Interleukin-23 receptor explained

The interleukin-23 receptor is a type I cytokine receptor. It is encoded in human by the IL23R gene.^[1] In complex with the interleukin-12 receptor β1 subunit (IL-12Rβ1), it is activated by the cytokine interleukin 23 (IL-23).^[2] The IL23R mRNA is 2.8 kilobases in length and includes 12 exons. The translated protein contains 629 amino acids; it is a type I penetrating protein and includes a signal peptide, an N-terminal fibronectin III-like domain and an intracellular part that contains three potential tyrosine phosphorylation domains. There are 24 IL23R splice variants in mitogen-activated lymphocytes.^[3] IL23R includes some single-nucleotide polymorphisms in the region encoding the domain that binds IL-23, which may lead to differences between people in Th17 activation.^[4] There is also a variant of IL-23R that consists of just the extracellular part and is known as soluble IL-23R. This form can compete with the membrane-bound form to bind IL-23, modulating the Th17 immune response and regulation of inflammation and immune function.^[5]

Function

The protein encoded by this gene is a subunit of the receptor for IL-23. This protein pairs with the receptor molecule IL-12Rβ1 (IL12RB1), together forming the IL-23 receptor complex, and both are required for IL-23 signaling. This protein associates constitutively with Janus kinase 2 (JAK2) and also binds to transcription activator STAT3 in a ligand-dependent manner.^[1]

Clinical significance

Three variants in the IL23R gene have been shown to protect against Crohn's disease and ulcerative colitis.^{[6] [7] [8]} The effect of IL-23R variations present in the population have been studied with an in vitro expression model system.^[9]

Further reading

• 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 . Journal of Immunology . 168 . 11 . 5699–708 . Jun 2002 . 12023369 . 10.4049/jimmunol.168.11.5699 . free .
• Zhang XY, Zhang HJ, Zhang Y, Fu YJ, He J, Zhu LP, Wang SH, Liu L . Identification and expression analysis of alternatively spliced isoforms of human interleukin-23 receptor gene in normal lymphoid cells and selected tumor cells . Immunogenetics . 57 . 12 . 934–43 . Jan 2006 . 16372191 . 10.1007/s00251-005-0067-0 . 35668044 .
• Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, Steinhart AH, Abraham C, Regueiro M, Griffiths A, Dassopoulos T, Bitton A, Yang H, Targan S, Datta LW, Kistner EO, Schumm LP, Lee AT, Gregersen PK, Barmada MM, Rotter JI, Nicolae DL, Cho JH . A genome-wide association study identifies IL23R as an inflammatory bowel disease gene . Science . 314 . 5804 . 1461–3 . Dec 2006 . 17068223 . 10.1126/science.1135245 . 4410764 . 2006Sci...314.1461D .
• Cargill M, Schrodi SJ, Chang M, Garcia VE, Brandon R, Callis KP, Matsunami N, Ardlie KG, Civello D, Catanese JJ, Leong DU, Panko JM, McAllister LB, Hansen CB, Papenfuss J, Prescott SM, White TJ, Leppert MF, Krueger GG, Begovich AB . A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes . American Journal of Human Genetics . 80 . 2 . 273–90 . Feb 2007 . 17236132 . 1785338 . 10.1086/511051 .
• Dubinsky MC, Wang D, Picornell Y, Wrobel I, Katzir L, Quiros A, Dutridge D, Wahbeh G, Silber G, Bahar R, Mengesha E, Targan SR, Taylor KD, Rotter JI . IL-23 receptor (IL-23R) gene protects against pediatric Crohn's disease . Inflammatory Bowel Diseases . 13 . 5 . 511–5 . May 2007 . 17309073 . 2169293 . 10.1002/ibd.20126 .
• Tremelling M, Cummings F, Fisher SA, Mansfield J, Gwilliam R, Keniry A, Nimmo ER, Drummond H, Onnie CM, Prescott NJ, Sanderson J, Bredin F, Berzuini C, Forbes A, Lewis CM, Cardon L, Deloukas P, Jewell D, Mathew CG, Parkes M, Satsangi J . IL23R variation determines susceptibility but not disease phenotype in inflammatory bowel disease . Gastroenterology . 132 . 5 . 1657–64 . May 2007 . 17484863 . 2696256 . 10.1053/j.gastro.2007.02.051 .
• Cummings JR, Ahmad T, Geremia A, Beckly J, Cooney R, Hancock L, Pathan S, Guo C, Cardon LR, Jewell DP . Contribution of the novel inflammatory bowel disease gene IL23R to disease susceptibility and phenotype . Inflammatory Bowel Diseases . 13 . 9 . 1063–8 . Sep 2007 . 17508420 . 10.1002/ibd.20180 . 21879558 . free .
• Yamazaki K, Onouchi Y, Takazoe M, Kubo M, Nakamura Y, Hata A . Association analysis of genetic variants in IL23R, ATG16L1 and 5p13.1 loci with Crohn's disease in Japanese patients . Journal of Human Genetics . 52 . 7 . 575–83 . 2007 . 17534574 . 10.1007/s10038-007-0156-z . free .
• Baldassano RN, Bradfield JP, Monos DS, Kim CE, Glessner JT, Casalunovo T, Frackelton EC, Otieno FG, Kanterakis S, Shaner JL, Smith RM, Eckert AW, Robinson LJ, Onyiah CC, Abrams DJ, Chiavacci RM, Skraban R, Devoto M, Grant SF, Hakonarson H . Association of variants of the interleukin-23 receptor gene with susceptibility to pediatric Crohn's disease . Clinical Gastroenterology and Hepatology . 5 . 8 . 972–6 . Aug 2007 . 17618837 . 10.1016/j.cgh.2007.04.024 . 4287202 .
• Sánchez E, Rueda B, Callejas JL, Sabio JM, Ortego-Centeno N, Jimenez-Alonso J, López-Nevot MA, Martín J . Analysis of interleukin-23 receptor (IL23R) gene polymorphisms in systemic lupus erythematosus . Tissue Antigens . 70 . 3 . 233–7 . Sep 2007 . 17661912 . 10.1111/j.1399-0039.2007.00881.x . free .
• Orozco G, Rueda B, Robledo G, García A, Martín J . Investigation of the IL23R gene in a Spanish rheumatoid arthritis cohort . Human Immunology . 68 . 8 . 681–4 . Aug 2007 . 17678723 . 10.1016/j.humimm.2007.05.008 .
• Oliver J, Rueda B, López-Nevot MA, Gómez-García M, Martín J . Replication of an association between IL23R gene polymorphism with inflammatory bowel disease . Clinical Gastroenterology and Hepatology . 5 . 8 . 977–81, 981.e1–2 . Aug 2007 . 17678845 . 10.1016/j.cgh.2007.05.002 . 10261/75893 .
• Raelson JV, Little RD, Ruether A, Fournier H, Paquin B, Van Eerdewegh P, Bradley WE, Croteau P, Nguyen-Huu Q, Segal J, Debrus S, Allard R, Rosenstiel P, Franke A, Jacobs G, Nikolaus S, Vidal JM, Szego P, Laplante N, Clark HF, Paulussen RJ, Hooper JW, Keith TP, Belouchi A, Schreiber S . Genome-wide association study for Crohn's disease in the Quebec Founder Population identifies multiple validated disease loci . Proceedings of the National Academy of Sciences of the United States of America . 104 . 37 . 14747–52 . Sep 2007 . 17804789 . 1965486 . 10.1073/pnas.0706645104 . free .
• Borgiani P, Perricone C, Ciccacci C, Romano S, Novelli G, Biancone L, Petruzziello C, Pallone F . Interleukin-23R Arg381Gln is associated with susceptibility to Crohn's disease but not with phenotype in an Italian population . Gastroenterology . 133 . 3 . 1049–51; author reply 1051–2 . Sep 2007 . 17854611 . 10.1053/j.gastro.2007.07.013 . free .

Notes and References

1. Web site: Entrez Gene: IL23R interleukin 23 receptor .
2. 6. 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. 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. 10.4049/jimmunol.168.11.5699. 12023369. free.
3. Kan SH, Mancini G, Gallagher G. October 2008. Identification and characterization of multiple splice forms of the human interleukin-23 receptor alpha chain in mitogen-activated leukocytes. Genes and Immunity. 9. 7. 631–9. 10.1038/gene.2008.64. 18754016. free.
4. Yu RY, Brazaitis J, Gallagher G. February 2015. The human IL-23 receptor rs11209026 A allele promotes the expression of a soluble IL-23R-encoding mRNA species. Journal of Immunology. 194. 3. 1062–8. 10.4049/jimmunol.1401850. 25552541. free.
5. Figure 8. with two source data miR-34a regulates Th17 cell-mediated proliferation.. 10.7554/elife.39479.025. free.
6. Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, Steinhart AH, Abraham C, Regueiro M, Griffiths A, Dassopoulos T, Bitton A, Yang H, Targan S, Datta LW, Kistner EO, Schumm LP, Lee AT, Gregersen PK, Barmada MM, Rotter JI, Nicolae DL, Cho JH . A genome-wide association study identifies IL23R as an inflammatory bowel disease gene . Science . 314 . 5804 . 1461–3 . Dec 2006 . 17068223 . 10.1126/science.1135245 . 6 . 4410764 . 2006Sci...314.1461D .
7. Rivas MA, Beaudoin M, Gardet A, Stevens C, Sharma Y, Zhang CK, Boucher G, Ripke S, Ellinghaus D, Burtt N, Fennell T, Kirby A, Latiano A, Goyette P, Green T, Halfvarson J, Haritunians T, Korn JM, Kuruvilla F, Lagacé C, Neale B, Lo KS, Schumm P, Törkvist L, Dubinsky MC, Brant SR, Silverberg MS, Duerr RH, Altshuler D, Gabriel S, Lettre G, Franke A, D'Amato M, McGovern DP, Cho JH, Rioux JD, Xavier RJ, Daly MJ . Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease . Nature Genetics . 43 . 11 . 1066–73 . Nov 2011 . 21983784 . 10.1038/ng.952 . 6 . 3378381.
8. Momozawa Y, Mni M, Nakamura K, Coppieters W, Almer S, Amininejad L, Cleynen I, Colombel JF, de Rijk P, Dewit O, Finkel Y, Gassull MA, Goossens D, Laukens D, Lémann M, Libioulle C, O'Morain C, Reenaers C, Rutgeerts P, Tysk C, Zelenika D, Lathrop M, Del-Favero J, Hugot JP, de Vos M, Franchimont D, Vermeire S, Louis E, Georges M . Resequencing of positional candidates identifies low frequency IL23R coding variants protecting against inflammatory bowel disease . Nature Genetics . 43 . 1 . 43–7 . Jan 2011 . 21151126 . 10.1038/ng.733 . 6 . 1854/LU-1145381 . 21340871 . free .
9. de Paus RA, van de Wetering D, van Dissel JT, van de Vosse E . IL-23 and IL-12 responses in activated human T cells retrovirally transduced with IL-23 receptor variants . Molecular Immunology . 45 . 15 . 3889–95 . September 2008 . 18675459 . 10.1016/j.molimm.2008.06.029 .