Interleukin 23 Explained

IL12B
Caption:Crystal structure of IL-12B
Width:200
Hgncid:5970
Symbol:IL12B
Altsymbols:CLMF2, NKSF2, p40
Entrezgene:3593
Omim:161561
Refseq:NM_002187
Uniprot:P29460
Pdb:1F42
Chromosome:5
Arm:q
Band:31.1
Locussupplementarydata:-33.1
interleukin 23, alpha subunit p19
Hgncid:15488
Symbol:IL23A
Entrezgene:51561
Refseq:NM_016584
Uniprot:Q9NPF7
Chromosome:12
Arm:q
Band:13.13

Interleukin 23 (IL-23) is a heterodimeric cytokine composed of an IL-12B (IL-12p40) subunit (which is shared with IL-12) and an IL-23A (IL-23p19) subunit.[1] IL-23 is part of the IL-12 family of cytokines.[2] The functional receptor for IL-23 (the IL-23 receptor) consists of a heterodimer between IL-12Rβ1 and IL-23R.[3]

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 an inflammatory cytokine. It has been shown to be a key cytokine for T helper type 17 cell (Th17 cell) maintenance and expansion. Polarisation to a Th17 phenotype is triggered by IL-6 and TGF-β, which activate the Th17 transcription factor RORγt. IL-23 stabilises RORγt and thus enables Th17 cells to release their effector cytokines, such as IL-17, IL-21, IL-22 and GM-CSF, which mediate protection against extracellular fungi and bacteria and participate in barrier immunity.[4] Effects similar to those IL-23 has on Th17 cells were described for type 3 innate lymphoid cells, which actively secrete Th17 cytokines upon IL-23 stimulation.[5] Natural killer cells also express the IL-23 receptor. They respond with increased interferon-γ secretion and enhanced antibody-dependent cellular cytotoxicity. IL-23 also induces proliferation of CD4 memory T cells (but not naïve T cells).[6] Besides its proinflammatory effects, IL-23 promotes angiogenesis.[7]  

IL-23 is mainly secreted by activated dendritic cells, macrophages or monocytes. Innate lymphoid cells and γδ T cells also produce IL-23. B cells produce IL-23 through B cell antigen receptor signaling.[8] Secretion is stimulated by an antigen stimulus recognised by a pattern recognition receptor.[9] IL-23 imbalance and increase is associated with autoimmune diseases and cancer. It is thus a target for therapeutic research. IL-23 expression by dendritic cells is further induced by thymic stromal lymphopoietin, a proallergic cytokine expressed by keratinocytes that is elevated in psoriatic lesions.[10] In the pathogenesis of psoriasis, dermal dendritic cells are stimulated to release IL-23 by nociceptive neurons.[11] IL-23 is also elevated during bacterial meningitis, leading to epithelial dysregulation and inflammation.[12]

Mycobacterium avium subspecies paratuberculosis-stimulated monocyte-derived macrophages are one of the contributors of IL-23, and thus cattle with Johne's disease have elevated IL-23.[13]

Prior to the discovery of IL-23, IL-12 had been proposed to represent a key mediator of inflammation in mouse models of inflammation.[14] However, many studies aimed at assessing the role of IL-12 by pharmacological blockade had targeted IL-12B, and were therefore not as specific as thought. Studies which blocked the function of IL-12A did not produce the same results as those targeting IL-12B, as would have been expected if both subunits formed part of IL-12 only.[15]

The discovery of an additional potential binding partner for IL-12B led to a reassessment of this role for IL-12. 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.[16] 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,[17] intestinal inflammation,[18] [19] [20] and psoriasis.[21] Low concentrations of IL-23 support lung tumor growth whereas high concentrations inhibit proliferation of lung cancer cells.[22] IL-23 and IL-23R were identified in serum from patients with non-small-cell lung cancer and have been proposed as prognostic serum markers.[23] IL-23 can also promote progression of cardiovascular diseases such as atherosclerosis, hypertension, aortic dissection, cardiac hypertrophy, myocardial infarction and acute cardiac injury. In brain, IL-23 is able to activate γδ T cells to increase their expression of IL-17, which contributes to the inflammatory response and thus plays a key role in secondary brain injury after spontaneous intracerebral hemorrhage.[24]

Monoclonal antibody drugs

IL-23 is one of the therapeutic targets to treat the inflammatory diseases.[25] Ustekinumab, a monoclonal antibody directed against this cytokine, is used to treat certain autoimmune conditions.[26] Guselkumab is another monoclonal antibody against IL-23. Blocking IL-23 can slow clinical manifestation of psoriasis, indirectly affecting Th17 immune response and production of IL-17.[27] Ixekizumab, an IL-17A antagonist, has been reported to have faster onset of action in treatment of psoriasis than guselkumab, tildrakizumab or risankizumab, which are inhibitors of the p19 subunit of IL-23.[28] However, risankizumab has been shown to have the best treatment results for psoriasis in comparison with other IL-23 inhibitors.[29] Adnectin-2 binds to IL-23 and competes with IL-23–IL-23R binding.

Signalling

The IL-23 heterodimer binds the receptor complex: the p19 subunit binds IL-23R while the p40 subunit binds IL-12RB1. Receptor binding 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 such as RORγt expression and transcription of Th17 cytokines. 

Notes and References

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  2. Cauli A, Piga M, Floris A, Mathieu A . 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 . 2015-10-01 . 27471723 . 4918258 . 10.2147/ITT.S62870 . free .
  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. Tang C, Chen S, Qian H, Huang W . Interleukin-23: as a drug target for autoimmune inflammatory diseases . Immunology . 135 . 2 . 112–24 . February 2012 . 22044352 . 3277713 . 10.1111/j.1365-2567.2011.03522.x .
  5. Zeng B, Shi S, Ashworth G, Dong C, Liu J, Xing F . ILC3 function as a double-edged sword in inflammatory bowel diseases . Cell Death & Disease . 10 . 4 . 315 . April 2019 . 30962426 . 6453898 . 10.1038/s41419-019-1540-2 .
  6. Li Y, Wang H, Lu H, Hua S . Regulation of Memory T Cells by Interleukin-23 . International Archives of Allergy and Immunology . 169 . 3 . 157–62 . 2016 . 27100864 . 10.1159/000445834 . 24274565 .
  7. Langowski JL, Zhang X, Wu L, Mattson JD, Chen T, Smith K, Basham B, McClanahan T, Kastelein RA, Oft M . 6 . IL-23 promotes tumour incidence and growth . Nature . 442 . 7101 . 461–5 . July 2006 . 16688182 . 10.1038/nature04808 . 2006Natur.442..461L . 4431794 .
  8. Gagro A, Servis D, Cepika AM, Toellner KM, Grafton G, Taylor DR, Branica S, Gordon J . 6 . Type I cytokine profiles of human naïve and memory B lymphocytes: a potential for memory cells to impact polarization . Immunology . 118 . 1 . 66–77 . May 2006 . 16630024 . 1782263 . 10.1111/j.1365-2567.2006.02342.x .
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  10. 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 . 6 . 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 . August 2014 . 24910175 . 10.1016/j.jaci.2014.04.022 . free .
  11. Riol-Blanco L, Ordovas-Montanes J, Perro M, Naval E, Thiriot A, Alvarez D, Paust S, Wood JN, von Andrian UH . 6 . Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation . Nature . 510 . 7503 . 157–61 . June 2014 . 24759321 . 10.1038/nature13199 . 4127885 . 2014Natur.510..157R .
  12. Srinivasan L, Kilpatrick L, Shah SS, Abbasi S, Harris MC . Elevations of novel cytokines in bacterial meningitis in infants . PLOS ONE . 13 . 2 . e0181449 . 2018-02-02 . 29394248 . 5796685 . 10.1371/journal.pone.0181449 . 2018PLoSO..1381449S . free .
  13. DeKuiper JL, Cooperider HE, Lubben N, Ancel CM, Coussens PM . paratuberculosis Drives an Innate Th17-Like T Cell Response Regardless of the Presence of Antigen-Presenting Cells . en . Frontiers in Veterinary Science . 7 . 108 . 2020 . 32258066 . 10.3389/fvets.2020.00108 . 7089878 . free .
  14. Leonard JP, Waldburger KE, Goldman SJ . Prevention of experimental autoimmune encephalomyelitis by antibodies against interleukin 12 . The Journal of Experimental Medicine . 181 . 1 . 381–6 . January 1995 . 7528773 . 2191822 . 10.1084/jem.181.1.381 .
  15. Becher B, Durell BG, Noelle RJ . Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12 . The Journal of Clinical Investigation . 110 . 4 . 493–7 . August 2002 . 12189243 . 150420 . 10.1172/JCI15751 .
  16. 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 . 6 . Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain . Nature . 421 . 6924 . 744–8 . February 2003 . 12610626 . 10.1038/nature01355 . 2003Natur.421..744C . 4380302 .
  17. Murphy CA, Langrish CL, Chen Y, Blumenschein W, McClanahan T, Kastelein RA, Sedgwick JD, Cua DJ . 6 . Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation . The Journal of Experimental Medicine . 198 . 12 . 1951–7 . December 2003 . 14662908 . 2194162 . 10.1084/jem.20030896 .
  18. 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 . 6 . 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 . May 2006 . 16670770 . 1451201 . 10.1172/JCI21404 .
  19. Kullberg MC, Jankovic D, Feng CG, Hue S, Gorelick PL, McKenzie BS, Cua DJ, Powrie F, Cheever AW, Maloy KJ, Sher A . 6 . IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis . The Journal of Experimental Medicine . 203 . 11 . 2485–94 . October 2006 . 17030948 . 2118119 . 10.1084/jem.20061082 .
  20. Hue S, Ahern P, Buonocore S, Kullberg MC, Cua DJ, McKenzie BS, Powrie F, Maloy KJ . 6 . Interleukin-23 drives innate and T cell-mediated intestinal inflammation . The Journal of Experimental Medicine . 203 . 11 . 2473–83 . October 2006 . 17030949 . 2118132 . 10.1084/jem.20061099 .
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