Interleukin 23 subunit alpha explained

Interleukin-23 subunit alpha is a protein that in humans is encoded by the IL23A gene.^{[1] [2]} 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).^[1] A functional receptor for IL-23 (the IL-23 receptor) has been identified and is composed of IL-12R β1 and IL-23R.^[3]

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.^[4]

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.^{[5] [6]}

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.^[7]

Knockdown of AHR decreases the expression of IL23A in THP-1 cells and primary macrophage.^[4]

See also

• Ustekinumab, a monoclonal antibody targeting both IL-12 and IL-23 and used to treat plaque psoriasis, launched in the United States under the brand name Stelara

Further reading

• Lankford CS, Frucht DM . A unique role for IL-23 in promoting cellular immunity . Journal of Leukocyte Biology . 73 . 1 . 49–56 . January 2003 . 12525561 . 10.1189/jlb.0602326 . 10.1.1.319.1141 . 13896804 .
• van de Vosse E, Lichtenauer-Kaligis EG, van Dissel JT, Ottenhoff TH . 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 . March 2003 . 12671732 . 10.1007/s00251-002-0534-9 . 34119140 .
• Kreymborg K, Böhlmann U, Becher B . IL-23: changing the verdict on IL-12 function in inflammation and autoimmunity . Expert Opinion on Therapeutic Targets . 9 . 6 . 1123–36 . December 2005 . 16300465 . 10.1517/14728222.9.6.1123 . 41416821 .
• Peluso I, Pallone F, Monteleone G . Interleukin-12 and Th1 immune response in Crohn's disease: pathogenetic relevance and therapeutic implication . World Journal of Gastroenterology . 12 . 35 . 5606–10 . September 2006 . 17007011 . 4088159 . 10.3748/wjg.v12.i35.5606 . free .
• Prashar Y, Weissman SM . 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 . January 1996 . 8570611 . 40108 . 10.1073/pnas.93.2.659 . 1996PNAS...93..659P . free .
• Wiekowski MT, Leach MW, Evans EW, Sullivan L, Chen SC, Vassileva G, Bazan JF, Gorman DM, Kastelein RA, Narula S, Lira SA . Ubiquitous transgenic expression of the IL-23 subunit p19 induces multiorgan inflammation, runting, infertility, and premature death . Journal of Immunology . 166 . 12 . 7563–70 . June 2001 . 11390512 . 10.4049/jimmunol.166.12.7563 . free .
• Broberg EK, Setälä N, Erälinna JP, Salmi AA, Röyttä M, Hukkanen V . 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 . June 2002 . 12162874 . 10.1089/10799900260100123 .
• Pirhonen J, Matikainen S, Julkunen I . Regulation of virus-induced IL-12 and IL-23 expression in human macrophages . Journal of Immunology . 169 . 10 . 5673–8 . November 2002 . 12421946 . 10.4049/jimmunol.169.10.5673 . free .
• Lo CH, Lee SC, Wu PY, Pan WY, Su J, Cheng CW, Roffler SR, Chiang BL, Lee CN, Wu CW, Tao MH . Antitumor and antimetastatic activity of IL-23 . Journal of Immunology . 171 . 2 . 600–7 . July 2003 . 12847224 . 10.4049/jimmunol.171.2.600. free .
• Lee E, Trepicchio WL, Oestreicher JL, Pittman D, Wang F, Chamian F, Dhodapkar M, Krueger JG . 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 . January 2004 . 14707118 . 1887731 . 10.1084/jem.20030451 .
• Verreck FA, de Boer T, Langenberg DM, Hoeve MA, Kramer M, Vaisberg E, Kastelein R, Kolk A, de Waal-Malefyt R, Ottenhoff TH . 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 . March 2004 . 15070757 . 384786 . 10.1073/pnas.0400983101 . 2004PNAS..101.4560V . free .
• Smits HH, van Beelen AJ, Hessle C, Westland R, de Jong E, Soeteman E, Wold A, Wierenga EA, Kapsenberg ML . 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 . May 2004 . 15114670 . 10.1002/eji.200324815 . 25630092 . free .
• Schnurr M, Toy T, Shin A, Wagner M, Cebon J, Maraskovsky E . 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 . February 2005 . 15486065 . 10.1182/blood-2004-05-1718 . free .

Notes and References

1. 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 . 6 . 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 . November 2000 . 11114383 . 10.1016/S1074-7613(00)00070-4 . free .
2. Web site: Entrez Gene: IL23A interleukin 23, alpha subunit p19.
3. 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 . 6 . 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 . June 2002 . 12023369 . 10.4049/jimmunol.168.11.5699 . free .
4. Memari B, Bouttier M, Dimitrov V, Ouellette M, Behr MA, Fritz JH, White JH . 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 . November 2015 . 26416282 . 10.4049/jimmunol.1501141 . free .
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 . 442 . 7101 . 461–5 . July 2006 . 16688182 . 10.1038/nature04808 . 2006Natur.442..461L . 4431794 .
6. Kikly K, Liu L, Na S, Sedgwick JD . The IL-23/Th(17) axis: therapeutic targets for autoimmune inflammation . Current Opinion in Immunology . 18 . 6 . 670–5 . December 2006 . 17010592 . 10.1016/j.coi.2006.09.008 .
7. Korn T, Bettelli E, Oukka M, Kuchroo VK . IL-17 and Th17 Cells . Annual Review of Immunology . 27 . 485–517 . 2009 . 19132915 . 10.1146/annurev.immunol.021908.132710 .