Interleukin 23 subunit alpha

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.

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.

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.

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

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. Risankizumab is another monoclonal antibody that targets IL-23A and is approved to treat plaque psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis.

References

References

1. (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.
2. "Entrez Gene: IL23A interleukin 23, alpha subunit p19".
3. (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.
4. (November 2015). "Engagement of the Aryl Hydrocarbon Receptor in Mycobacterium tuberculosis-Infected Macrophages Has Pleiotropic Effects on Innate Immune Signaling". Journal of Immunology.
5. (July 2006). "IL-23 promotes tumour incidence and growth". Nature.
6. (December 2006). "The IL-23/Th(17) axis: therapeutic targets for autoimmune inflammation". Current Opinion in Immunology.
7. (2009). "IL-17 and Th17 Cells". Annual Review of Immunology.
8. (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.
9. (2018). "Risankizumab: an anti-IL-23 antibody for the treatment of psoriasis". Drug Design, Development and Therapy.
10. (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.
11. Brooks, Abigail. (18 June 2024). "FDA Approves Risankizumab (Skyrizi) for Ulcerative Colitis".