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'''Interleukin-23''' ('''IL-23''') is a [[heterodimer]]ic cytokine composed of an [[IL12B]] ([[IL-12p40]]) subunit (that is shared with [[Interleukin 12|IL12]]) and the [https://www.genenames.org/cgi-bin/gene_symbol_report?hgnc_id=15488 IL23A] ([[IL-23p19]]) subunit.<ref name="pmid11114383">{{cite journal | vauthors = 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 | display-authors = 6 | title = Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12 | journal = Immunity | volume = 13 | issue = 5 | pages = 715–25 | date = November 2000 | pmid = 11114383 | pmc = | doi = 10.1016/S1074-7613(00)00070-4 }}</ref> IL-23 is part of IL-12 family of cytokines.<ref name=":1">{{Cite journal|last=Cauli|first=Alberto|last2=Piga|first2=Matteo|last3=Floris|first3=Alberto|last4=Mathieu|first4=Alessandro|date=2015-10-01|title=Current perspective on the role of the interleukin-23/interleukin-17 axis in inflammation and disease (chronic arthritis and psoriasis)|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4918258/|journal=Immunotargets and Therapy|volume=4|pages=185–190|doi=10.2147/ITT.S62870|issn=2253-1556|pmc=4918258|pmid=27471723}}</ref> A functional [[Receptor (biochemistry)|receptor]] for IL-23 (the [[Interleukin-23 receptor|IL-23 receptor]]) has been identified and is composed of [[Interleukin 12 receptor, beta 1 subunit|IL-12R β1]] and [[Interleukin-23 receptor|IL-23R]].<ref name=pmid12023369 >{{cite journal | vauthors = 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 | display-authors = 6 | title = A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R | journal = Journal of Immunology | volume = 168 | issue = 11 | pages = 5699–708 | date = June 2002 | pmid = 12023369 | doi = 10.4049/jimmunol.168.11.5699 | url = http://www.jimmunol.org/content/168/11/5699.long | doi-access = free }}</ref> Adnectin-2 is binding to IL-23 and compete with IL-23/IL-23R.<ref name=":2">{{Cite journal|last=Iacob|first=Roxana E.|last2=Krystek|first2=Stanley R.|last3=Huang|first3=Richard Y.-C.|last4=Wei|first4=Hui|last5=Tao|first5=Li|last6=Lin|first6=Zheng|last7=Morin|first7=Paul E.|last8=Doyle|first8=Michael L.|last9=Tymiak|first9=Adrienne A.|last10=Engen|first10=John R.|last11=Chen|first11=Guodong|date=2015-03-04|title=Hydrogen/deuterium exchange mass spectrometry applied to IL-23 interaction characteristics: potential impact for therapeutics|url=https://doi.org/10.1586/14789450.2015.1018897|journal=Expert Review of Proteomics|volume=12|issue=2|pages=159–169|doi=10.1586/14789450.2015.1018897|issn=1478-9450|pmc=PMC4409866|pmid=25711416}}</ref> mRNA of IL-23R is 2,8 kB in length and includes 12 exons. The translated protein contains 629 amino acids, which is a type I penetrating protein includes signal peptide, an N-terminal fibronectin III-like domain and an intracellular part contains 3 potential tyrosine phosphorylation domains.<ref>{{Cite web|title=A Receptor for the Heterodimeric Cytokine IL-23 Is Composed of IL-12Rbeta1 and a Novel Cytokine Receptor Subunit, IL-23R|url=https://pubmed.ncbi.nlm.nih.gov/12023369/|last=C|first=Parham|last2=M|first2=Chirica|date=2002-06-01|website=Journal of immunology (Baltimore, Md. : 1950)|language=en|pmid=12023369|access-date=2020-05-24|last3=J|first3=Timans|last4=E|first4=Vaisberg|last5=M|first5=Travis|last6=J|first6=Cheung|last7=S|first7=Pflanz|last8=R|first8=Zhang|last9=Kp|first9=Singh}}</ref> There are 24 variants of splicing of IL-23R in mitogen-activated lymphocytes.<ref>{{Cite web|title=Identification and Characterization of Multiple Splice Forms of the Human interleukin-23 Receptor Alpha Chain in Mitogen-Activated Leukocytes|url=https://pubmed.ncbi.nlm.nih.gov/18754016/|last=Sh|first=Kan|last2=G|first2=Mancini|date=2008 Oct|website=Genes and immunity|language=en|pmid=18754016|access-date=2020-05-24|last3=G|first3=Gallagher}}</ref> IL-23R has some single nucleotide polymorphisms in the domain of binding IL-23 so there can be differences in activation of Th17.<ref>{{Cite journal|last=Yu|first=Raymond Y.|last2=Brazaitis|first2=Jonathan|last3=Gallagher|first3=Grant|date=2015-02-01|title=The Human IL-23 Receptor rs11209026 A Allele Promotes the Expression of a Soluble IL-23R–Encoding mRNA Species|url=https://www.jimmunol.org/content/194/3/1062|journal=The Journal of Immunology|language=en|volume=194|issue=3|pages=1062–1068|doi=10.4049/jimmunol.1401850|issn=0022-1767|pmid=25552541}}</ref> There is also variant of IL-23R which has just extracellular part and it´s known as soluble IL-23R. This form can compete with membrane form to bind IL-23 and there can be difference in activation of Th17 immune response and regulation of inflammation and immune function.<ref>{{Cite web|title=Figure 8. with two source data miR-34a regulates Th17 cell-mediated proliferation.|url=http://dx.doi.org/10.7554/elife.39479.025|website=dx.doi.org|access-date=2020-05-24}}</ref>
'''Interleukin-23''' ('''IL-23''') is a [[heterodimer]]ic cytokine composed of an [[IL12B]] ([[IL-12p40]]) subunit (that is shared with [[Interleukin 12|IL12]]) and the [https://www.genenames.org/cgi-bin/gene_symbol_report?hgnc_id=15488 IL23A] ([[IL-23p19]]) subunit.<ref name="pmid11114383">{{cite journal | vauthors = 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 | display-authors = 6 | title = Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12 | journal = Immunity | volume = 13 | issue = 5 | pages = 715–25 | date = November 2000 | pmid = 11114383 | pmc = | doi = 10.1016/S1074-7613(00)00070-4 }}</ref> IL-23 is part of IL-12 family of cytokines.<ref name=":1">{{cite journal | vauthors = Cauli A, Piga M, Floris A, Mathieu A | title = Current perspective on the role of the interleukin-23/interleukin-17 axis in inflammation and disease (chronic arthritis and psoriasis) | journal = ImmunoTargets and Therapy | volume = 4 | pages = 185–90 | date = 2015-10-01 | pmid = 27471723 | pmc = 4918258 | doi = 10.2147/ITT.S62870 }}</ref> A functional [[Receptor (biochemistry)|receptor]] for IL-23 (the [[Interleukin-23 receptor|IL-23 receptor]]) has been identified and is composed of [[Interleukin 12 receptor, beta 1 subunit|IL-12R β1]] and [[Interleukin-23 receptor|IL-23R]].<ref name=pmid12023369 >{{cite journal | vauthors = 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 | display-authors = 6 | title = A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R | journal = Journal of Immunology | volume = 168 | issue = 11 | pages = 5699–708 | date = June 2002 | pmid = 12023369 | doi = 10.4049/jimmunol.168.11.5699 | doi-access = free }}</ref> Adnectin-2 is binding to IL-23 and compete with IL-23/IL-23R.<ref name=":2">{{cite journal | vauthors = Iacob RE, Krystek SR, Huang RY, Wei H, Tao L, Lin Z, Morin PE, Doyle ML, Tymiak AA, Engen JR, Chen G | display-authors = 6 | title = Hydrogen/deuterium exchange mass spectrometry applied to IL-23 interaction characteristics: potential impact for therapeutics | journal = Expert Review of Proteomics | volume = 12 | issue = 2 | pages = 159–69 | date = April 2015 | pmid = 25711416 | pmc = 4409866 | doi = 10.1586/14789450.2015.1018897 }}</ref> mRNA of IL-23R is 2,8 kB in length and includes 12 exons. The translated protein contains 629 amino acids, which is a type I penetrating protein includes signal peptide, an N-terminal fibronectin III-like domain and an intracellular part contains 3 potential tyrosine phosphorylation domains.<ref>{{cite journal | vauthors = 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 | display-authors = 6 | title = A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R | journal = Journal of Immunology | volume = 168 | issue = 11 | pages = 5699–708 | date = June 2002 | pmid = 12023369 | doi = 10.4049/jimmunol.168.11.5699 }}</ref> There are 24 variants of splicing of IL-23R in mitogen-activated lymphocytes.<ref>{{cite journal | vauthors = Kan SH, Mancini G, Gallagher G | title = Identification and characterization of multiple splice forms of the human interleukin-23 receptor alpha chain in mitogen-activated leukocytes | journal = Genes and Immunity | volume = 9 | issue = 7 | pages = 631–9 | date = October 2008 | pmid = 18754016 | doi = 10.1038/gene.2008.64 }}</ref> IL-23R has some single nucleotide polymorphisms in the domain of binding IL-23 so there can be differences in activation of Th17.<ref>{{cite journal | vauthors = Yu RY, Brazaitis J, Gallagher G | title = The human IL-23 receptor rs11209026 A allele promotes the expression of a soluble IL-23R-encoding mRNA species | journal = Journal of Immunology | volume = 194 | issue = 3 | pages = 1062–8 | date = February 2015 | pmid = 25552541 | doi = 10.4049/jimmunol.1401850 }}</ref> There is also variant of IL-23R which has just extracellular part and it´s known as soluble IL-23R. This form can compete with membrane form to bind IL-23 and there can be difference in activation of Th17 immune response and regulation of inflammation and immune function.<ref>{{Cite document|title=Figure 8. with two source data miR-34a regulates Th17 cell-mediated proliferation.|doi=10.7554/elife.39479.025}}</ref>


== Discovery ==
== Discovery ==
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IL-23 is a proinflammatory [[cytokine]]. IL-23 has been shown to be a key cytokine for [[Th17]] maintenance and expansion. [[Th17]] are polarised by [[Interleukin 6|IL-6]] and [[Transforming growth factor beta|TGF-β]] which activate [[Th17]] [[transcription factor]] [[RAR-related orphan receptor gamma|RORγt]]. IL-23 stabilises [[RAR-related orphan receptor gamma|RORγt]] and thus enables [[T helper 17 cell|Th17]] to properly function and release their effector cytokines such as [[Interleukin 17|IL-17]], [[Interleukin 21|IL-21]], [[Interleukin 22|IL-22]] and [[Granulocyte-macrophage colony-stimulating factor|GM-CSF]] which mediate protection against extracellular parasites (fungi and bacteria) and participate in barrier immunity. <ref name=":0">{{cite journal | vauthors = Tang C, Chen S, Qian H, Huang W | title = Interleukin-23: as a drug target for autoimmune inflammatory diseases | journal = Immunology | volume = 135 | issue = 2 | pages = 112–24 | date = February 2012 | pmid = 22044352 | pmc = 3277713 | doi = 10.1111/j.1365-2567.2011.03522.x }}</ref> Similar effects as IL-23 has on [[Th17]] cells were described on [[type 3 innate lymphoid cells]] which actively secrete [[Th17]] [[Cytokine|cytokines]] upon IL-23 stimulation. <ref>{{cite journal | vauthors = Zeng B, Shi S, Ashworth G, Dong C, Liu J, Xing F | title = ILC3 function as a double-edged sword in inflammatory bowel diseases | journal = Cell Death & Disease | volume = 10 | issue = 4 | pages = 315 | date = April 2019 | pmid = 30962426 | pmc = 6453898 | doi = 10.1038/s41419-019-1540-2 }}</ref> [[Natural killer cell|NK cells]] express IL-23 receptor too. They respond with increased [[Interferon gamma|IFN-γ]] secretion and enhanced [[antibody-dependent cellular cytotoxicity]]. IL-23 also induces proliferation of [[CD4]] [[Memory T cell|memory T cells]] (not naïve cells). <ref>{{cite journal | vauthors = Li Y, Wang H, Lu H, Hua S | title = Regulation of Memory T Cells by Interleukin-23 | journal = International Archives of Allergy and Immunology | volume = 169 | issue = 3 | pages = 157–62 | date = 2016 | pmid = 27100864 | doi = 10.1159/000445834 }}</ref> Along with mentioned proinflammatory effects IL-23 promotes [[angiogenesis]]. <ref>{{cite journal | vauthors = Langowski JL, Zhang X, Wu L, Mattson JD, Chen T, Smith K, Basham B, McClanahan T, Kastelein RA, Oft M | display-authors = 6 | title = IL-23 promotes tumour incidence and growth | journal = Nature | volume = 442 | issue = 7101 | pages = 461–5 | date = July 2006 | pmid = 16688182 | doi = 10.1038/nature04808 | bibcode = 2006Natur.442..461L }}</ref> 
IL-23 is a proinflammatory [[cytokine]]. IL-23 has been shown to be a key cytokine for [[Th17]] maintenance and expansion. [[Th17]] are polarised by [[Interleukin 6|IL-6]] and [[Transforming growth factor beta|TGF-β]] which activate [[Th17]] [[transcription factor]] [[RAR-related orphan receptor gamma|RORγt]]. IL-23 stabilises [[RAR-related orphan receptor gamma|RORγt]] and thus enables [[T helper 17 cell|Th17]] to properly function and release their effector cytokines such as [[Interleukin 17|IL-17]], [[Interleukin 21|IL-21]], [[Interleukin 22|IL-22]] and [[Granulocyte-macrophage colony-stimulating factor|GM-CSF]] which mediate protection against extracellular parasites (fungi and bacteria) and participate in barrier immunity. <ref name=":0">{{cite journal | vauthors = Tang C, Chen S, Qian H, Huang W | title = Interleukin-23: as a drug target for autoimmune inflammatory diseases | journal = Immunology | volume = 135 | issue = 2 | pages = 112–24 | date = February 2012 | pmid = 22044352 | pmc = 3277713 | doi = 10.1111/j.1365-2567.2011.03522.x }}</ref> Similar effects as IL-23 has on [[Th17]] cells were described on [[type 3 innate lymphoid cells]] which actively secrete [[Th17]] [[Cytokine|cytokines]] upon IL-23 stimulation. <ref>{{cite journal | vauthors = Zeng B, Shi S, Ashworth G, Dong C, Liu J, Xing F | title = ILC3 function as a double-edged sword in inflammatory bowel diseases | journal = Cell Death & Disease | volume = 10 | issue = 4 | pages = 315 | date = April 2019 | pmid = 30962426 | pmc = 6453898 | doi = 10.1038/s41419-019-1540-2 }}</ref> [[Natural killer cell|NK cells]] express IL-23 receptor too. They respond with increased [[Interferon gamma|IFN-γ]] secretion and enhanced [[antibody-dependent cellular cytotoxicity]]. IL-23 also induces proliferation of [[CD4]] [[Memory T cell|memory T cells]] (not naïve cells). <ref>{{cite journal | vauthors = Li Y, Wang H, Lu H, Hua S | title = Regulation of Memory T Cells by Interleukin-23 | journal = International Archives of Allergy and Immunology | volume = 169 | issue = 3 | pages = 157–62 | date = 2016 | pmid = 27100864 | doi = 10.1159/000445834 }}</ref> Along with mentioned proinflammatory effects IL-23 promotes [[angiogenesis]]. <ref>{{cite journal | vauthors = Langowski JL, Zhang X, Wu L, Mattson JD, Chen T, Smith K, Basham B, McClanahan T, Kastelein RA, Oft M | display-authors = 6 | title = IL-23 promotes tumour incidence and growth | journal = Nature | volume = 442 | issue = 7101 | pages = 461–5 | date = July 2006 | pmid = 16688182 | doi = 10.1038/nature04808 | bibcode = 2006Natur.442..461L }}</ref> 


IL-23 is mainly secreted by activated [[Dendritic cell|dendritic cells]], [[Macrophage|macrophages]] or [[Monocyte|monocytes]]. Innate lymphoid cells and also gamma delta T cells also produce IL-23. <ref name=":1" /> B cells produces IL-23 threw BCR signaling.<ref>{{Cite journal|last=Gagro|first=Alenka|last2=Servis|first2=Drazen|last3=Cepika|first3=Alma-Martina|last4=Toellner|first4=Kai-Michael|last5=Grafton|first5=Gillian|last6=Taylor|first6=Dale R.|last7=Branica|first7=Srecko|last8=Gordon|first8=John|date=2006-05|title=Type I cytokine profiles of human naive and memory B lymphocytes: a potential for memory cells to impact polarization|url=http://doi.wiley.com/10.1111/j.1365-2567.2006.02342.x|journal=Immunology|language=en|volume=118|issue=1|pages=66–77|doi=10.1111/j.1365-2567.2006.02342.x|issn=0019-2805|pmc=PMC1782263|pmid=16630024}}</ref> Secretion is stimulated by an antigen stimulus recognised by a [[pattern recognition receptor]]. <ref>{{cite journal | vauthors = Re F, Strominger JL | title = Toll-like receptor 2 (TLR2) and TLR4 differentially activate human dendritic cells | journal = The Journal of Biological Chemistry | volume = 276 | issue = 40 | pages = 37692–9 | date = October 2001 | pmid = 11477091 | doi = 10.1074/jbc.M105927200 | doi-access = free }}</ref> IL-23 imbalance and increase is associated with [[Autoimmunity|autoimmune]] and [[Cancer|cancerous]] diseases. It is thus a target for therapeutic research. <ref name=":0" /> IL-23 expressed by dendritic cells is further induced by thymic stromal lymphopoietin – a proallergic cytokine expressed by keratinocytes which is elevated in psoriatic lesions. So inhibition of this cytokine can be potential therapeutic option for patients with psoriasis by decreasing dendritic cells activation and thereby reduction of IL-23.<ref>{{Cite web|title=Thymic Stromal Lymphopoietin Links Keratinocytes and Dendritic Cell-Derived IL-23 in Patients With Psoriasis|url=https://pubmed.ncbi.nlm.nih.gov/24910175/|last=E|first=Volpe|last2=L|first2=Pattarini|date=2014 Aug|website=The Journal of allergy and clinical immunology|language=en|pmid=24910175|access-date=2020-05-24|last3=C|first3=Martinez-Cingolani|last4=S|first4=Meller|last5=Mh|first5=Donnadieu|last6=Si|first6=Bogiatzi|last7=Mi|first7=Fernandez|last8=M|first8=Touzot|last9=Jc|first9=Bichet}}</ref> Dermal dendritic cells are in contact with nociceptive neurons and if they are pharmacologically canceled there will be no dendritic cells to produce IL-23. If there is no IL-23 there will not be also inflammatory cells in the skin of psoriatic patients.<ref>{{Cite web|title=Nociceptive Sensory Neurons Drive interleukin-23-mediated Psoriasiform Skin Inflammation|url=https://pubmed.ncbi.nlm.nih.gov/24759321/|last=L|first=Riol-Blanco|last2=J|first2=Ordovas-Montanes|date=2014-06-05|website=Nature|language=en|pmid=24759321|access-date=2020-05-24|last3=M|first3=Perro|last4=E|first4=Naval|last5=A|first5=Thiriot|last6=D|first6=Alvarez|last7=S|first7=Paust|last8=Jn|first8=Wood|last9=Uh|first9=von Andrian}}</ref> IL-23 is also elevated during bacterial meningitis. This production makes epithelial dysregulation and inflammation.<ref>{{Cite journal|last=Srinivasan|first=Lakshmi|last2=Kilpatrick|first2=Laurie|last3=Shah|first3=Samir S.|last4=Abbasi|first4=Soraya|last5=Harris|first5=Mary C.|date=2018-02-02|title=Elevations of novel cytokines in bacterial meningitis in infants|url=https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0181449|journal=PLOS ONE|language=en|volume=13|issue=2|pages=e0181449|doi=10.1371/journal.pone.0181449|issn=1932-6203|pmc=PMC5796685|pmid=29394248}}</ref>
IL-23 is mainly secreted by activated [[Dendritic cell|dendritic cells]], [[Macrophage|macrophages]] or [[Monocyte|monocytes]]. Innate lymphoid cells and also gamma delta T cells also produce IL-23. <ref name=":1" /> B cells produces IL-23 threw BCR signaling.<ref>{{cite journal | vauthors = Gagro A, Servis D, Cepika AM, Toellner KM, Grafton G, Taylor DR, Branica S, Gordon J | display-authors = 6 | title = Type I cytokine profiles of human naïve and memory B lymphocytes: a potential for memory cells to impact polarization | journal = Immunology | volume = 118 | issue = 1 | pages = 66–77 | date = May 2006 | pmid = 16630024 | pmc = 1782263 | doi = 10.1111/j.1365-2567.2006.02342.x }}</ref> Secretion is stimulated by an antigen stimulus recognised by a [[pattern recognition receptor]]. <ref>{{cite journal | vauthors = Re F, Strominger JL | title = Toll-like receptor 2 (TLR2) and TLR4 differentially activate human dendritic cells | journal = The Journal of Biological Chemistry | volume = 276 | issue = 40 | pages = 37692–9 | date = October 2001 | pmid = 11477091 | doi = 10.1074/jbc.M105927200 | doi-access = free }}</ref> IL-23 imbalance and increase is associated with [[Autoimmunity|autoimmune]] and [[Cancer|cancerous]] diseases. It is thus a target for therapeutic research. <ref name=":0" /> IL-23 expressed by dendritic cells is further induced by thymic stromal lymphopoietin – a proallergic cytokine expressed by keratinocytes which is elevated in psoriatic lesions. So inhibition of this cytokine can be potential therapeutic option for patients with psoriasis by decreasing dendritic cells activation and thereby reduction of IL-23.<ref>{{cite journal | vauthors = Volpe E, Pattarini L, Martinez-Cingolani C, Meller S, Donnadieu MH, Bogiatzi SI, Fernandez MI, Touzot M, Bichet JC, Reyal F, Paronetto MP, Chiricozzi A, Chimenti S, Nasorri F, Cavani A, Kislat A, Homey B, Soumelis V | display-authors = 6 | title = Thymic stromal lymphopoietin links keratinocytes and dendritic cell-derived IL-23 in patients with psoriasis | journal = The Journal of Allergy and Clinical Immunology | volume = 134 | issue = 2 | pages = 373–81 | date = August 2014 | pmid = 24910175 | doi = 10.1016/j.jaci.2014.04.022 }}</ref> Dermal dendritic cells are in contact with nociceptive neurons and if they are pharmacologically canceled there will be no dendritic cells to produce IL-23. If there is no IL-23 there will not be also inflammatory cells in the skin of psoriatic patients.<ref>{{cite journal | vauthors = Riol-Blanco L, Ordovas-Montanes J, Perro M, Naval E, Thiriot A, Alvarez D, Paust S, Wood JN, von Andrian UH | display-authors = 6 | title = Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation | journal = Nature | volume = 510 | issue = 7503 | pages = 157–61 | date = June 2014 | pmid = 24759321 | doi = 10.1038/nature13199 | pmc = 4127885 | bibcode = 2014Natur.510..157R }}</ref> IL-23 is also elevated during bacterial meningitis. This production makes epithelial dysregulation and inflammation.<ref>{{cite journal | vauthors = Srinivasan L, Kilpatrick L, Shah SS, Abbasi S, Harris MC | title = Elevations of novel cytokines in bacterial meningitis in infants | journal = PloS One | volume = 13 | issue = 2 | pages = e0181449 | date = 2018-02-02 | pmid = 29394248 | pmc = 5796685 | doi = 10.1371/journal.pone.0181449 | bibcode = 2018PLoSO..1381449S }}</ref>


Prior to the discovery of IL-23, [[interleukin 12|IL-12]] had been proposed to represent a key mediator of [[inflammation]] in mouse models of inflammation.<ref name="pmid7528773">{{cite journal | vauthors = Leonard JP, Waldburger KE, Goldman SJ | title = Prevention of experimental autoimmune encephalomyelitis by antibodies against interleukin 12 | journal = The Journal of Experimental Medicine | volume = 181 | issue = 1 | pages = 381–6 | date = January 1995 | pmid = 7528773 | pmc = 2191822 | doi = 10.1084/jem.181.1.381 }}</ref> However, many studies aimed at assessing the role of IL-12 had blocked the activity of [[IL-12p40]], and were therefore not as specific as thought. Studies which blocked the function of [[IL-12p35]] did not produce the same results as those targeting IL-12p40 as would have been expected if both [[Protein subunit|subunit]]s formed part of IL-12 only.<ref name="pmid12189243">{{cite journal | vauthors = Becher B, Durell BG, Noelle RJ | title = Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12 | journal = The Journal of Clinical Investigation | volume = 110 | issue = 4 | pages = 493–7 | date = August 2002 | pmid = 12189243 | pmc = 150420 | doi = 10.1172/JCI15751 }}</ref> Also Mycobacterium avium subspecies paratuberculosis stimulated monocyte-derived macrophages are one of the contributors of IL-23. Cows with John´s disease had elevated IL-23.<ref>{{Cite journal|last=DeKuiper|first=Justin L.|last2=Cooperider|first2=Hannah E.|last3=Lubben|first3=Noah|last4=Ancel|first4=Caitlin M.|last5=Coussens|first5=Paul M.|date=2020|title=Mycobacterium avium Subspecies paratuberculosis Drives an Innate Th17-Like T Cell Response Regardless of the Presence of Antigen-Presenting Cells|url=https://www.frontiersin.org/articles/10.3389/fvets.2020.00108/full|journal=Frontiers in Veterinary Science|language=English|volume=7|doi=10.3389/fvets.2020.00108|issn=2297-1769}}</ref>
Prior to the discovery of IL-23, [[interleukin 12|IL-12]] had been proposed to represent a key mediator of [[inflammation]] in mouse models of inflammation.<ref name="pmid7528773">{{cite journal | vauthors = Leonard JP, Waldburger KE, Goldman SJ | title = Prevention of experimental autoimmune encephalomyelitis by antibodies against interleukin 12 | journal = The Journal of Experimental Medicine | volume = 181 | issue = 1 | pages = 381–6 | date = January 1995 | pmid = 7528773 | pmc = 2191822 | doi = 10.1084/jem.181.1.381 }}</ref> However, many studies aimed at assessing the role of IL-12 had blocked the activity of [[IL-12p40]], and were therefore not as specific as thought. Studies which blocked the function of [[IL-12p35]] did not produce the same results as those targeting IL-12p40 as would have been expected if both [[Protein subunit|subunit]]s formed part of IL-12 only.<ref name="pmid12189243">{{cite journal | vauthors = Becher B, Durell BG, Noelle RJ | title = Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12 | journal = The Journal of Clinical Investigation | volume = 110 | issue = 4 | pages = 493–7 | date = August 2002 | pmid = 12189243 | pmc = 150420 | doi = 10.1172/JCI15751 }}</ref> Also Mycobacterium avium subspecies paratuberculosis stimulated monocyte-derived macrophages are one of the contributors of IL-23. Cows with John´s disease had elevated IL-23.<ref>{{cite journal | vauthors = DeKuiper JL, Cooperider HE, Lubben N, Ancel CM, Coussens PM | title = paratuberculosis Drives an Innate Th17-Like T Cell Response Regardless of the Presence of Antigen-Presenting Cells | language = English | journal = Frontiers in Veterinary Science | volume = 7 | pages = 108 | date = 2020 | pmid = 32258066 | doi = 10.3389/fvets.2020.00108 | pmc = 7089878 }}</ref>


The discovery of an additional potential binding partner for IL-12p40 led to a reassessment of this role for IL-12. Seminal studies in [[experimental autoimmune encephalomyelitis]], a mouse model of [[multiple sclerosis]], showed that IL-23 was responsible for the inflammation observed, not IL-12 as previously thought.<ref name="pmid12610626 ">{{cite journal | vauthors = Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, Lucian L, To W, Kwan S, Churakova T, Zurawski S, Wiekowski M, Lira SA, Gorman D, Kastelein RA, Sedgwick JD | display-authors = 6 | title = Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain | journal = Nature | volume = 421 | issue = 6924 | pages = 744–8 | date = February 2003 | pmid = 12610626 | pmc = | doi = 10.1038/nature01355 | bibcode = 2003Natur.421..744C }}</ref> Subsequently, IL-23 was shown to facilitate development of inflammation in numerous other models of immune pathology where IL-12 had previously been implicated including models of [[arthritis]],<ref name="pmid14662908 ">{{cite journal | vauthors = Murphy CA, Langrish CL, Chen Y, Blumenschein W, McClanahan T, Kastelein RA, Sedgwick JD, Cua DJ | display-authors = 6 | title = Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation | journal = The Journal of Experimental Medicine | volume = 198 | issue = 12 | pages = 1951–7 | date = December 2003 | pmid = 14662908 | pmc = 2194162 | doi = 10.1084/jem.20030896 }}</ref> intestinal inflammation,<ref name="pmid16670770 ">{{cite journal | vauthors = Yen D, Cheung J, Scheerens H, Poulet F, McClanahan T, McKenzie B, Kleinschek MA, Owyang A, Mattson J, Blumenschein W, Murphy E, Sathe M, Cua DJ, Kastelein RA, Rennick D | display-authors = 6 | title = IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6 | journal = The Journal of Clinical Investigation | volume = 116 | issue = 5 | pages = 1310–6 | date = May 2006 | pmid = 16670770 | pmc = 1451201 | doi = 10.1172/JCI21404 }}</ref><ref name="pmid17030948 ">{{cite journal | vauthors = Kullberg MC, Jankovic D, Feng CG, Hue S, Gorelick PL, McKenzie BS, Cua DJ, Powrie F, Cheever AW, Maloy KJ, Sher A | display-authors = 6 | title = IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis | journal = The Journal of Experimental Medicine | volume = 203 | issue = 11 | pages = 2485–94 | date = October 2006 | pmid = 17030948 | pmc = 2118119 | doi = 10.1084/jem.20061082 }}</ref><ref>{{cite journal | vauthors = Hue S, Ahern P, Buonocore S, Kullberg MC, Cua DJ, McKenzie BS, Powrie F, Maloy KJ | display-authors = 6 | title = Interleukin-23 drives innate and T cell-mediated intestinal inflammation | journal = The Journal of Experimental Medicine | volume = 203 | issue = 11 | pages = 2473–83 | date = October 2006 | pmid = 17030949 | pmc = 2118132 | doi = 10.1084/jem.20061099 }}</ref> and [[psoriasis]].<ref name="pmid17074928 ">{{cite journal | vauthors = Chan JR, Blumenschein W, Murphy E, Diveu C, Wiekowski M, Abbondanzo S, Lucian L, Geissler R, Brodie S, Kimball AB, Gorman DM, Smith K, de Waal Malefyt R, Kastelein RA, McClanahan TK, Bowman EP | display-authors = 6 | title = IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis | journal = The Journal of Experimental Medicine | volume = 203 | issue = 12 | pages = 2577–87 | date = November 2006 | pmid = 17074928 | pmc = 2118145 | doi = 10.1084/jem.20060244 }}</ref> Low concentrations of IL-23 support lung tumor growth and high concentrations of IL-23 inhibit proliferation of lung cancer cells.<ref>{{Cite web|title=Interleukin 23 Regulates Proliferation of Lung Cancer Cells in a Concentration-Dependent Way in Association With the interleukin-23 Receptor|url=https://pubmed.ncbi.nlm.nih.gov/23250909/|last=J|first=Li|last2=L|first2=Zhang|date=2013 Mar|website=Carcinogenesis|language=en|pmid=23250909|access-date=2020-05-24|last3=J|first3=Zhang|last4=Y|first4=Wei|last5=K|first5=Li|last6=L|first6=Huang|last7=S|first7=Zhang|last8=B|first8=Gao|last9=X|first9=Wang}}</ref> IL-23 and IL-23R were identified in serum of non-small cell lung cancer patients and they can be potential prognostic serum marker.<ref>{{Cite journal|last=Liu|first=Dan|last2=Xing|first2=Shan|last3=Wang|first3=Wan|last4=Huang|first4=Xianzhang|last5=Lin|first5=Haibiao|last6=Chen|first6=Yonghe|last7=Lan|first7=Kai|last8=Chen|first8=Lin|last9=Luo|first9=Fudong|last10=Qin|first10=Sheng|last11=Liang|first11=Rongliang|date=2020-04|title=Prognostic value of serum soluble interleukin‐23 receptor and related T‐helper 17 cell cytokines in non‐small cell lung carcinoma|url=https://onlinelibrary.wiley.com/doi/abs/10.1111/cas.14343|journal=Cancer Science|language=en|volume=111|issue=4|pages=1093–1102|doi=10.1111/cas.14343|issn=1347-9032|pmc=PMC7156824|pmid=32020720}}</ref> IL-23 can also make progression of cardiovascular disease as atherosclerosis, hypertension, aortic dissection, cardiac hypertrophy, myocardial infarction and acute cardiac injury.
The discovery of an additional potential binding partner for IL-12p40 led to a reassessment of this role for IL-12. Seminal studies in [[experimental autoimmune encephalomyelitis]], a mouse model of [[multiple sclerosis]], showed that IL-23 was responsible for the inflammation observed, not IL-12 as previously thought.<ref name="pmid12610626 ">{{cite journal | vauthors = Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, Lucian L, To W, Kwan S, Churakova T, Zurawski S, Wiekowski M, Lira SA, Gorman D, Kastelein RA, Sedgwick JD | display-authors = 6 | title = Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain | journal = Nature | volume = 421 | issue = 6924 | pages = 744–8 | date = February 2003 | pmid = 12610626 | pmc = | doi = 10.1038/nature01355 | bibcode = 2003Natur.421..744C }}</ref> Subsequently, IL-23 was shown to facilitate development of inflammation in numerous other models of immune pathology where IL-12 had previously been implicated including models of [[arthritis]],<ref name="pmid14662908 ">{{cite journal | vauthors = Murphy CA, Langrish CL, Chen Y, Blumenschein W, McClanahan T, Kastelein RA, Sedgwick JD, Cua DJ | display-authors = 6 | title = Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation | journal = The Journal of Experimental Medicine | volume = 198 | issue = 12 | pages = 1951–7 | date = December 2003 | pmid = 14662908 | pmc = 2194162 | doi = 10.1084/jem.20030896 }}</ref> intestinal inflammation,<ref name="pmid16670770 ">{{cite journal | vauthors = Yen D, Cheung J, Scheerens H, Poulet F, McClanahan T, McKenzie B, Kleinschek MA, Owyang A, Mattson J, Blumenschein W, Murphy E, Sathe M, Cua DJ, Kastelein RA, Rennick D | display-authors = 6 | title = IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6 | journal = The Journal of Clinical Investigation | volume = 116 | issue = 5 | pages = 1310–6 | date = May 2006 | pmid = 16670770 | pmc = 1451201 | doi = 10.1172/JCI21404 }}</ref><ref name="pmid17030948 ">{{cite journal | vauthors = Kullberg MC, Jankovic D, Feng CG, Hue S, Gorelick PL, McKenzie BS, Cua DJ, Powrie F, Cheever AW, Maloy KJ, Sher A | display-authors = 6 | title = IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis | journal = The Journal of Experimental Medicine | volume = 203 | issue = 11 | pages = 2485–94 | date = October 2006 | pmid = 17030948 | pmc = 2118119 | doi = 10.1084/jem.20061082 }}</ref><ref>{{cite journal | vauthors = Hue S, Ahern P, Buonocore S, Kullberg MC, Cua DJ, McKenzie BS, Powrie F, Maloy KJ | display-authors = 6 | title = Interleukin-23 drives innate and T cell-mediated intestinal inflammation | journal = The Journal of Experimental Medicine | volume = 203 | issue = 11 | pages = 2473–83 | date = October 2006 | pmid = 17030949 | pmc = 2118132 | doi = 10.1084/jem.20061099 }}</ref> and [[psoriasis]].<ref name="pmid17074928 ">{{cite journal | vauthors = Chan JR, Blumenschein W, Murphy E, Diveu C, Wiekowski M, Abbondanzo S, Lucian L, Geissler R, Brodie S, Kimball AB, Gorman DM, Smith K, de Waal Malefyt R, Kastelein RA, McClanahan TK, Bowman EP | display-authors = 6 | title = IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis | journal = The Journal of Experimental Medicine | volume = 203 | issue = 12 | pages = 2577–87 | date = November 2006 | pmid = 17074928 | pmc = 2118145 | doi = 10.1084/jem.20060244 }}</ref> Low concentrations of IL-23 support lung tumor growth and high concentrations of IL-23 inhibit proliferation of lung cancer cells.<ref>{{cite journal | vauthors = Li J, Zhang L, Zhang J, Wei Y, Li K, Huang L, Zhang S, Gao B, Wang X, Lin P | display-authors = 6 | title = Interleukin 23 regulates proliferation of lung cancer cells in a concentration-dependent way in association with the interleukin-23 receptor | journal = Carcinogenesis | volume = 34 | issue = 3 | pages = 658–66 | date = March 2013 | pmid = 23250909 | doi = 10.1093/carcin/bgs384 }}</ref> IL-23 and IL-23R were identified in serum of non-small cell lung cancer patients and they can be potential prognostic serum marker.<ref>{{cite journal | vauthors = Liu D, Xing S, Wang W, Huang X, Lin H, Chen Y, Lan K, Chen L, Luo F, Qin S, Liang R, Bai C, Xu J, Liu W | display-authors = 6 | title = Prognostic value of serum soluble interleukin-23 receptor and related T-helper 17 cell cytokines in non-small cell lung carcinoma | journal = Cancer Science | volume = 111 | issue = 4 | pages = 1093–1102 | date = April 2020 | pmid = 32020720 | pmc = 7156824 | doi = 10.1111/cas.14343 }}</ref> IL-23 can also make progression of cardiovascular disease as atherosclerosis, hypertension, aortic dissection, cardiac hypertrophy, myocardial infarction and acute cardiac injury.


=== Monoclonal antibodies - drugs ===
=== Monoclonal antibodies - drugs ===
IL-23 is one of the terapeutic targets to treat the inflammatory diseases.<ref name=":2" /> [[Ustekinumab]], a monoclonal antibody directed against this cytokine, is used clinically to treat certain autoimmune conditions.<ref name="pmid20069753">{{cite journal|vauthors=Cingoz O|date=2009|title=Ustekinumab|journal=mAbs|volume=1|issue=3|pages=216–21|doi=10.4161/mabs.1.3.8593|pmc=2726595|pmid=20069753}}</ref> Guselkumab is also monoclonal antibady against IL-23. Blocking IL-23 can slow clinical manifestation of psoriasis indirectly affecting Th17 immune response and producting of IL-17.<ref>{{Cite web|title=Comparison of cumulative clinical
IL-23 is one of the terapeutic targets to treat the inflammatory diseases.<ref name=":2" /> [[Ustekinumab]], a monoclonal antibody directed against this cytokine, is used clinically to treat certain autoimmune conditions.<ref name="pmid20069753">{{cite journal | vauthors = Cingoz O | title = Ustekinumab | journal = mAbs | volume = 1 | issue = 3 | pages = 216–21 | date = 2009 | pmid = 20069753 | pmc = 2726595 | doi = 10.4161/mabs.1.3.8593 }}</ref> Guselkumab is also monoclonal antibady against IL-23. Blocking IL-23 can slow clinical manifestation of psoriasis indirectly affecting Th17 immune response and producting of IL-17.<ref>{{cite journal | vauthors = Warren RB, Gooderham M, Burge R, Zhu B, Amato D, Liu KH, Shrom D, Guo J, Brnabic A, Blauvelt A | display-authors = 6 | title = Comparison of cumulative clinical benefits of biologics for the treatment of psoriasis over 16 weeks: Results from a network meta-analysis | journal = Journal of the American Academy of Dermatology | volume = 82 | issue = 5 | pages = 1138–1149 | date = May 2020 | pmid = 31884091 | doi = 10.1016/j.jaad.2019.12.038 | url = https://www.jaad.org/article/S0190-9622(19)33315-8/pdf }}</ref> For treating of psoriasis is better to use ixekizumab which is IL-17A antagonist because its faster than guselkumab, tildrakizumab or riskankizumab which are inhibitors of p19 of IL-23.<ref>{{cite journal | vauthors = Gottlieb AB, Saure D, Wilhelm S, Dossenbach M, Schuster C, Smith SD, Ramot Y, Thaçi D | display-authors = 6 | title = Indirect comparisons of ixekizumab versus three interleukin-23 p19 inhibitors in patients with moderate-to-severe plaque psoriasis - efficacy findings up to week 12 | journal = The Journal of Dermatological Treatment | pages = 1–8 | date = April 2020 | pmid = 32299269 | doi = 10.1080/09546634.2020.1747592 }}</ref> Risankizumab has the best treatment results for psoriasis in comparison with other IL-23 inhibitors.<ref>{{cite journal | vauthors = Yasmeen N, Sawyer LM, Malottki K, Levin LÅ, Didriksen Apol E, Jemec GB | title = Targeted therapies for patients with moderate-to-severe psoriasis: a systematic review and network meta-analysis of PASI response at 1 year | journal = The Journal of Dermatological Treatment | pages = 1–15 | date = April 2020 | pmid = 32202445 | doi = 10.1080/09546634.2020.1743811 }}</ref>
benefits of biologics for the treatment of
psoriasis over 16 weeks: Results from a
network meta-analysis.|url=https://www.jaad.org/article/S0190-9622(19)33315-8/pdf|last=|first=|date=|website=|url-status=live|archive-url=|archive-date=|access-date=}}</ref> For treating of psoriasis is better to use ixekizumab which is IL-17A antagonist because its faster than guselkumab, tildrakizumab or riskankizumab which are inhibitors of p19 of IL-23.<ref>{{Cite journal|last=Gottlieb|first=Alice B.|last2=Saure|first2=Daniel|last3=Wilhelm|first3=Stefan|last4=Dossenbach|first4=Martin|last5=Schuster|first5=Christopher|last6=Smith|first6=Saxon D.|last7=Ramot|first7=Yuval|last8=Thaçi|first8=Diamant|date=2020-04-17|title=Indirect comparisons of ixekizumab versus three interleukin-23 p19 inhibitors in patients with moderate-to-severe plaque psoriasis – efficacy findings up to week 12|url=https://www.tandfonline.com/doi/full/10.1080/09546634.2020.1747592|journal=Journal of Dermatological Treatment|language=en|pages=1–8|doi=10.1080/09546634.2020.1747592|issn=0954-6634}}</ref> Risankizumab has the best treatment results for psoriasis in comparison with other IL-23 inhibitors.<ref>{{Cite journal|last=Yasmeen|first=Najeeda|last2=Sawyer|first2=Laura M.|last3=Malottki|first3=Kinga|last4=Levin|first4=Lars-Åke|last5=Didriksen Apol|first5=Eydna|last6=Jemec|first6=Gregor B.|date=2020-04-02|title=Targeted therapies for patients with moderate-to-severe psoriasis: a systematic review and network meta-analysis of PASI response at 1 year|url=https://www.tandfonline.com/doi/full/10.1080/09546634.2020.1743811|journal=Journal of Dermatological Treatment|language=en|pages=1–15|doi=10.1080/09546634.2020.1743811|issn=0954-6634}}</ref>


== Signalling ==
== Signalling ==

Revision as of 17:06, 24 May 2020

IL12B
Crystal structure of IL-12B
Identifiers
SymbolIL12B
Alt. symbolsCLMF2, NKSF2, p40
NCBI gene3593
HGNC5970
OMIM161561
PDB1F42
RefSeqNM_002187
UniProtP29460
Other data
LocusChr. 5 q31.1-33.1
Search for
StructuresSwiss-model
DomainsInterPro
interleukin 23, alpha subunit p19
Identifiers
SymbolIL23A
NCBI gene51561
HGNC15488
RefSeqNM_016584
Other data
LocusChr. 12 q13.13

Interleukin-23 (IL-23) is a heterodimeric cytokine composed of an IL12B (IL-12p40) subunit (that is shared with IL12) and the IL23A (IL-23p19) subunit.[1] IL-23 is part of IL-12 family of cytokines.[2] A functional receptor for IL-23 (the IL-23 receptor) has been identified and is composed of IL-12R β1 and IL-23R.[3] Adnectin-2 is binding to IL-23 and compete with IL-23/IL-23R.[4] mRNA of IL-23R is 2,8 kB in length and includes 12 exons. The translated protein contains 629 amino acids, which is a type I penetrating protein includes signal peptide, an N-terminal fibronectin III-like domain and an intracellular part contains 3 potential tyrosine phosphorylation domains.[5] There are 24 variants of splicing of IL-23R in mitogen-activated lymphocytes.[6] IL-23R has some single nucleotide polymorphisms in the domain of binding IL-23 so there can be differences in activation of Th17.[7] There is also variant of IL-23R which has just extracellular part and it´s known as soluble IL-23R. This form can compete with membrane form to bind IL-23 and there can be difference in activation of Th17 immune response and regulation of inflammation and immune function.[8]

Discovery

IL-23 was first described by Robert Kastelein and colleagues at the DNAX research institute using a combination of computational, biochemical and cellular immunology approaches.[1]

Function

IL-23 is a proinflammatory cytokine. IL-23 has been shown to be a key cytokine for Th17 maintenance and expansion. Th17 are polarised by IL-6 and TGF-β which activate Th17 transcription factor RORγt. IL-23 stabilises RORγt and thus enables Th17 to properly function and release their effector cytokines such as IL-17, IL-21, IL-22 and GM-CSF which mediate protection against extracellular parasites (fungi and bacteria) and participate in barrier immunity. [9] Similar effects as IL-23 has on Th17 cells were described on type 3 innate lymphoid cells which actively secrete Th17 cytokines upon IL-23 stimulation. [10] NK cells express IL-23 receptor too. They respond with increased IFN-γ secretion and enhanced antibody-dependent cellular cytotoxicity. IL-23 also induces proliferation of CD4 memory T cells (not naïve cells). [11] Along with mentioned proinflammatory effects IL-23 promotes angiogenesis. [12] 

IL-23 is mainly secreted by activated dendritic cells, macrophages or monocytes. Innate lymphoid cells and also gamma delta T cells also produce IL-23. [2] B cells produces IL-23 threw BCR signaling.[13] Secretion is stimulated by an antigen stimulus recognised by a pattern recognition receptor. [14] IL-23 imbalance and increase is associated with autoimmune and cancerous diseases. It is thus a target for therapeutic research. [9] IL-23 expressed by dendritic cells is further induced by thymic stromal lymphopoietin – a proallergic cytokine expressed by keratinocytes which is elevated in psoriatic lesions. So inhibition of this cytokine can be potential therapeutic option for patients with psoriasis by decreasing dendritic cells activation and thereby reduction of IL-23.[15] Dermal dendritic cells are in contact with nociceptive neurons and if they are pharmacologically canceled there will be no dendritic cells to produce IL-23. If there is no IL-23 there will not be also inflammatory cells in the skin of psoriatic patients.[16] IL-23 is also elevated during bacterial meningitis. This production makes epithelial dysregulation and inflammation.[17]

Prior to the discovery of IL-23, IL-12 had been proposed to represent a key mediator of inflammation in mouse models of inflammation.[18] However, many studies aimed at assessing the role of IL-12 had blocked the activity of IL-12p40, and were therefore not as specific as thought. Studies which blocked the function of IL-12p35 did not produce the same results as those targeting IL-12p40 as would have been expected if both subunits formed part of IL-12 only.[19] Also Mycobacterium avium subspecies paratuberculosis stimulated monocyte-derived macrophages are one of the contributors of IL-23. Cows with John´s disease had elevated IL-23.[20]

The discovery of an additional potential binding partner for IL-12p40 led to a reassessment of this role for IL-12. Seminal studies in experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis, showed that IL-23 was responsible for the inflammation observed, not IL-12 as previously thought.[21] Subsequently, IL-23 was shown to facilitate development of inflammation in numerous other models of immune pathology where IL-12 had previously been implicated including models of arthritis,[22] intestinal inflammation,[23][24][25] and psoriasis.[26] Low concentrations of IL-23 support lung tumor growth and high concentrations of IL-23 inhibit proliferation of lung cancer cells.[27] IL-23 and IL-23R were identified in serum of non-small cell lung cancer patients and they can be potential prognostic serum marker.[28] IL-23 can also make progression of cardiovascular disease as atherosclerosis, hypertension, aortic dissection, cardiac hypertrophy, myocardial infarction and acute cardiac injury.

Monoclonal antibodies - drugs

IL-23 is one of the terapeutic targets to treat the inflammatory diseases.[4] Ustekinumab, a monoclonal antibody directed against this cytokine, is used clinically to treat certain autoimmune conditions.[29] Guselkumab is also monoclonal antibady against IL-23. Blocking IL-23 can slow clinical manifestation of psoriasis indirectly affecting Th17 immune response and producting of IL-17.[30] For treating of psoriasis is better to use ixekizumab which is IL-17A antagonist because its faster than guselkumab, tildrakizumab or riskankizumab which are inhibitors of p19 of IL-23.[31] Risankizumab has the best treatment results for psoriasis in comparison with other IL-23 inhibitors.[32]

Signalling

IL-23 heterodimer binds the receptor complex - p19 subunit binds IL-23R while p40 subunit binds IL-12RB1 which leads to recruitment of Janus kinase 2 and Tyrosine kinase 2 kinases. Janus kinase 2 and Tyrosine kinase 2 transduce the signal and phosphorylate STAT3 and STAT4. STATs dimerise and activate transcription of target genes in nucleus. STAT3 is responsible for key Th17 development attributes like RORγt expression or transcription of Th17 cytokines.[9] 

References

  1. ^ a b 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.
  2. ^ a b Cauli A, Piga M, Floris A, Mathieu A (2015-10-01). "Current perspective on the role of the interleukin-23/interleukin-17 axis in inflammation and disease (chronic arthritis and psoriasis)". ImmunoTargets and Therapy. 4: 185–90. doi:10.2147/ITT.S62870. PMC 4918258. PMID 27471723.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  3. ^ 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.
  4. ^ a b Iacob RE, Krystek SR, Huang RY, Wei H, Tao L, Lin Z, et al. (April 2015). "Hydrogen/deuterium exchange mass spectrometry applied to IL-23 interaction characteristics: potential impact for therapeutics". Expert Review of Proteomics. 12 (2): 159–69. doi:10.1586/14789450.2015.1018897. PMC 4409866. PMID 25711416.
  5. ^ 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.
  6. ^ 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. doi:10.1038/gene.2008.64. PMID 18754016.
  7. ^ 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. doi:10.4049/jimmunol.1401850. PMID 25552541.
  8. ^ "Figure 8. with two source data miR-34a regulates Th17 cell-mediated proliferation" (Document). doi:10.7554/elife.39479.025. {{cite document}}: Cite document requires |publisher= (help)CS1 maint: unflagged free DOI (link)
  9. ^ a b c Tang C, Chen S, Qian H, Huang W (February 2012). "Interleukin-23: as a drug target for autoimmune inflammatory diseases". Immunology. 135 (2): 112–24. doi:10.1111/j.1365-2567.2011.03522.x. PMC 3277713. PMID 22044352.
  10. ^ Zeng B, Shi S, Ashworth G, Dong C, Liu J, Xing F (April 2019). "ILC3 function as a double-edged sword in inflammatory bowel diseases". Cell Death & Disease. 10 (4): 315. doi:10.1038/s41419-019-1540-2. PMC 6453898. PMID 30962426.
  11. ^ Li Y, Wang H, Lu H, Hua S (2016). "Regulation of Memory T Cells by Interleukin-23". International Archives of Allergy and Immunology. 169 (3): 157–62. doi:10.1159/000445834. PMID 27100864.
  12. ^ Langowski JL, Zhang X, Wu L, Mattson JD, Chen T, Smith K, et al. (July 2006). "IL-23 promotes tumour incidence and growth". Nature. 442 (7101): 461–5. Bibcode:2006Natur.442..461L. doi:10.1038/nature04808. PMID 16688182.
  13. ^ Gagro A, Servis D, Cepika AM, Toellner KM, Grafton G, Taylor DR, et al. (May 2006). "Type I cytokine profiles of human naïve and memory B lymphocytes: a potential for memory cells to impact polarization". Immunology. 118 (1): 66–77. doi:10.1111/j.1365-2567.2006.02342.x. PMC 1782263. PMID 16630024.
  14. ^ Re F, Strominger JL (October 2001). "Toll-like receptor 2 (TLR2) and TLR4 differentially activate human dendritic cells". The Journal of Biological Chemistry. 276 (40): 37692–9. doi:10.1074/jbc.M105927200. PMID 11477091.
  15. ^ Volpe E, Pattarini L, Martinez-Cingolani C, Meller S, Donnadieu MH, Bogiatzi SI, et al. (August 2014). "Thymic stromal lymphopoietin links keratinocytes and dendritic cell-derived IL-23 in patients with psoriasis". The Journal of Allergy and Clinical Immunology. 134 (2): 373–81. doi:10.1016/j.jaci.2014.04.022. PMID 24910175.
  16. ^ Riol-Blanco L, Ordovas-Montanes J, Perro M, Naval E, Thiriot A, Alvarez D, et al. (June 2014). "Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation". Nature. 510 (7503): 157–61. Bibcode:2014Natur.510..157R. doi:10.1038/nature13199. PMC 4127885. PMID 24759321.
  17. ^ Srinivasan L, Kilpatrick L, Shah SS, Abbasi S, Harris MC (2018-02-02). "Elevations of novel cytokines in bacterial meningitis in infants". PloS One. 13 (2): e0181449. Bibcode:2018PLoSO..1381449S. doi:10.1371/journal.pone.0181449. PMC 5796685. PMID 29394248.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  18. ^ Leonard JP, Waldburger KE, Goldman SJ (January 1995). "Prevention of experimental autoimmune encephalomyelitis by antibodies against interleukin 12". The Journal of Experimental Medicine. 181 (1): 381–6. doi:10.1084/jem.181.1.381. PMC 2191822. PMID 7528773.
  19. ^ Becher B, Durell BG, Noelle RJ (August 2002). "Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12". The Journal of Clinical Investigation. 110 (4): 493–7. doi:10.1172/JCI15751. PMC 150420. PMID 12189243.
  20. ^ DeKuiper JL, Cooperider HE, Lubben N, Ancel CM, Coussens PM (2020). "paratuberculosis Drives an Innate Th17-Like T Cell Response Regardless of the Presence of Antigen-Presenting Cells". Frontiers in Veterinary Science. 7: 108. doi:10.3389/fvets.2020.00108. PMC 7089878. PMID 32258066.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  21. ^ Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, et al. (February 2003). "Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain". Nature. 421 (6924): 744–8. Bibcode:2003Natur.421..744C. doi:10.1038/nature01355. PMID 12610626.
  22. ^ Murphy CA, Langrish CL, Chen Y, Blumenschein W, McClanahan T, Kastelein RA, et al. (December 2003). "Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation". The Journal of Experimental Medicine. 198 (12): 1951–7. doi:10.1084/jem.20030896. PMC 2194162. PMID 14662908.
  23. ^ Yen D, Cheung J, Scheerens H, Poulet F, McClanahan T, McKenzie B, et al. (May 2006). "IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6". The Journal of Clinical Investigation. 116 (5): 1310–6. doi:10.1172/JCI21404. PMC 1451201. PMID 16670770.
  24. ^ Kullberg MC, Jankovic D, Feng CG, Hue S, Gorelick PL, McKenzie BS, et al. (October 2006). "IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis". The Journal of Experimental Medicine. 203 (11): 2485–94. doi:10.1084/jem.20061082. PMC 2118119. PMID 17030948.
  25. ^ Hue S, Ahern P, Buonocore S, Kullberg MC, Cua DJ, McKenzie BS, et al. (October 2006). "Interleukin-23 drives innate and T cell-mediated intestinal inflammation". The Journal of Experimental Medicine. 203 (11): 2473–83. doi:10.1084/jem.20061099. PMC 2118132. PMID 17030949.
  26. ^ Chan JR, Blumenschein W, Murphy E, Diveu C, Wiekowski M, Abbondanzo S, et al. (November 2006). "IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis". The Journal of Experimental Medicine. 203 (12): 2577–87. doi:10.1084/jem.20060244. PMC 2118145. PMID 17074928.
  27. ^ Li J, Zhang L, Zhang J, Wei Y, Li K, Huang L, et al. (March 2013). "Interleukin 23 regulates proliferation of lung cancer cells in a concentration-dependent way in association with the interleukin-23 receptor". Carcinogenesis. 34 (3): 658–66. doi:10.1093/carcin/bgs384. PMID 23250909.
  28. ^ Liu D, Xing S, Wang W, Huang X, Lin H, Chen Y, et al. (April 2020). "Prognostic value of serum soluble interleukin-23 receptor and related T-helper 17 cell cytokines in non-small cell lung carcinoma". Cancer Science. 111 (4): 1093–1102. doi:10.1111/cas.14343. PMC 7156824. PMID 32020720.
  29. ^ Cingoz O (2009). "Ustekinumab". mAbs. 1 (3): 216–21. doi:10.4161/mabs.1.3.8593. PMC 2726595. PMID 20069753.
  30. ^ Warren RB, Gooderham M, Burge R, Zhu B, Amato D, Liu KH, et al. (May 2020). "Comparison of cumulative clinical benefits of biologics for the treatment of psoriasis over 16 weeks: Results from a network meta-analysis". Journal of the American Academy of Dermatology. 82 (5): 1138–1149. doi:10.1016/j.jaad.2019.12.038. PMID 31884091.
  31. ^ Gottlieb AB, Saure D, Wilhelm S, Dossenbach M, Schuster C, Smith SD, et al. (April 2020). "Indirect comparisons of ixekizumab versus three interleukin-23 p19 inhibitors in patients with moderate-to-severe plaque psoriasis - efficacy findings up to week 12". The Journal of Dermatological Treatment: 1–8. doi:10.1080/09546634.2020.1747592. PMID 32299269.
  32. ^ Yasmeen N, Sawyer LM, Malottki K, Levin LÅ, Didriksen Apol E, Jemec GB (April 2020). "Targeted therapies for patients with moderate-to-severe psoriasis: a systematic review and network meta-analysis of PASI response at 1 year". The Journal of Dermatological Treatment: 1–15. doi:10.1080/09546634.2020.1743811. PMID 32202445.
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