Interleukin 23 subunit alpha

Last updated
IL23A
Protein IL23A PDB 3D85.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases IL23A , IL-23, IL-23A, IL23P19, P19, SGRF, Interleukin 23, interleukin 23 subunit alpha
External IDs OMIM: 605580; MGI: 1932410; HomoloGene: 12832; GeneCards: IL23A; OMA:IL23A - orthologs
Orthologs
SpeciesHumanMouse
Entrez

51561

83430

Ensembl

ENSG00000110944

ENSMUSG00000025383

UniProt

Q9NPF7

Q9EQ14

RefSeq (mRNA)

NM_016584

NM_031252

RefSeq (protein)

NP_057668

NP_112542

Location (UCSC) Chr 12: 56.33 – 56.34 Mb Chr 10: 128.13 – 128.13 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Interleukin-23 subunit alpha is a protein that in humans is encoded by the IL23A gene. [5] [6] The protein is also known as IL-23p19. It is one of the two subunits of the cytokine Interleukin-23.

Contents

Interleukin-23 (IL-23) is a heterodimeric cytokine composed of an Interleukin 23 alpha subunit and an IL-12p40 subunit. The IL-12p40, also known as Interleukin 12 subunit beta, is used by both IL-23 (where it partners with IL-23p19) and IL-12 (where it partners with IL-12A). [5] A functional receptor for IL-23 (the IL-23 receptor) has been identified and is composed of IL-12R β1 and IL-23R. [7]

Function

Produced by dendritic cells and macrophages, IL-23 is an important part of the inflammatory response against infection. It promotes upregulation of the matrix metalloprotease MMP9, 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. [8]

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. [9] [10]

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. [11]

Knockdown of AHR decreases the expression of IL23A in THP-1 cells and primary macrophage. [8]

Pharmacology

Several biologic drugs work by targeting IL-23A. Ustekinumab, a monoclonal antibody targeting both IL-12 and IL-23 and used to treat plaque psoriasis, psoriatic arthritis, and Crohn's disease, launched in the United States under the brand name Stelara. [12] Risankizumab is another monoclonal antibody that targets IL-23A and is approved to treat plaque psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis. [13] [14] [15]

Related Research Articles

<span class="mw-page-title-main">Interleukin 10</span> Anti-inflammatory cytokine

Interleukin 10 (IL-10), also known as human cytokine synthesis inhibitory factor (CSIF), is an anti-inflammatory cytokine. In humans, interleukin 10 is encoded by the IL10 gene. IL-10 signals through a receptor complex consisting of two IL-10 receptor-1 and two IL-10 receptor-2 proteins. Consequently, the functional receptor consists of four IL-10 receptor molecules. IL-10 binding induces STAT3 signalling via the phosphorylation of the cytoplasmic tails of IL-10 receptor 1 + IL-10 receptor 2 by JAK1 and Tyk2 respectively.

<span class="mw-page-title-main">Interleukin 12</span> Interleukin

Interleukin 12 (IL-12) is an interleukin that is naturally produced by dendritic cells, macrophages, neutrophils, helper T cells and human B-lymphoblastoid cells (NC-37) in response to antigenic stimulation. IL-12 belongs to the family of interleukin-12. IL-12 family is unique in comprising the only heterodimeric cytokines, which includes IL-12, IL-23, IL-27 and IL-35. Despite sharing many structural features and molecular partners, they mediate surprisingly diverse functional effects.

<span class="mw-page-title-main">Interleukin 21</span> Mammalian protein found in humans

Interleukin 21 (IL-21) is a protein that in humans is encoded by the IL21 gene.

<span class="mw-page-title-main">Interleukin 30</span> Protein-coding gene in the species Homo sapiens

Interleukin 30 (IL-30) forms one chain of the heterodimeric cytokine called interleukin 27 (IL-27), thus it is also called IL27-p28. IL-27 is composed of α chain p28 and β chain Epstain-Barr induce gene-3 (EBI3). The p28 subunit, or IL-30, has an important role as a part of IL-27, but it can be secreted as a separate monomer and has its own functions in the absence of EBI3. The discovery of IL-30 as individual cytokine is relatively new and thus its role in the modulation of the immune response is not fully understood.

<span class="mw-page-title-main">Interleukin 26</span>

Interleukin-26 (IL-26) is a protein that in humans is encoded by the IL26 gene.

<span class="mw-page-title-main">Interleukin 22</span> Protein, encoded in humans by IL22 gene

Interleukin-22 (IL-22) is a protein that in humans is encoded by the IL22 gene.

<span class="mw-page-title-main">Interleukin 17</span> Group of proteins

Interleukin 17 family is a family of pro-inflammatory cystine knot cytokines. They are produced by a group of T helper cell known as T helper 17 cell in response to their stimulation with IL-23. Originally, Th17 was identified in 1993 by Rouvier et al. who isolated IL17A transcript from a rodent T-cell hybridoma. The protein encoded by IL17A is a founding member of IL-17 family. IL17A protein exhibits a high homology with a viral IL-17-like protein encoded in the genome of T-lymphotropic rhadinovirus Herpesvirus saimiri. In rodents, IL-17A is often referred to as CTLA8.

<span class="mw-page-title-main">STAT4</span> Protein-coding gene in the species Homo sapiens

Signal transducer and activator of transcription 4 (STAT4) is a transcription factor belonging to the STAT protein family, composed of STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6. STAT proteins are key activators of gene transcription which bind to DNA in response to cytokine gradient. STAT proteins are a common part of Janus kinase (JAK)- signalling pathways, activated by cytokines.STAT4 is required for the development of Th1 cells from naive CD4+ T cells and IFN-γ production in response to IL-12. There are two known STAT4 transcripts, STAT4α and STAT4β, differing in the levels of interferon-gamma production downstream.

T helper 17 cells (Th17) are a subset of pro-inflammatory T helper cells defined by their production of interleukin 17 (IL-17). They are related to T regulatory cells and the signals that cause Th17s to actually inhibit Treg differentiation. However, Th17s are developmentally distinct from Th1 and Th2 lineages. Th17 cells play an important role in maintaining mucosal barriers and contributing to pathogen clearance at mucosal surfaces; such protective and non-pathogenic Th17 cells have been termed as Treg17 cells.

<span class="mw-page-title-main">Interleukin-4 receptor</span> Protein-coding gene in the species Homo sapiens

The interleukin 4 receptor is a type I cytokine receptor. It is a heterodimer, that is, composed of two subunits. IL4R is the human gene coding for IL-4Rα, the subunit which combines with either common gamma chain or with IL-13Rα1.

<span class="mw-page-title-main">Interleukin-12 subunit beta</span> Protein-coding gene in the species Homo sapiens

Subunit beta of interleukin 12 is a protein subunit that in humans is encoded by the IL12B gene. IL-12B is a common subunit of interleukin 12 and interleukin 23.

<span class="mw-page-title-main">C-C chemokine receptor type 6</span> Mammalian protein found in Homo sapiens

Chemokine receptor 6 also known as CCR6 is a CC chemokine receptor protein which in humans is encoded by the CCR6 gene. CCR6 has also recently been designated CD196. The gene is located on the long arm of Chromosome 6 (6q27) on the Watson (plus) strand. It is 139,737 bases long and encodes a protein of 374 amino acids.

<span class="mw-page-title-main">Interleukin 12 receptor, beta 1 subunit</span> Protein and coding gene in humans

Interleukin-12 receptor, beta 1, or IL-12Rβ1 in short, is a subunit of the interleukin 12 receptor and the interleukin 23 receptor. IL12RB1, is the name of its human gene. IL-12Rβ1 is also known as CD212.

<span class="mw-page-title-main">Interleukin-23 receptor</span> Protein-coding gene in the species Homo sapiens

The interleukin-23 receptor is a type I cytokine receptor. It is encoded in human by the IL23R gene. In complex with the interleukin-12 receptor β1 subunit (IL-12Rβ1), it is activated by the cytokine interleukin 23 (IL-23). 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. 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. 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.

The interleukin-27 receptor is a type I cytokine receptor for interleukin-27. It is a heterodimer composed of the interleukin 27 receptor, alpha subunit and glycoprotein 130.

<span class="mw-page-title-main">Interleukin-17A</span> Protein-coding gene in the species Homo sapiens

Interleukin-17A is a protein that in humans is encoded by the IL17A gene. In rodents, IL-17A used to be referred to as CTLA8, after the similarity with a viral gene.

<span class="mw-page-title-main">Interleukin-17 receptor</span> Type of protein receptor

Interleukin-17 receptor (IL-17R) is a cytokine receptor which belongs to new subfamily of receptors binding proinflammatory cytokine interleukin 17A, a member of IL-17 family ligands produced by T helper 17 cells (Th17). IL-17R family consists of 5 members: IL-17RA, IL-17RB, IL-17RC, IL-17RD and IL-17RE. Functional IL-17R is a transmembrane receptor complex usually consisting of one IL-17RA, which is a founding member of the family, and second other family subunit, thus forming heteromeric receptor binding different ligands. IL-17A, a founding member of IL-17 ligand family binds to heteromeric IL-17RA/RC receptor complex. IL-17RB binds preferentially IL-17B and IL-17E and heteromeric IL-17RA/RE complex binds IL-17C. However, there is still unknown ligand for IL-17RD. The first identified member IL-17RA is located on human chromosome 22, whereas other subunits IL-17RB to IL-17RD are encoded within human chromosome 3.

<span class="mw-page-title-main">Interleukin-1 family</span> Group of cytokines playing a key role in the regulation of immune and inflammatory responses

The Interleukin-1 family is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults.

<span class="mw-page-title-main">Interleukin 23</span> Heterodimeric cytokine acting as mediator of inflammation

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

<span class="mw-page-title-main">Interleukin 17F</span>

Interleukin 17F (IL-17F) is signaling protein that is in human is encoded by the IL17F gene and is considered a pro-inflammatory cytokine. This protein belongs to the interleukin 17 family and is mainly produced by the T helper 17 cells after their stimulation with interleukin 23. However, IL-17F can be also produced by a wide range of cell types, including innate immune cells and epithelial cells.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000110944 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000025383 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 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.
  6. ↑ "Entrez Gene: IL23A interleukin 23, alpha subunit p19".
  7. ↑ 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.
  8. 1 2 Memari 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 . PMID   26416282.
  9. ↑ 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. Bibcode:2006Natur.442..461L. doi:10.1038/nature04808. PMID   16688182. S2CID   4431794.
  10. ↑ 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. PMID   17010592.
  11. ↑ Korn T, Bettelli E, Oukka M, Kuchroo VK (2009). "IL-17 and Th17 Cells". Annual Review of Immunology. 27: 485–517. doi:10.1146/annurev.immunol.021908.132710. PMID   19132915.
  12. ↑ van Vollenhoven RF, Hahn BH, Tsokos GC, Wagner CL, Lipsky P, Touma Z, Werth VP, Gordon RM, Zhou B, Hsu B, Chevrier M, Triebel M, Jordan JL, Rose S (October 2018). "Efficacy and safety of ustekinumab, an IL-12 and IL-23 inhibitor, in patients with active systemic lupus erythematosus: results of a multicentre, double-blind, phase 2, randomised, controlled study". Lancet (London, England). 392 (10155): 1330–1339. doi:10.1016/S0140-6736(18)32167-6. PMID   30249507.
  13. ↑ Haugh IM, Preston AK, Kivelevitch DN, Menter AM (2018). "Risankizumab: an anti-IL-23 antibody for the treatment of psoriasis". Drug Design, Development and Therapy. 12: 3879–3883. doi: 10.2147/DDDT.S167149 . PMC   6237136 . PMID   30518998.
  14. ↑ Huth L, Amann PM, Marquardt Y, Jansen M, Baron JM, Huth S (June 2024). "Understanding the impact of risankizumab on keratinocyte-derived IL-23A in a novel organotypic 3D skin model containing IL-23A responsive and IL-17A producing γδ-T-cells". Cutaneous and Ocular Toxicology. 43 (2): 124–128. doi:10.1080/15569527.2024.2310243. PMID   38284163.
  15. ↑ Brooks, Abigail (18 June 2024). "FDA Approves Risankizumab (Skyrizi) for Ulcerative Colitis". HCP Live. Retrieved 2 November 2024.

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