Interleukin 23 subunit alpha

IL23A
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3D85, 3D87, 3DUH, 3QWR, 4GRW, 4OE8, 4OG9
Identifiers
Aliases	IL23A, IL-23, IL-23A, IL23P19, P19, SGRF, Interleukin 23, interleukin 23 subunit alpha
External IDs	OMIM: 605580; MGI: 1932410; HomoloGene: 12832; GeneCards: IL23A; OMA:IL23A - orthologs
Gene location (Human) Chr. Chromosome 12 (human)[1] Band 12q13.3 Start 56,334,174 bp[1] End 56,340,410 bp[1]
Gene location (Mouse) Chr. Chromosome 10 (mouse)[2] Band 10|10 D3 Start 128,132,008 bp[2] End 128,134,621 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in testicle left testis right testis pancreatic ductal cell granulocyte sperm cartilage tissue gonad oocyte oral cavity Top expressed in secondary oocyte morula zygote primary oocyte decidua atrioventricular valve optic nerve cumulus cell endocardial cushion embryo More reference expression data BioGPS More reference expression data
Gene ontology Molecular function cytokine activity interleukin-23 receptor binding protein binding Cellular component interleukin-23 complex extracellular region extracellular space endoplasmic reticulum lumen Biological process negative regulation of interleukin-10 production positive regulation of inflammatory response positive regulation of interleukin-12 production positive regulation of interleukin-10 production immune system process positive regulation of T cell mediated cytotoxicity positive regulation of interferon-gamma production positive regulation of natural killer cell activation positive regulation of osteoclast differentiation positive regulation of T-helper 17 cell lineage commitment positive regulation of NK T cell activation T cell proliferation positive regulation of natural killer cell proliferation positive regulation of NK T cell proliferation positive regulation of T-helper 17 type immune response defense response to virus positive regulation of tissue remodeling positive regulation of T-helper 1 type immune response positive regulation of granulocyte macrophage colony-stimulating factor production defense response to Gram-negative bacterium positive regulation of T cell proliferation immune response positive regulation of memory T cell differentiation positive regulation of neutrophil chemotaxis positive regulation of tumor necrosis factor production positive regulation of interleukin-17 production innate immune response inflammatory response tissue remodeling positive regulation of transcription by RNA polymerase II positive regulation of activated T cell proliferation positive regulation of defense response to virus by host positive regulation of activation of Janus kinase activity regulation of tyrosine phosphorylation of STAT protein positive regulation of tyrosine phosphorylation of STAT protein regulation of signaling receptor activity cytokine-mediated signaling pathway interleukin-23-mediated signaling pathway positive regulation of NIK/NF-kappaB signaling Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 51561 83430 Ensembl ENSG00000110944 ENSMUSG00000025383 UniProt Q9NPF7 Q9EQ14 RefSeq (mRNA) NM_016584 NM_031252 RefSeq (protein) NP_057668 NP_112542 Location (UCSC) Chr 12: 56.33 – 56.34 Mb Chr 10: 128.13 – 128.13 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Interleukin-23 subunit alpha is a protein that in humans is encoded by the IL23A gene.^[5][6] The protein is also known as IL-23p19. It is one of the two subunits of the cytokine Interleukin-23.

Interleukin-23 (IL-23) is a heterodimeric cytokine composed of an Interleukin 23 alpha subunit and an IL-12p40 subunit. The IL-12p40, also known as Interleukin 12 subunit beta, is used by both IL-23 (where it partners with IL-23p19) and IL-12 (where it partners with IL-12A).^[5] A functional receptor for IL-23 (the IL-23 receptor) has been identified and is composed of IL-12R β1 and IL-23R.^[7]

Function

Produced by dendritic cells and macrophages, IL-23 is an important part of the inflammatory response against infection. It promotes upregulation of the matrix metalloprotease MMP9, increases angiogenesis and reduces CD8+ T-cell infiltration into tumours. IL-23 mediates its effects on both innate and adaptive arms of the immune system that express the IL-23 receptor. T_h17 cells represent the most prominent T cell subset that responds to IL-23, although IL-23 has been implicated in inhibiting the development of regulatory T cell development in the intestine. T_h17 cells produce IL-17, a proinflammatory cytokine that enhances T cell priming and stimulates the production of other proinflammatory molecules such as IL-1, IL-6, TNF-alpha, NOS-2, and chemokines resulting in inflammation.

The expression of IL23A is decreased after AHR knockdown in THP-1 cells and primary mouse macrophages.^[8]

Clinical significance

Knockout mice deficient in either p40 or p19, or in either subunit of the IL-23 receptor (IL-23R and IL12R-β1) develop less severe symptoms of experimental autoimmune encephalomyelitis (EAE) and inflammatory bowel disease highlighting the importance of IL-23 in the inflammatory pathway.^[9][10]

Discovery

A computational search for IL-12 homologue genes found p19, a gene that encodes a cytokine chain. Experimental work revealed that p19 formed a heterodimer by binding to p40, a subunit of IL-12. This new heterodimer was named IL-23.^[11]

Knockdown of AHR decreases the expression of IL23A in THP-1 cells and primary macrophage.^[8]

Pharmacology

Several biologic drugs work by targeting IL-23A. Ustekinumab, a monoclonal antibody targeting both IL-12 and IL-23 and used to treat plaque psoriasis, psoriatic arthritis, and Crohn's disease, launched in the United States under the brand name Stelara.^[12] Risankizumab is another monoclonal antibody that targets IL-23A and is approved to treat plaque psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis.^[13][14][15]

References

1. GRCh38: Ensembl release 89: ENSG00000110944 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000025383 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, et al. (November 2000). "Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12". Immunity. 13 (5): 715–25. doi:10.1016/S1074-7613(00)00070-4. PMID 11114383.
6. "Entrez Gene: IL23A interleukin 23, alpha subunit p19".
7. Parham C, Chirica M, Timans J, Vaisberg E, Travis M, Cheung J, et al. (June 2002). "A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R". Journal of Immunology. 168 (11): 5699–708. doi:10.4049/jimmunol.168.11.5699. PMID 12023369.
8. Memari B, Bouttier M, Dimitrov V, Ouellette M, Behr MA, Fritz JH, White JH (November 2015). "Engagement of the Aryl Hydrocarbon Receptor in Mycobacterium tuberculosis-Infected Macrophages Has Pleiotropic Effects on Innate Immune Signaling". Journal of Immunology. 195 (9): 4479–91. doi:10.4049/jimmunol.1501141. PMID 26416282.
9. Langowski JL, Zhang X, Wu L, Mattson JD, Chen T, Smith K, Basham B, McClanahan T, Kastelein RA, Oft M (July 2006). "IL-23 promotes tumour incidence and growth". Nature. 442 (7101): 461–5. Bibcode:2006Natur.442..461L. doi:10.1038/nature04808. PMID 16688182. S2CID 4431794.
10. Kikly K, Liu L, Na S, Sedgwick JD (December 2006). "The IL-23/Th(17) axis: therapeutic targets for autoimmune inflammation". Current Opinion in Immunology. 18 (6): 670–5. doi:10.1016/j.coi.2006.09.008. PMID 17010592.
11. Korn T, Bettelli E, Oukka M, Kuchroo VK (2009). "IL-17 and Th17 Cells". Annual Review of Immunology. 27: 485–517. doi:10.1146/annurev.immunol.021908.132710. PMID 19132915.
12. van Vollenhoven RF, Hahn BH, Tsokos GC, Wagner CL, Lipsky P, Touma Z, Werth VP, Gordon RM, Zhou B, Hsu B, Chevrier M, Triebel M, Jordan JL, Rose S (October 2018). "Efficacy and safety of ustekinumab, an IL-12 and IL-23 inhibitor, in patients with active systemic lupus erythematosus: results of a multicentre, double-blind, phase 2, randomised, controlled study". Lancet. 392 (10155): 1330–1339. doi:10.1016/S0140-6736(18)32167-6. PMID 30249507.
13. Haugh IM, Preston AK, Kivelevitch DN, Menter AM (2018). "Risankizumab: an anti-IL-23 antibody for the treatment of psoriasis". Drug Design, Development and Therapy. 12: 3879–3883. doi:10.2147/DDDT.S167149. PMC 6237136. PMID 30518998.
14. Huth L, Amann PM, Marquardt Y, Jansen M, Baron JM, Huth S (June 2024). "Understanding the impact of risankizumab on keratinocyte-derived IL-23A in a novel organotypic 3D skin model containing IL-23A responsive and IL-17A producing γδ-T-cells". Cutaneous and Ocular Toxicology. 43 (2): 124–128. doi:10.1080/15569527.2024.2310243. PMID 38284163.
15. Brooks, Abigail (18 June 2024). "FDA Approves Risankizumab (Skyrizi) for Ulcerative Colitis". HCP Live. Retrieved 2 November 2024.

Further reading

• Lankford CS, Frucht DM (January 2003). "A unique role for IL-23 in promoting cellular immunity". Journal of Leukocyte Biology. 73 (1): 49–56. CiteSeerX 10.1.1.319.1141. doi:10.1189/jlb.0602326. PMID 12525561. S2CID 13896804.
• van de Vosse E, Lichtenauer-Kaligis EG, van Dissel JT, Ottenhoff TH (March 2003). "Genetic variations in the interleukin-12/interleukin-23 receptor (beta1) chain, and implications for IL-12 and IL-23 receptor structure and function". Immunogenetics. 54 (12): 817–29. doi:10.1007/s00251-002-0534-9. PMID 12671732. S2CID 34119140.
• Kreymborg K, Böhlmann U, Becher B (December 2005). "IL-23: changing the verdict on IL-12 function in inflammation and autoimmunity". Expert Opinion on Therapeutic Targets. 9 (6): 1123–36. doi:10.1517/14728222.9.6.1123. PMID 16300465. S2CID 41416821.
• Peluso I, Pallone F, Monteleone G (September 2006). "Interleukin-12 and Th1 immune response in Crohn's disease: pathogenetic relevance and therapeutic implication". World Journal of Gastroenterology. 12 (35): 5606–10. doi:10.3748/wjg.v12.i35.5606. PMC 4088159. PMID 17007011.
• Prashar Y, Weissman SM (January 1996). "Analysis of differential gene expression by display of 3' end restriction fragments of cDNAs". Proceedings of the National Academy of Sciences of the United States of America. 93 (2): 659–63. Bibcode:1996PNAS...93..659P. doi:10.1073/pnas.93.2.659. PMC 40108. PMID 8570611.
• Wiekowski MT, Leach MW, Evans EW, Sullivan L, Chen SC, Vassileva G, Bazan JF, Gorman DM, Kastelein RA, Narula S, Lira SA (June 2001). "Ubiquitous transgenic expression of the IL-23 subunit p19 induces multiorgan inflammation, runting, infertility, and premature death". Journal of Immunology. 166 (12): 7563–70. doi:10.4049/jimmunol.166.12.7563. PMID 11390512.
• Broberg EK, Setälä N, Erälinna JP, Salmi AA, Röyttä M, Hukkanen V (June 2002). "Herpes simplex virus type 1 infection induces upregulation of interleukin-23 (p19) mRNA expression in trigeminal ganglia of BALB/c mice". Journal of Interferon & Cytokine Research. 22 (6): 641–51. doi:10.1089/10799900260100123. PMID 12162874.
• Pirhonen J, Matikainen S, Julkunen I (November 2002). "Regulation of virus-induced IL-12 and IL-23 expression in human macrophages". Journal of Immunology. 169 (10): 5673–8. doi:10.4049/jimmunol.169.10.5673. PMID 12421946.
• Lo CH, Lee SC, Wu PY, Pan WY, Su J, Cheng CW, Roffler SR, Chiang BL, Lee CN, Wu CW, Tao MH (July 2003). "Antitumor and antimetastatic activity of IL-23". Journal of Immunology. 171 (2): 600–7. doi:10.4049/jimmunol.171.2.600. PMID 12847224.
• Lee E, Trepicchio WL, Oestreicher JL, Pittman D, Wang F, Chamian F, Dhodapkar M, Krueger JG (January 2004). "Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris". The Journal of Experimental Medicine. 199 (1): 125–30. doi:10.1084/jem.20030451. PMC 1887731. PMID 14707118.
• Verreck FA, de Boer T, Langenberg DM, Hoeve MA, Kramer M, Vaisberg E, Kastelein R, Kolk A, de Waal-Malefyt R, Ottenhoff TH (March 2004). "Human IL-23-producing type 1 macrophages promote but IL-10-producing type 2 macrophages subvert immunity to (myco)bacteria". Proceedings of the National Academy of Sciences of the United States of America. 101 (13): 4560–5. Bibcode:2004PNAS..101.4560V. doi:10.1073/pnas.0400983101. PMC 384786. PMID 15070757.
• Smits HH, van Beelen AJ, Hessle C, Westland R, de Jong E, Soeteman E, Wold A, Wierenga EA, Kapsenberg ML (May 2004). "Commensal Gram-negative bacteria prime human dendritic cells for enhanced IL-23 and IL-27 expression and enhanced Th1 development". European Journal of Immunology. 34 (5): 1371–80. doi:10.1002/eji.200324815. PMID 15114670. S2CID 25630092.
• Schnurr M, Toy T, Shin A, Wagner M, Cebon J, Maraskovsky E (February 2005). "Extracellular nucleotide signaling by P2 receptors inhibits IL-12 and enhances IL-23 expression in human dendritic cells: a novel role for the cAMP pathway". Blood. 105 (4): 1582–9. doi:10.1182/blood-2004-05-1718. PMID 15486065.