IL-23 Pathway in Autoimmune Diseases

Abstract: Interleukin-23(IL-23) is the important pro-inflammatory cytokine of IL-12 family, mainly produced by macrophages and dendritic cells. IL-23 consists of IL-12p40 and IL-23p19. Binding with IL-23 receptor activates cell signaling and promotes proliferation and differentiation of Th17 cells, which is very important for autoimmune diseases. Thus, IL-23 pathway promotes immune response via activating immune cells and inducing cascade reaction of cytokines.

Keywords: IL-23 Signaling Pathway, Autoimmune Diseases, Inflammation, Cancer Treatment

1. IL-23 Signaling Pathway

IL-23 pathway activates two tyrosine kinases(Jak2 and Tyk2). These kinases phosphorylate receptors to form binding site of STAT protein. Then, dimerized and phosphorylated STAT protein enters nucleus to activate the target gene. The phosphorylation of STAT4 promotes secretion of IFN-γ and differentiation of Th1 cell. The phosphorylation of STAT3 is very important for the growth of Th17 cells.

2. IL-23 Role in Autoimmune Diseases

IL-23 is the important cytokine for innate and adaptive immunity. Roles in early local immune response are significant, including induction of IFN-γ production, involvement in Th1 response, and improved immunity against intracellular pathogens. IL-23 is also predominant in activation of NK cells, promotion of T cell proliferation and regulation of antibody production. Researches show the increase of IL-23 is related to various autoimmune diseases, e.g. psoriasis, rheumatoid arthritis and multiple sclerosis.

As the mature factor of Th17 cells, IL-23 is important for signaling pathway and drug development of autoimmune diseases. Pharmaceutical companies focus more on IL-23. Currently, various IL-23 targeted antibody drugs and biosimilars have been approved for treatment of diverse autoimmune diseases. Effective relief of symptoms improves patients’ quality of life, showing better curative effects in clinical applications. Currently, five IL-23 antibody drugs are available, including Ustekinumab, Guselkumab, Tildrakizumab, Risankizumab and Mirikizumab.

3. IL-23 in Cancer Treatment

IL-23 is the pro-inflammatory cytokine, and its potentiality in cancer treatment is studied. The latest research shows IL-23 promotes tumor growth in tumor model, and is related to poor prognosis. In 2024, University of Zurich team revealed in Nature Immunology tumor-associated macrophages were main sources of IL-23. IL-23 receptor principally existed on tumor-infiltrating regulatory T cells(Treg). IL-23 improved immunosuppression to further inhibit anti-tumor immunity via stabilizing Treg cell. This research shows IL-23/IL-23R axis is the potential target for cancer immunotherapy. Deeper investigation of IL-23 in the treatment of tumor and autoimmune diseases leads to wider clinical applications.

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REFERENCES

[1]Tubuloside B alleviates con A-induced acute liver injury by inhibiting the IL-23/JAK2/STAT3 signaling pathway hyperactivation during Th17 cell differentiation, PMID: 41043315.
[2]Association Between Polymorphisms of IL-23/IL-17 Pathway and Clinical Phenotypes of Autoimmune Thyroid Diseases, PMID: 35767887.