonstrated a molecular connection between the rise in tumor-associated inflammation and a lack of tumor immune surveillance. Expression of the heterodimeric cytokine IL23, but not of its close relative IL12, is increased in human tumors. Expression of these cytokines antagonistically regulates local inflammatory responses in the tumor microenvironment and infiltration of intraepithelial lymphocytes. Whereas IL12 promotes infiltration of cytotoxic T cells, IL23 promotes inflammatory responses such as upregulation of the matrix metalloprotease MMP9, and increases angiogenesis but reduces CD8 T-cell infiltration. Genetic deletion or antibody-mediated elimination of IL23 leads to increased infiltration of cytotoxic T cells into the transformed tissue, rendering a protective effect against chemically induced carcinogenesis. Transplanted tumors are growth-restricted in hosts depleted for IL23 or in IL23 receptor (607562)-deficient mice. Langowski et al. (2006) noted that although many strategies for immune therapy of cancer attempt to stimulate an immune response against solid tumors, infiltration of effector cells into the tumor tissue often appears to be a critical hurdle. Langowski et al. (2006) showed that IL23 is an important molecular link between tumor-promoter proinflammatory processes and the failure of the adaptive immune surveillance to infiltrate tumors.

Hu et al. (2006) detected the IL23p19 protein in cerebrospinal fluid isolated from 5 patients with Guillain-Barre syndrome (GBS; 139393). Sural nerve biopsies from these patients showed IL23p19 immunostaining in endoneurial macrophages. IL23A RNA was upregulated in sciatic nerve samples from 5 rats with experimental autoimmune neuritis (EAN), an animal model of GBS. Peak expression of IL23A RNA in the diseased animals occurred 2 days prior to peak clinical disease severity and then decreased to undetectable levels with clinical improvement. Hu et al. (2006) concluded that IL23 may play a role in the early effector phase of immune-mediated demyelination of the peripheral nerve.

CD4+ T helper cells that selectively produce interleukin-17 (Th17) are critical for host defense and immunity. Ghoreschi et al. (2010) showed that Th17 differentiation can occur in the absence of TGF-beta (190180) signaling. Neither IL6 (147620) nor IL23 alone efficiently generated Th17 cells; however, these cytokines in combination with IL1-beta (147720) effectively induced IL17 production in naive precursors, independently of TGF-beta. Epigenetic modification of the IL17A (603149), IL17F (606496), and RORC (602943) promoters proceeded without TGF-beta-1, allowing the generation of cells that coexpressed ROR-gamma-t (encoded by RORC) and Tbet (TBX21; 604895). Tbet+ROR-gamma-t+Th17 cells are generated in vivo during experimental allergic encephalomyelitis, and adoptively transferred Th17 cells generated with IL23 without TGF-beta-1 were pathogenic in this disease model. Ghoreschi et al. (2010) concluded that their data indicated an alternative mode for Th17 differentiation, and that, consistent with genetic data linking IL23R (607562) with autoimmunity, their findings reemphasized the importance of IL23 and therefore may have therapeutic implications.

By flow cytometric and immunohistochemical analyses, Tonel et al. (2010) demonstrated that expression of IL23 and IL23R was increased in the tissues of psoriasis patients. Injection of a neutralizing monoclonal antibody to IL23 in a xenotransplant mouse model showed IL23-dependent inhibition of psoriasis comparable to results obtained with anti-TNF (191160) blockers. Tonel et al. (2010) concluded that the IL23 pathway has a critical role in the pathogenesis of psoriasis.

Grivennikov et al. (2012) investigated mechanisms responsible for tumor-elicited inflammation in a mouse model of colorectal tumorigenesis which, like human colorectal cancer, exhibits upregulation of IL23 and IL17. They showed that IL23 signaling promotes tumor growth and progression and development of tumoral IL17 response. IL23 is mainly produced by tumor-associated myeloid cells that are likely to be activated by microbial products, which penetrate the tumors but not adjacent tissue. Both early and late colorectal neoplasms exhibit defective expression of several barrier proteins. Grivennikov et al. (2012) proposed that barrier deterioration induced by colorectal cancer-initiating genetic lesions results in adenoma invasion by microbial products that trigger tumor-elicited inflammation, which in turn drives tumor growth.

Wu et al. (2013) used transcriptional profiling of developing T(H)17 cells to construct a model of their signaling network and nominate major nodes that regulate T(H)17 development. Wu et al. (2013) identified serum glucocorticoid kinase-1 (SGK1; 602958), a serine/threonine kinase, as an essential node downstream of IL23 signaling. SGK1 is critical for regulating IL23R expression and stabilizing the T(H)17 cell phenotype by deactivation of mouse Foxo1 (136533), a direct repressor of IL23R expression. SGK1 has been shown to govern sodium transport and salt (NaCl) homeostasis in other cells. Wu et al. (2013) showed that a modest increase in salt concentration induces SGK1 expression, promotes IL23R expression, and enhances T(H)17 cell differentiation in vitro and in vivo, accelerating the development of autoimmunity. Loss of SGK1 abrogated sodium-mediated T(H)17 differentiation in an IL23-dependent manner. Wu et al. (2013) concluded that their data demonstrated that SGK1 has a critical role in the induction of pathogenic T(H)17 cells and provided a molecular insight into a mechanism by which an environmental factor such as a high-salt diet triggers T(H)17 development and promotes tissue inflammation.

Brain et al. (2013) detected upregulated expression of MIR29A (610782), MIR29B (see 610783), and MIR29C (610784) in human dendritic cells (DCs) stimulated with NOD2 (605956). They found that MIR29 regulated expression of multiple immune mediators. Notably, MIR29 downregulated IL23 by targeting its IL12p40 component directly and its IL23p19 component indirectly, most likely through a reduction of the transcription factor ATF2 (123811). Dextran sodium sulfate (DSS)-induced colitis was exacerbated in mice lacking Mir29 and was associated with elevated Il23 and Th17 cytokines in intestinal mucosa. DCs from Crohn disease (266600) patients expressing NOD2 polymorphisms failed to induce MIR29 after stimulation of pathogen pattern recognition receptors, and these DCs showed enhanced release of IL12p40 on exposure to adherent E. coli. Brain et al. (2013) proposed that loss of MIR29-mediated immune regulation in Crohn disease DCs may contribute to elevated IL23 in patients with the disease.

Riol-Blanco et al. (2014) exposed the skin of mice to imiquimod, which induces IL23-dependent psoriasis-like inflammation, and showed that a subset of sensory neurons expressing the ion channels TRPV1 (602076) and NAV1.8 (SCN10A; 604427) is essential to drive this inflammatory response. Imaging of intact skin revealed that a large fraction of dermal dendritic cells (DDCs), the principal source of IL23, is in close contact with these nociceptors. Upon selective pharmacologic or genetic ablation of nociceptors, DDCs failed to produce IL23 in imiquimod-exposed skin. Consequently, the local production of IL23-dependent inflammatory cytokines by dermal gamma-delta-T17 cells and the subsequent recruitment of inflammatory cells to the skin were markedly reduced. Intradermal injection of IL23 bypassed the requirement for nociceptor communication with DDCs and restored the inflammatory response. Riol-Blanco et al. (2014) concluded that TRPV1-positive/NAV1.8-positive nociceptors, by interacting with DDCs, regulate the IL23/IL17 (603149) pathway and control cutaneous immune responses.

To provide clinical proof that specific targeting of IL23p19 results in symptomatic improvement of disease severity in human subjects, Kopp et al. (2015) evaluated tildrakizumab, a monoclonal antibody that targets the IL23p19 subunit, in a 3-part, randomized, placebo-controlled, sequential, rising multiple dose phase I study in patients with moderate to severe psoriasis (177900). A 75% reduction in the psoriasis area and severity index (PASI) score (PASI75) was achieved by all subjects in parts 1 and 3 (pooled) in the 3 and 10 mg per kg groups by day 196. In part 2, 10 of 15 subjects in the 3 mg per kg group and 13 of 14 subjects in the 10 mg per kg group achieved a PASI75 by day 112. Tildrakizumab demonstrated important clinical improvement in moderate to severe psoriasis patients as demonstrated by improvements in PASI scores and histologic samples.

Calcinotto et al. (2018) identified IL23 produced by myeloid-derived suppressor cells (MDSCs) as a driver of castration-resistant prostate cancer (CRPC) in mice and patients with CRPC. Mechanistically, IL23 secreted by MDSCs can activate the androgen receptor (AR; 313700) pathway in prostate tumor cells, promoting cell survival and proliferation in androgen-deprived conditions. Intratumor MDSC infiltration and IL23 concentration are increased in blood and tumor samples from patients with CRPC. Antibody-mediated inactivation of IL23 restored sensitivity to androgen-deprivation therapy in mice. Calcinotto et al. (2018) concluded that MDSCs promote CRPC by acting in a non-cell-autonomous manner.


▼ Mapping

The International Radiation Hybrid Mapping Consortium mapped the p19 gene to chromosome 12 (stSG47812).

▼ Animal Model

Wiekowski et al. (2001) generated mice transgenic for ubiquitous expression of IL23A (p19). These mice showed multiorgan inflammation, elevated serum levels of IL1 (see 147760) and tumor necrosis factor (TNF; 191160), chronic expression of hepatic acute phase proteins, anemia, runting, premature death, and infertility. Liver-specific expression of IL23A failed to reproduce these abnormalities. Bone marrow transfer experiments showed that expression of IL23A by hemopoietic cells alone recapitulated the phenotype induced by widespread expression. The authors concluded that IL23A has biologic properties related to those of IL6, GCSF (CSF3; 138970), and IL12.

IL12 is composed of p35 and p40 subunits, while IL23 is composed of a p19 subunit and the IL12 p40 subunit. Cua et al. (2003) generated mice lacking only IL23 (p19 -/-), only IL12 (p35 -/-), or both IL23 and IL12 (p40 -/-) and immunized them with myelin oligodendrocyte glycoprotein 35-55 (MOG) in an experimental allergic encephalomyelitis (EAE) model of multiple sclerosis. The p19 -/- mice were generated by completely removing the p19 locus. Mice lacking p19 or p40 were resistant to development of EAE, whereas mice lacking only p35 were at least as susceptible as wildtype mice. Exogenous IL23 delivered into the central nervous system (CNS), but not intravenously, 2 days before expected onset of disease reconstituted EAE in both p19 -/- and p40 -/- mice, although onset in the latter was delayed and disease was less severe. Administration of recombinant IL12 for 7 days, followed by IL23 gene transfer on day 8, also induced intense EAE, suggesting that IL12 promotes the development of Th1 cells, while IL23 is required for subsequent inflammatory events. MOG immunization induced Th1 cells and proinflammatory cytokines in p19 -/- mice, whereas in p35 -/- and p40 -/- mice, a Th2 phenotype was observed. Flow cytometric and real-time PCR analyses demonstrated the entry of Th1 cells into the CNS in the absence of IL23, without the recruitment of additional T cells or macrophages or the activation of resident microglia. During EAE, IL23R (607562) and IL12RB1 were coexpressed by inflammatory macrophages, whereas resident microglia expressed only IL12RB1. Although resident microglia and inflammatory macrophages produced IL23, only inflammatory macrophages responded to IL23. In contrast, IL12 was produced primarily by inflammatory macrophages, and both macrophages and microglia had the potential to respond to IL12. Cua et al. (2003) concluded that IL12 promotes the development of naive T cells, while IL23 mediates late-stage inflammation and seems to be necessary for chronic inflammation. In a commentary, Watford and O'Shea (2003) noted that IL12 now has an 'alibi' in the development of autoimmune disease and that previous studies attributing these deleterious effects to IL12 may need reevaluation, including precise determination of the role of each subunit in this family of dimeric cytokines.

Chen et al. (2006) found that treating mice with anti-Il23 p19, like anti-Il23 p40, effectively blocked both acute EAE and EAE relapse. Anti-Il23 treatment blocked invasion of the CNS by T cells and inflammatory macrophages, and it reduced serum Il17 (603149) levels and CNS expression of Ifng, Ip10 (CXCL10; 147310), Il17, Il6, and Tnf mRNA. Anti-Il23 prevented EAE relapse, at least in part, by inhibiting epitope spreading. Although anti-Il17 blocked EAE relapse, it did not significantly reduce the number of infiltration foci, suggesting no effect on inflammatory cell migration but a possible downregulation of inflammatory effector cell function.

Mice deficient in Il10 develop spontaneous inflammatory bowel disease (IBD; see 266600). Yen et al. (2006) found that mice deficient in both Il10 and Il12 p35, but not mice deficient in both Il10 and Il23 p19, developed spontaneous IBD, indicating that IL23, but not IL12, is necessary for chronic intestinal inflammation. Adding recombinant IL23 to T cells from Il10 -/- mice adoptively transferred to T cell-deficient mice accelerated IBD development, which was accompanied by enhanced production of Il6 and Il17. Blockade of Il6 and Il17 ameliorated IBD. Yen et al. (2006) concluded that IL23 promotes development and expansion of a pathogenic IL6- and IL17-producing memory-activated T-cell population that triggers the inflammatory cascade leading to intestinal inflammation.

Using 2 mouse models of Helicobacter hepaticus-induced T-cell-dependent colitis, Kullberg et al. (2006) showed that Il23, but not Il12, was essential for development of maximal intestinal disease. They proposed that IL23 drives both IFNG and IL17 responses that synergize to trigger severe intestinal inflammation.

Smith et al. (2007) found that mice lacking the Il12b subunit of Il23 had reduced circulating neutrophils compared with wildtype mice. Mice lacking both Il12b and Itgb2 (600065) and thereby deficient in beta-2 integrins, Il12, and Il23 had blunted neutrophilia compared with Itgb2 -/- mice. Treatment of both Il12b -/- mice and Il12b -/- Itgb2 -/- mice with Il23, but not with Il12, restored circulating neutrophil counts. Serum Il17a and tissue Il17a mRNA were readily detected in Itgb2 -/- mice, but not in Il12b -/- Itgb2 -/- mice, indicating that IL17A production is reduced when IL23 is absent. Cd3-positive Il17a-producing neutrophil regulatory T cells (Tn cells), particularly gamma-delta T cells, were significantly reduced in Il12b -/- Itgb2 -/- mice. Smith et al. (2007) concluded that IL23 has a prominent role in the regulation of granulopoiesis and prevalence of IL17A-producing Tn cells.

In mice, Buonocore et al. (2010) demonstrated that bacteria-driven innate colitis is associated with an increased production of IL17 and interferon-gamma (147570) in the colon. Stimulation of colonic leukocytes with IL23 induced the production of IL17 and interferon-gamma exclusively by innate lymphoid cells expressing Thy1 (188230), stem cell antigen-1, retinoic acid-related orphan receptor (Ror)-gamma-t; (RORC; 602943), and IL23R, and these cells markedly accumulated in the inflamed colon. IL23-responsive innate intestinal cells are also a feature of T cell-dependent models of colitis. The transcription factor Ror-gamma-t, which controls IL23R expression, has a functional role, because Rag (see 179615)-null/Rorc-null mice failed to develop innate colitis. Last, depletion of Thy1+ innate lymphoid cells completely abrogated acute and chronic innate colitis. Buonocore et al. (2010) concluded their results identified a previously unrecognized IL23-responsive innate lymphoid population that mediates intestinal immune pathology and may therefore represent a target in inflammatory bowel disease.

Town et al. (2009) found that mice lacking Tlr7 (300365) or Myd88 (602170), but not those lacking Tlr9 (605474), had increased West Nile virus (WNV; see 610379) viremia and susceptibility to lethal WNV infection. Although tissue concentrations of most innate cytokines were increased, Cd45 (PTPRC; 151460)-positive leukocytes and Cd11b (ITGAM; 120980)-positive macrophages failed to home to WNV-infected cells in Tlr7 -/- mice. This failure was associated with reduced Il12b and Il23a expression in Tlr7 -/- mice and Tlr7 -/- macrophages. Mice lacking Il12b or Il23a, but not those lacking Il12a, were more susceptible to lethal WNV infection, similar to Tlr7 -/- mice. Town et al. (2009) concluded that TLR7- and IL23-dependent responses are vital to host defense by affecting immune cell homing to WNV-infected target cells.

Kagami et al. (2010) observed delayed healing and decreased Il17a production following skin infection with Candida albicans in mice lacking Il23 or Il17a compared with wildtype mice or mice lacking Il12 or Il22 (605330). Histologic analysis revealed epidermal hyperplasia overlying infected dermis in wildtype mice, but fungal burden was greater and epidermal hyperplasia was severely reduced in Il23 -/- mice. Il23 -/- mice also failed to express Il17a or Il22 mRNA. Injection of recombinant Il17a promoted rapid healing in wildtype mice and mice lacking Il23 or Il12. Kagami et al. (2010) concluded that IL23 and IL17A, but not IL12 or IL22, are required for optimal host defense against cutaneous candidiasis. They also proposed that cutaneous candidiasis may be treatable with recombinant IL17A.

Kudva et al. (2011) found that mice lacking Il17a, Il17f, Il17ra (605461), or Il22 (605330), all of which are components of Th17 immunity, had impaired clearance of Staphylococcus aureus. Deletion of Il22 did not diminish neutrophil recruitment. Wildtype mice challenged with influenza A and then by S. aureus had increased inflammation and decreased clearance of both pathogens, accompanied by greater production of type I IFN (e.g., IFNA1; 147660) and type II IFN (i.e., IFNG) in lung, compared with mice infected with virus alone. Coinfection with influenza A substantially decreased Il17, Il22, and Il23 production after S. aureus infection in a type II IFN-independent and type I IFN-dependent manner. Overexpression of Il23 in coinfected mice rescued induction of Il17 and Il22 and markedly improved bacterial clearance. Kudva et al. (2011) concluded that type I IFNs induced by influenza A infection inhibit Th17 immunity and increase susceptibility to secondary bacterial pneumonia.


▼ REFERENCES

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Contributors:
Ada Hamosh - updated : 09/17/2018
Ada Hamosh - updated : 06/26/2015
Paul J. Converse - updated : 9/22/2014
Ada Hamosh - updated : 6/26/2014
Ada Hamosh - updated : 5/7/2013
Ada Hamosh - updated : 12/4/2012
Paul J. Converse - updated : 2/13/2012
Paul J. Converse - updated : 1/24/2011
Ada Hamosh - updated : 1/4/2011
Paul J. Converse - updated : 12/15/2010
Ada Hamosh - updated : 6/11/2010
Paul J. Converse - updated : 1/27/2009
Paul J. Converse - updated : 10/26/2007
Cassandra L. Kniffin - updated : 3/12/2007
Paul J. Converse - updated : 8/31/2006
Ada Hamosh - updated : 8/11/2006
Paul J. Converse - updated : 6/20/2006
Paul J. Converse - updated : 11/18/2004
Paul J. Converse - updated : 2/12/2003
Paul J. Converse - updated : 11/5/2001
Creation Date:
Paul J. Converse : 1/24/2001
Edit History:
alopez : 09/17/2018
alopez : 06/26/2015
mgross : 9/30/2014
mcolton : 9/22/2014
alopez : 6/26/2014
alopez : 5/7/2013
alopez : 5/7/2013
alopez : 12/6/2012
terry : 12/4/2012
mgross : 2/16/2012
terry : 2/13/2012
mgross : 5/3/2011
terry : 3/25/2011
mgross : 2/4/2011
mgross : 2/2/2011
terry : 1/24/2011
alopez : 1/4/2011
terry : 12/15/2010
alopez : 6/17/2010
terry : 6/11/2010
alopez : 6/9/2009
terry : 5/19/2009
mgross : 1/27/2009
terry : 1/27/2009
mgross : 10/26/2007
wwang : 3/13/2007
ckniffin : 3/12/2007
mgross : 9/26/2006
terry : 8/31/2006
carol : 8/14/2006
terry : 8/11/2006
mgross : 6/20/2006
mgross : 6/20/2006
mgross : 6/20/2006
wwang : 7/6/2005
terry : 7/5/2005
mgross : 11/18/2004
mgross : 2/12/2003
mgross : 2/12/2003
mgross : 11/5/2001
mgross : 4/16/2001
mgross : 1/24/2001

* 605580

INTERLEUKIN 23-ALPHA; IL23A


Alternative titles; symbols

INTERLEUKIN 23, p19 SUBUNIT
p19
SGRF


HGNC Approved Gene Symbol: IL23A

Cytogenetic location: 12q13.3   Genomic coordinates (GRCh38) : 12:56,338,884-56,340,410 (from NCBI)


TEXT

Description

Cytokines are soluble protein factors that regulate the proliferation, differentiation, and effector functions of immune cells. Based on sequence and structural analysis, cytokines can be classified into discrete families and subfamilies, such as the interleukin-6 (IL6; 147620)-like cytokines, which include the p35 subunit of IL12 (IL12A; 161560). IL12A is only active in cell-mediated immunity when associated with the IL12 p40 subunit (IL12B; 161561) as a composite molecule. IL23 is composed of the IL12 p40 subunit and the p19 subunit (IL23A) (Oppmann et al., 2000).


Cloning and Expression

By computationally screening databases for sequences similar to IL6 subfamily members, Oppmann et al. (2000) identified a cDNA encoding a calculated 19-kD cytokine, p19. The deduced 189-amino acid protein, which is 70% identical to the 196-residue mouse sequence, contains 4 alpha helices, 5 cysteine residues, and no N-linked glycosylation sites.


Gene Function

Functional analysis by Oppmann et al. (2000) indicated that cells transfected with p19 were unable to efficiently secrete the protein, and p19 was inactive in the absence of expression of IL12B but not other IL6 subfamily members. Immunoprecipitation analysis determined that IL12B and p19 form a soluble cytokine/receptor complex, which the authors termed IL23. RT-PCR analysis showed that high levels of p19 are expressed by dendritic cells. Immunoprecipitation and 2-dimensional SDS-PAGE analysis detected expression of high levels of IL23 in activated dendritic cells. Functional analysis determined that IL23 enhanced the secretion of gamma-interferon (IFNG; 147570) by memory (CD45RO) but not naive (CD45RA) T cells in an IL2 (147680)-dependent manner; however, this occurred at lower levels than in IL12-stimulated cells. Receptor-binding analysis established that IL23 and IL12 share IL12RB1 (601604), but that only IL12 binds to IL12RB2 (601642). However, IL23 stimulation did result in STAT4 (600558) activation at lower levels than those observed with IL12/IL12RB2 signaling, suggesting that IL23 has a unique receptor as well. Oppmann et al. (2000) pointed out that anti-IL12B antibodies used to evaluate IL12 in immunity and immunopathology do not discriminate between IL12 and IL23.

Psoriasis (see 177900) is characterized by the presence of IFNG and multiple IFN-related inflammatory genes in lesions. Because IL23 is involved in the recruitment of inflammatory cells in Th1-mediated diseases, Lee et al. (2004) examined psoriatic lesions for IL23 production. Quantitative RT-PCR detected significantly increased levels of IL23A and IL12B, but not IL12A, in psoriatic lesions compared with nonlesional skin. IL23 expression was found mainly in dermal cells of psoriatic lesions, particularly monocytes and mature dendritic cells, suggesting that IL23 plays a more dominant role than IL12 in psoriasis.

By RT-PCR, immunoblot, ELISA, and functional analyses, Piskin et al. (2006) found that culture supernatants and cell lysates of keratinocytes from normal and lesional psoriatic skin had low levels of IL23 sufficient to enhance IFNG production by memory T cells. Immunohistochemical analysis showed expression of both IL23 subunits in keratinocytes, and IL23 p19 was detected in dermal dendritic cells, macrophages, and epidermal Langerhans cells. Piskin et al. (2006) proposed that the ability of keratinocyte-expressed IL23 to enhance IFNG expression may contribute to the perpetuation of inflammation in psoriasis.

Langowski et al. (2006) demonstrated a molecular connection between the rise in tumor-associated inflammation and a lack of tumor immune surveillance. Expression of the heterodimeric cytokine IL23, but not of its close relative IL12, is increased in human tumors. Expression of these cytokines antagonistically regulates local inflammatory responses in the tumor microenvironment and infiltration of intraepithelial lymphocytes. Whereas IL12 promotes infiltration of cytotoxic T cells, IL23 promotes inflammatory responses such as upregulation of the matrix metalloprotease MMP9, and increases angiogenesis but reduces CD8 T-cell infiltration. Genetic deletion or antibody-mediated elimination of IL23 leads to increased infiltration of cytotoxic T cells into the transformed tissue, rendering a protective effect against chemically induced carcinogenesis. Transplanted tumors are growth-restricted in hosts depleted for IL23 or in IL23 receptor (607562)-deficient mice. Langowski et al. (2006) noted that although many strategies for immune therapy of cancer attempt to stimulate an immune response against solid tumors, infiltration of effector cells into the tumor tissue often appears to be a critical hurdle. Langowski et al. (2006) showed that IL23 is an important molecular link between tumor-promoter proinflammatory processes and the failure of the adaptive immune surveillance to infiltrate tumors.

Hu et al. (2006) detected the IL23p19 protein in cerebrospinal fluid isolated from 5 patients with Guillain-Barre syndrome (GBS; 139393). Sural nerve biopsies from these patients showed IL23p19 immunostaining in endoneurial macrophages. IL23A RNA was upregulated in sciatic nerve samples from 5 rats with experimental autoimmune neuritis (EAN), an animal model of GBS. Peak expression of IL23A RNA in the diseased animals occurred 2 days prior to peak clinical disease severity and then decreased to undetectable levels with clinical improvement. Hu et al. (2006) concluded that IL23 may play a role in the early effector phase of immune-mediated demyelination of the peripheral nerve.

CD4+ T helper cells that selectively produce interleukin-17 (Th17) are critical for host defense and immunity. Ghoreschi et al. (2010) showed that Th17 differentiation can occur in the absence of TGF-beta (190180) signaling. Neither IL6 (147620) nor IL23 alone efficiently generated Th17 cells; however, these cytokines in combination with IL1-beta (147720) effectively induced IL17 production in naive precursors, independently of TGF-beta. Epigenetic modification of the IL17A (603149), IL17F (606496), and RORC (602943) promoters proceeded without TGF-beta-1, allowing the generation of cells that coexpressed ROR-gamma-t (encoded by RORC) and Tbet (TBX21; 604895). Tbet+ROR-gamma-t+Th17 cells are generated in vivo during experimental allergic encephalomyelitis, and adoptively transferred Th17 cells generated with IL23 without TGF-beta-1 were pathogenic in this disease model. Ghoreschi et al. (2010) concluded that their data indicated an alternative mode for Th17 differentiation, and that, consistent with genetic data linking IL23R (607562) with autoimmunity, their findings reemphasized the importance of IL23 and therefore may have therapeutic implications.

By flow cytometric and immunohistochemical analyses, Tonel et al. (2010) demonstrated that expression of IL23 and IL23R was increased in the tissues of psoriasis patients. Injection of a neutralizing monoclonal antibody to IL23 in a xenotransplant mouse model showed IL23-dependent inhibition of psoriasis comparable to results obtained with anti-TNF (191160) blockers. Tonel et al. (2010) concluded that the IL23 pathway has a critical role in the pathogenesis of psoriasis.

Grivennikov et al. (2012) investigated mechanisms responsible for tumor-elicited inflammation in a mouse model of colorectal tumorigenesis which, like human colorectal cancer, exhibits upregulation of IL23 and IL17. They showed that IL23 signaling promotes tumor growth and progression and development of tumoral IL17 response. IL23 is mainly produced by tumor-associated myeloid cells that are likely to be activated by microbial products, which penetrate the tumors but not adjacent tissue. Both early and late colorectal neoplasms exhibit defective expression of several barrier proteins. Grivennikov et al. (2012) proposed that barrier deterioration induced by colorectal cancer-initiating genetic lesions results in adenoma invasion by microbial products that trigger tumor-elicited inflammation, which in turn drives tumor growth.

Wu et al. (2013) used transcriptional profiling of developing T(H)17 cells to construct a model of their signaling network and nominate major nodes that regulate T(H)17 development. Wu et al. (2013) identified serum glucocorticoid kinase-1 (SGK1; 602958), a serine/threonine kinase, as an essential node downstream of IL23 signaling. SGK1 is critical for regulating IL23R expression and stabilizing the T(H)17 cell phenotype by deactivation of mouse Foxo1 (136533), a direct repressor of IL23R expression. SGK1 has been shown to govern sodium transport and salt (NaCl) homeostasis in other cells. Wu et al. (2013) showed that a modest increase in salt concentration induces SGK1 expression, promotes IL23R expression, and enhances T(H)17 cell differentiation in vitro and in vivo, accelerating the development of autoimmunity. Loss of SGK1 abrogated sodium-mediated T(H)17 differentiation in an IL23-dependent manner. Wu et al. (2013) concluded that their data demonstrated that SGK1 has a critical role in the induction of pathogenic T(H)17 cells and provided a molecular insight into a mechanism by which an environmental factor such as a high-salt diet triggers T(H)17 development and promotes tissue inflammation.

Brain et al. (2013) detected upregulated expression of MIR29A (610782), MIR29B (see 610783), and MIR29C (610784) in human dendritic cells (DCs) stimulated with NOD2 (605956). They found that MIR29 regulated expression of multiple immune mediators. Notably, MIR29 downregulated IL23 by targeting its IL12p40 component directly and its IL23p19 component indirectly, most likely through a reduction of the transcription factor ATF2 (123811). Dextran sodium sulfate (DSS)-induced colitis was exacerbated in mice lacking Mir29 and was associated with elevated Il23 and Th17 cytokines in intestinal mucosa. DCs from Crohn disease (266600) patients expressing NOD2 polymorphisms failed to induce MIR29 after stimulation of pathogen pattern recognition receptors, and these DCs showed enhanced release of IL12p40 on exposure to adherent E. coli. Brain et al. (2013) proposed that loss of MIR29-mediated immune regulation in Crohn disease DCs may contribute to elevated IL23 in patients with the disease.

Riol-Blanco et al. (2014) exposed the skin of mice to imiquimod, which induces IL23-dependent psoriasis-like inflammation, and showed that a subset of sensory neurons expressing the ion channels TRPV1 (602076) and NAV1.8 (SCN10A; 604427) is essential to drive this inflammatory response. Imaging of intact skin revealed that a large fraction of dermal dendritic cells (DDCs), the principal source of IL23, is in close contact with these nociceptors. Upon selective pharmacologic or genetic ablation of nociceptors, DDCs failed to produce IL23 in imiquimod-exposed skin. Consequently, the local production of IL23-dependent inflammatory cytokines by dermal gamma-delta-T17 cells and the subsequent recruitment of inflammatory cells to the skin were markedly reduced. Intradermal injection of IL23 bypassed the requirement for nociceptor communication with DDCs and restored the inflammatory response. Riol-Blanco et al. (2014) concluded that TRPV1-positive/NAV1.8-positive nociceptors, by interacting with DDCs, regulate the IL23/IL17 (603149) pathway and control cutaneous immune responses.

To provide clinical proof that specific targeting of IL23p19 results in symptomatic improvement of disease severity in human subjects, Kopp et al. (2015) evaluated tildrakizumab, a monoclonal antibody that targets the IL23p19 subunit, in a 3-part, randomized, placebo-controlled, sequential, rising multiple dose phase I study in patients with moderate to severe psoriasis (177900). A 75% reduction in the psoriasis area and severity index (PASI) score (PASI75) was achieved by all subjects in parts 1 and 3 (pooled) in the 3 and 10 mg per kg groups by day 196. In part 2, 10 of 15 subjects in the 3 mg per kg group and 13 of 14 subjects in the 10 mg per kg group achieved a PASI75 by day 112. Tildrakizumab demonstrated important clinical improvement in moderate to severe psoriasis patients as demonstrated by improvements in PASI scores and histologic samples.

Calcinotto et al. (2018) identified IL23 produced by myeloid-derived suppressor cells (MDSCs) as a driver of castration-resistant prostate cancer (CRPC) in mice and patients with CRPC. Mechanistically, IL23 secreted by MDSCs can activate the androgen receptor (AR; 313700) pathway in prostate tumor cells, promoting cell survival and proliferation in androgen-deprived conditions. Intratumor MDSC infiltration and IL23 concentration are increased in blood and tumor samples from patients with CRPC. Antibody-mediated inactivation of IL23 restored sensitivity to androgen-deprivation therapy in mice. Calcinotto et al. (2018) concluded that MDSCs promote CRPC by acting in a non-cell-autonomous manner.


Mapping

The International Radiation Hybrid Mapping Consortium mapped the p19 gene to chromosome 12 (stSG47812).

Animal Model

Wiekowski et al. (2001) generated mice transgenic for ubiquitous expression of IL23A (p19). These mice showed multiorgan inflammation, elevated serum levels of IL1 (see 147760) and tumor necrosis factor (TNF; 191160), chronic expression of hepatic acute phase proteins, anemia, runting, premature death, and infertility. Liver-specific expression of IL23A failed to reproduce these abnormalities. Bone marrow transfer experiments showed that expression of IL23A by hemopoietic cells alone recapitulated the phenotype induced by widespread expression. The authors concluded that IL23A has biologic properties related to those of IL6, GCSF (CSF3; 138970), and IL12.

IL12 is composed of p35 and p40 subunits, while IL23 is composed of a p19 subunit and the IL12 p40 subunit. Cua et al. (2003) generated mice lacking only IL23 (p19 -/-), only IL12 (p35 -/-), or both IL23 and IL12 (p40 -/-) and immunized them with myelin oligodendrocyte glycoprotein 35-55 (MOG) in an experimental allergic encephalomyelitis (EAE) model of multiple sclerosis. The p19 -/- mice were generated by completely removing the p19 locus. Mice lacking p19 or p40 were resistant to development of EAE, whereas mice lacking only p35 were at least as susceptible as wildtype mice. Exogenous IL23 delivered into the central nervous system (CNS), but not intravenously, 2 days before expected onset of disease reconstituted EAE in both p19 -/- and p40 -/- mice, although onset in the latter was delayed and disease was less severe. Administration of recombinant IL12 for 7 days, followed by IL23 gene transfer on day 8, also induced intense EAE, suggesting that IL12 promotes the development of Th1 cells, while IL23 is required for subsequent inflammatory events. MOG immunization induced Th1 cells and proinflammatory cytokines in p19 -/- mice, whereas in p35 -/- and p40 -/- mice, a Th2 phenotype was observed. Flow cytometric and real-time PCR analyses demonstrated the entry of Th1 cells into the CNS in the absence of IL23, without the recruitment of additional T cells or macrophages or the activation of resident microglia. During EAE, IL23R (607562) and IL12RB1 were coexpressed by inflammatory macrophages, whereas resident microglia expressed only IL12RB1. Although resident microglia and inflammatory macrophages produced IL23, only inflammatory macrophages responded to IL23. In contrast, IL12 was produced primarily by inflammatory macrophages, and both macrophages and microglia had the potential to respond to IL12. Cua et al. (2003) concluded that IL12 promotes the development of naive T cells, while IL23 mediates late-stage inflammation and seems to be necessary for chronic inflammation. In a commentary, Watford and O'Shea (2003) noted that IL12 now has an 'alibi' in the development of autoimmune disease and that previous studies attributing these deleterious effects to IL12 may need reevaluation, including precise determination of the role of each subunit in this family of dimeric cytokines.

Chen et al. (2006) found that treating mice with anti-Il23 p19, like anti-Il23 p40, effectively blocked both acute EAE and EAE relapse. Anti-Il23 treatment blocked invasion of the CNS by T cells and inflammatory macrophages, and it reduced serum Il17 (603149) levels and CNS expression of Ifng, Ip10 (CXCL10; 147310), Il17, Il6, and Tnf mRNA. Anti-Il23 prevented EAE relapse, at least in part, by inhibiting epitope spreading. Although anti-Il17 blocked EAE relapse, it did not significantly reduce the number of infiltration foci, suggesting no effect on inflammatory cell migration but a possible downregulation of inflammatory effector cell function.

Mice deficient in Il10 develop spontaneous inflammatory bowel disease (IBD; see 266600). Yen et al. (2006) found that mice deficient in both Il10 and Il12 p35, but not mice deficient in both Il10 and Il23 p19, developed spontaneous IBD, indicating that IL23, but not IL12, is necessary for chronic intestinal inflammation. Adding recombinant IL23 to T cells from Il10 -/- mice adoptively transferred to T cell-deficient mice accelerated IBD development, which was accompanied by enhanced production of Il6 and Il17. Blockade of Il6 and Il17 ameliorated IBD. Yen et al. (2006) concluded that IL23 promotes development and expansion of a pathogenic IL6- and IL17-producing memory-activated T-cell population that triggers the inflammatory cascade leading to intestinal inflammation.

Using 2 mouse models of Helicobacter hepaticus-induced T-cell-dependent colitis, Kullberg et al. (2006) showed that Il23, but not Il12, was essential for development of maximal intestinal disease. They proposed that IL23 drives both IFNG and IL17 responses that synergize to trigger severe intestinal inflammation.

Smith et al. (2007) found that mice lacking the Il12b subunit of Il23 had reduced circulating neutrophils compared with wildtype mice. Mice lacking both Il12b and Itgb2 (600065) and thereby deficient in beta-2 integrins, Il12, and Il23 had blunted neutrophilia compared with Itgb2 -/- mice. Treatment of both Il12b -/- mice and Il12b -/- Itgb2 -/- mice with Il23, but not with Il12, restored circulating neutrophil counts. Serum Il17a and tissue Il17a mRNA were readily detected in Itgb2 -/- mice, but not in Il12b -/- Itgb2 -/- mice, indicating that IL17A production is reduced when IL23 is absent. Cd3-positive Il17a-producing neutrophil regulatory T cells (Tn cells), particularly gamma-delta T cells, were significantly reduced in Il12b -/- Itgb2 -/- mice. Smith et al. (2007) concluded that IL23 has a prominent role in the regulation of granulopoiesis and prevalence of IL17A-producing Tn cells.

In mice, Buonocore et al. (2010) demonstrated that bacteria-driven innate colitis is associated with an increased production of IL17 and interferon-gamma (147570) in the colon. Stimulation of colonic leukocytes with IL23 induced the production of IL17 and interferon-gamma exclusively by innate lymphoid cells expressing Thy1 (188230), stem cell antigen-1, retinoic acid-related orphan receptor (Ror)-gamma-t; (RORC; 602943), and IL23R, and these cells markedly accumulated in the inflamed colon. IL23-responsive innate intestinal cells are also a feature of T cell-dependent models of colitis. The transcription factor Ror-gamma-t, which controls IL23R expression, has a functional role, because Rag (see 179615)-null/Rorc-null mice failed to develop innate colitis. Last, depletion of Thy1+ innate lymphoid cells completely abrogated acute and chronic innate colitis. Buonocore et al. (2010) concluded their results identified a previously unrecognized IL23-responsive innate lymphoid population that mediates intestinal immune pathology and may therefore represent a target in inflammatory bowel disease.

Town et al. (2009) found that mice lacking Tlr7 (300365) or Myd88 (602170), but not those lacking Tlr9 (605474), had increased West Nile virus (WNV; see 610379) viremia and susceptibility to lethal WNV infection. Although tissue concentrations of most innate cytokines were increased, Cd45 (PTPRC; 151460)-positive leukocytes and Cd11b (ITGAM; 120980)-positive macrophages failed to home to WNV-infected cells in Tlr7 -/- mice. This failure was associated with reduced Il12b and Il23a expression in Tlr7 -/- mice and Tlr7 -/- macrophages. Mice lacking Il12b or Il23a, but not those lacking Il12a, were more susceptible to lethal WNV infection, similar to Tlr7 -/- mice. Town et al. (2009) concluded that TLR7- and IL23-dependent responses are vital to host defense by affecting immune cell homing to WNV-infected target cells.

Kagami et al. (2010) observed delayed healing and decreased Il17a production following skin infection with Candida albicans in mice lacking Il23 or Il17a compared with wildtype mice or mice lacking Il12 or Il22 (605330). Histologic analysis revealed epidermal hyperplasia overlying infected dermis in wildtype mice, but fungal burden was greater and epidermal hyperplasia was severely reduced in Il23 -/- mice. Il23 -/- mice also failed to express Il17a or Il22 mRNA. Injection of recombinant Il17a promoted rapid healing in wildtype mice and mice lacking Il23 or Il12. Kagami et al. (2010) concluded that IL23 and IL17A, but not IL12 or IL22, are required for optimal host defense against cutaneous candidiasis. They also proposed that cutaneous candidiasis may be treatable with recombinant IL17A.

Kudva et al. (2011) found that mice lacking Il17a, Il17f, Il17ra (605461), or Il22 (605330), all of which are components of Th17 immunity, had impaired clearance of Staphylococcus aureus. Deletion of Il22 did not diminish neutrophil recruitment. Wildtype mice challenged with influenza A and then by S. aureus had increased inflammation and decreased clearance of both pathogens, accompanied by greater production of type I IFN (e.g., IFNA1; 147660) and type II IFN (i.e., IFNG) in lung, compared with mice infected with virus alone. Coinfection with influenza A substantially decreased Il17, Il22, and Il23 production after S. aureus infection in a type II IFN-independent and type I IFN-dependent manner. Overexpression of Il23 in coinfected mice rescued induction of Il17 and Il22 and markedly improved bacterial clearance. Kudva et al. (2011) concluded that type I IFNs induced by influenza A infection inhibit Th17 immunity and increase susceptibility to secondary bacterial pneumonia.


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Contributors:
Ada Hamosh - updated : 09/17/2018
Ada Hamosh - updated : 06/26/2015
Paul J. Converse - updated : 9/22/2014
Ada Hamosh - updated : 6/26/2014
Ada Hamosh - updated : 5/7/2013
Ada Hamosh - updated : 12/4/2012
Paul J. Converse - updated : 2/13/2012
Paul J. Converse - updated : 1/24/2011
Ada Hamosh - updated : 1/4/2011
Paul J. Converse - updated : 12/15/2010
Ada Hamosh - updated : 6/11/2010
Paul J. Converse - updated : 1/27/2009
Paul J. Converse - updated : 10/26/2007
Cassandra L. Kniffin - updated : 3/12/2007
Paul J. Converse - updated : 8/31/2006
Ada Hamosh - updated : 8/11/2006
Paul J. Converse - updated : 6/20/2006
Paul J. Converse - updated : 11/18/2004
Paul J. Converse - updated : 2/12/2003
Paul J. Converse - updated : 11/5/2001

Creation Date:
Paul J. Converse : 1/24/2001

Edit History:
alopez : 09/17/2018
alopez : 06/26/2015
mgross : 9/30/2014
mcolton : 9/22/2014
alopez : 6/26/2014
alopez : 5/7/2013
alopez : 5/7/2013
alopez : 12/6/2012
terry : 12/4/2012
mgross : 2/16/2012
terry : 2/13/2012
mgross : 5/3/2011
terry : 3/25/2011
mgross : 2/4/2011
mgross : 2/2/2011
terry : 1/24/2011
alopez : 1/4/2011
terry : 12/15/2010
alopez : 6/17/2010
terry : 6/11/2010
alopez : 6/9/2009
terry : 5/19/2009
mgross : 1/27/2009
terry : 1/27/2009
mgross : 10/26/2007
wwang : 3/13/2007
ckniffin : 3/12/2007
mgross : 9/26/2006
terry : 8/31/2006
carol : 8/14/2006
terry : 8/11/2006
mgross : 6/20/2006
mgross : 6/20/2006
mgross : 6/20/2006
wwang : 7/6/2005
terry : 7/5/2005
mgross : 11/18/2004
mgross : 2/12/2003
mgross : 2/12/2003
mgross : 11/5/2001
mgross : 4/16/2001
mgross : 1/24/2001



NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers, and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
OMIM® and Online Mendelian Inheritance in Man® are registered trademarks of the Johns Hopkins University.
Copyright® 1966-2025 Johns Hopkins University.

NOTE: OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers, and by advanced students in science and medicine. While the OMIM database is open to the public, users seeking information about a personal medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.
OMIM® and Online Mendelian Inheritance in Man® are registered trademarks of the Johns Hopkins University.
Copyright® 1966-2025 Johns Hopkins University.
Printed: June 19, 2025