IL-23 is an important part of the inflammatory response against infection. It promotes upregulation of the matrix metalloproteaseMMP9, 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. Th17 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. Th17 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
References
↑ Jump up to: 1.01.1Oppmann 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. PMID11114383.
↑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. PMID12023369.
↑ Jump up to: 4.04.1Memari 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. PMID26416282.
↑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. doi:10.1038/nature04808. PMID16688182.
↑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. PMID17010592.
Lankford CS, Frucht DM (January 2003). "A unique role for IL-23 in promoting cellular immunity". Journal of Leukocyte Biology. 73 (1): 49–56. doi:10.1189/jlb.0602326. PMID12525561.
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. PMID12671732.
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. PMID16300465.
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. PMID17007011.
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. PMID11390512.
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. PMID12162874.
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. PMID12421946.
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. PMID12847224.
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. PMID15114670.
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. PMID15486065.