Interleukin 23: Difference between revisions

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__NOTOC__
{{infobox protein
{{SI}}
| Name = [[Interleukin-12 subunit beta|IL12B]]
{{CMG}}
| caption = Crystal structure of IL-12B
| image = IL12b_Crystal_Structure.rsh.png
| width = 200
| HGNCid = 5970
| Symbol = IL12B
| AltSymbols = CLMF2, NKSF2, p40
| EntrezGene = 3593
| OMIM = 161561
| RefSeq = NM_002187
| UniProt = P29460
| PDB = 1F42
| ECnumber =
| Chromosome = 5
| Arm = q
| Band = 31.1
| LocusSupplementaryData = -33.1
}}
{{infobox protein
| name = [[interleukin 23, alpha subunit p19]]
| caption =
| image =
| width =
| HGNCid = 15488
| Symbol = [[Interleukin 23 subunit alpha|IL23A]]
| AltSymbols =
| EntrezGene = 51561
| OMIM =
| RefSeq = NM_016584
| UniProt =
| PDB =
| ECnumber =
| Chromosome = 12
| Arm = q
| Band = 13.13
| LocusSupplementaryData =
}}


{{SK}} IL-23
'''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 [http://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 | 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 = Jan 2001 | pmid = 11114383 | pmc =  | doi = 10.1016/S1074-7613(00)00070-4 }}</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 | title = A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R | language =  | journal = Journal of Immunology | volume = 168 | issue = 11 | pages = 5699–708 | year = 2000 | pmid = 12023369 | doi = 10.4049/jimmunol.168.11.5699 | url = http://www.jimmunol.org/content/168/11/5699.long }}</ref>


==Overview==
== Discovery ==
Interleukin-23 is a [[heterodimer]]ic [[cytokine]] consisting of two subunits, one called p40, which is shared with another cytokine, [[interleukin 12|IL-12]], and another called p19 (the IL-23 alpha subunit). IL-23 is an important part of the [[inflammation|inflammatory response]] against [[infection]]. It promotes upregulation of the matrix [[metalloprotease]] [[MMP9]], increases [[angiogenesis]] and reduces [[cytotoxic T cell|CD8+ T-cell]] infiltration.  Recently, IL-23 has been implicated in the development of cancerous tumors.  In conjunction with [[interleukin-6|IL-6]] and [[TGF]]-β1, IL-23 stimulates naive [[helper T cells|CD4+ T cells]] to differentiate into a novel subset of cells called Th17 cells, which are distinct from the classical Th1 and Th2 cells.  Th17 cells produce [[interleukin 17|IL-17]], a proinflammatory cytokine that enhances T cell priming and stimulates the production of proinflammatory molecules such as [[interleukin 1|IL-1]], [[interleukin 6|IL-6]], [[TNF-alpha]], [[nitric oxide synthase|NOS-2]], and [[chemokines]] resulting in inflammation.  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 multiple sclerosis and inflammatory bowel disease highlighting the importance of IL-23 in the inflammatory pathway<ref>http://www.nature.com/nature/journal/v442/n7101/full/nature04808.html</ref><ref> Kristine Kikly, Ling Liu, Songqing Na and Jonathon D Sedgwick. The IL-23/Th(17) axis: therapeutic targets for autoimmune inflammation. Curr Opin Immunol. 2006, Volume 18, pages 670-5.</ref>. Entheseal-resident T cells are sensitive to IL-23 overexpression and they respond vigorously by releasing IL-17 and IL-22 which lead to local inflammatory changes and osteoblast-mediated bone remodeling. These T cells are also present in the aortic root and valve, leading to aortitis that may be seen in patients with ankylosing spondylitis.


==See also==
IL-23 was first described by Robert Kastelein and colleagues at the DNAX research institute using a combination of [[Computational biology|computational]], [[biochemical]] and cellular  [[immunology]] approaches.<ref name="pmid11114383"/>
* [[CNTO 1275]]


==References==
== Function ==
<references/>


[[Category:Cytokines]]
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 = Journal of Experimental Medicine| volume = 181 | issue = 1 | pages = 381–6 | date = Jan 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 = Journal of Clinical Investigation | volume = 110 | issue = 4 | pages = 493–7 | date = Aug 2002 | pmid = 12189243| pmc =  150420| doi = 10.1172/JCI15751}}</ref>


{{WH}}
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 |author1=Cua DJ |author2=Sherlock J |author3=Chen Y |author4=Murphy CA |author5=Joyce B |author6=Seymour B |author7=Lucien L |author8=To W |author9=Kwan S |author10=Churakova T |author11=Zurawski S |author12=Wiekowski M |author13=Lira SA |author14=Gorman D |author15=Kastelein RA. Sedgwick JD | 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 = Feb 2003 | pmid = 12610626 | pmc =  | doi = 10.1038/nature01355}}</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 | title = Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation | journal = Journal of Experimental Medicine | volume = 198 | issue = 12 | pages =1951–7 | date = Dec 2002 | pmid = 14662908| pmc =  2194162| doi = 10.1084/jem.20030896}}</ref> intestinal inflammation,<ref name="pmid16670770 ">{{cite journal | author = Yen D1, 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. | title = IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6 | journal = 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 | title = IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis | journal = Journal of Experimental Medicine | volume = 203 | issue = 11 | pages =2485–94 | date = Oct 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 |title=Interleukin-23 drives innate and T cell-mediated intestinal inflammation|year=2006|journal=Journal of ExperimentalMedicine|pmid=17030949|doi=10.1084/jem.20061099|volume=203|issue=11|pmc=2118132|pages=2473–83}}</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 | title = IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis.| journal = Journal of Experimental Medicine | volume = 203 | issue = 12 | pages =2577–87 | date = Oct 2006 | pmid = 17074928 | pmc =  2118145| doi = 10.1084/jem.20060244}}</ref>
{{WS}}
 
== References ==
{{Reflist}}
 
{{Interleukins}}
{{Interleukin receptor modulators}}
 
[[Category:Interleukins]]

Revision as of 13:41, 13 September 2017

IL12B
Crystal structure of IL-12B
Identifiers
SymbolIL12B
Alt. symbolsCLMF2, NKSF2, p40
Entrez3593
HUGO5970
OMIM161561
PDB1F42
RefSeqNM_002187
UniProtP29460
Other data
LocusChr. 5 q31.1-33.1
interleukin 23, alpha subunit p19
Identifiers
SymbolIL23A
Entrez51561
HUGO15488
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] A functional receptor for IL-23 (the IL-23 receptor) has been identified and is composed of IL-12R β1 and IL-23R.[2]

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

Prior to the discovery of IL-23, IL-12 had been proposed to represent a key mediator of inflammation in mouse models of inflammation.[3] 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.[4]

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.[5] 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,[6] intestinal inflammation,[7][8][9] and psoriasis.[10]

References

  1. ↑ 1.0 1.1 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 (Jan 2001). "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. ↑ 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 (2000). "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.
  3. ↑ Leonard JP, Waldburger KE, Goldman SJ (Jan 1995). "Prevention of experimental autoimmune encephalomyelitis by antibodies against interleukin 12". Journal of Experimental Medicine. 181 (1): 381–6. doi:10.1084/jem.181.1.381. PMC 2191822. PMID 7528773.
  4. ↑ Becher B, Durell BG, Noelle RJ (Aug 2002). "Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12". Journal of Clinical Investigation. 110 (4): 493–7. doi:10.1172/JCI15751. PMC 150420. PMID 12189243.
  5. ↑ Cua DJ; Sherlock J; Chen Y; Murphy CA; Joyce B; Seymour B; Lucien L; To W; Kwan S; Churakova T; Zurawski S; Wiekowski M; Lira SA; Gorman D; Kastelein RA. Sedgwick JD (Feb 2003). "Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain". Nature. 421 (6924): 744–8. doi:10.1038/nature01355. PMID 12610626.
  6. ↑ Murphy CA, Langrish CL, Chen Y, Blumenschein W, McClanahan T, Kastelein RA, Sedgwick JD, Cua DJ (Dec 2002). "Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation". Journal of Experimental Medicine. 198 (12): 1951–7. doi:10.1084/jem.20030896. PMC 2194162. PMID 14662908.
  7. ↑ Yen D1, 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. (May 2006). "IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6". Journal of Clinical Investigation. 116 (5): 1310–6. doi:10.1172/JCI21404. PMC 1451201. PMID 16670770.
  8. ↑ Kullberg MC, Jankovic D, Feng CG, Hue S, Gorelick PL, McKenzie BS, Cua DJ, Powrie F, Cheever AW, Maloy KJ, Sher A (Oct 2006). "IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis". Journal of Experimental Medicine. 203 (11): 2485–94. doi:10.1084/jem.20061082. PMC 2118119. PMID 17030948.
  9. ↑ Hue S, Ahern P, Buonocore S, Kullberg MC, Cua DJ, McKenzie BS, Powrie F, Maloy KJ (2006). "Interleukin-23 drives innate and T cell-mediated intestinal inflammation". Journal of ExperimentalMedicine. 203 (11): 2473–83. doi:10.1084/jem.20061099. PMC 2118132. PMID 17030949.
  10. ↑ 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 (Oct 2006). "IL-23 stimulates epidermal hyperplasia via TNF and IL-20R2-dependent mechanisms with implications for psoriasis pathogenesis". Journal of Experimental Medicine. 203 (12): 2577–87. doi:10.1084/jem.20060244. PMC 2118145. PMID 17074928.
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