Interleukin-23

Interleukins (from Latin inter = between and Greek λευκός = white and κινεῖν = to move) are a group of endogenous, short-chain regulatory proteins (cytokines) of the immune system. Interleukins are mediators for the induction, progression and control of T-cell-mediated cytotoxic immune reactions and B-cell activation (antibody production). They are mainly produced and secreted by stimulated leukocytes, monocytes and macrophages. To date, around 38 different interleukins have been clearly identified. Each cytokine of the interleukin group is assigned a nomenclatural number for its classification (IL-1 to IL-38).

Some structurally related substances have been grouped into families. Their members often have a similar function or are involved in the fine regulation of immune reactions, for example by regulating the synthesis of related interleukins.

Interleukin-23 (IL-23) is a heterodimeric, pleiotropic cytokine that belongs to the interleukin-12 family. The cytokine is composed of two subunits: the IL-12B subunit (which is identical to IL-12p40, a subunit of interleukin-12) and the IL-23A subunit (IL-23p19). Interleukin-23 was discovered when experimental approaches revealed the existence of another potent binding partner for the IL-12p40 subunit of interleukin-12.

Interleukin-23, like interleukin-12, is mainly produced by B lymphocytes after induction, primarily by bacteria or bacterial components; to a lesser extent also by activated T cells, but also by subsets of dendritic cells (e.g. lamina propria dendritic cells - CD103+ and CD11b+ LPDC) or by activated synovial fibroblasts.

Experimental studies on autoimmune encephalomyelitis years ago showed that it was not interleukin-12, as originally assumed, that was responsible for the inflammatory reaction, but a then unknown interleukin, IL-23. Interleukin-23 also binds to the IL-12p40 subunit. Analogous study results in other inflammatory models, such as arthritis, inflammatory bowel disease and psoriasis, confirmed the hypothesis of dual utilization of the IL-12p40 subunit by interleukins 12 and 23.

Interleukin-23 binds to the interleukin-23 receptor. This has been identified and is composed of the IL-12R β1 receptor portion and the IL-23R receptor portion. IL-23 functions can be considered part of the innate and adaptive immune system response to peripheral tissue infections.

Interleukin-23 has an activating effect on the proliferation of T cells (T helper cells, Th-17 cells), NK cells and possibly macrophages and osteoclasts. After binding to its receptor, it activates the JAK/STAT signaling cascade and triggers the phosphoinositide 3-kinase (PI3K) of RAC-alpha serine/threonine kinase (AKT) and NF-κB.

IL-23 is partly responsible for inflammatory processes in autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, psoriasis, Crohn's disease and nephritis in systemic lupus erythematosus. The cytokine also plays a pathogenetic role in allergic bronchial asthma. Here it is responsible for the infiltration of the mucosa with neutrophil granulocytes. Interleukin-23 plays a role in the development of tumors by suppressing the tumor-destroying effects of interleukin-12.

Interleukin-23 inhibits interleukin-10 production, but activates interleukin-12 and -17 production.

The human IgG antibody ustekinumab (as well as briakinumab) binds to the common p40 subunit of unbound IL-12 and -23 and inhibits their binding to the common receptor IL-12R on the surface of naïve T cells. Both cytokines promote T cell differentiation into mature Th1 and Th17 cells and their release of TNF-α and IFN-γ. Ustekinumab inhibits the differentiation of T cells and the release of pro-inflammatory cytokines and is highly effective in psoriasis and psoriatic arthritis.

Guselkumab, a fully humanized monoclonal antibody, binds to interleukin-23 and was shown to be superior to adalimumab in a randomized, double-blind phase III study (VOYAGE 2). The antibody is approved as an effective treatment option for moderate to severe psoriasis (Reich et al 2017).

Risankizumab is an interleukin-23 inhibitor currently undergoing clinical trials. In two pivotal, randomized, placebo-controlled, double-blind studies (ultIMMa-1 / ultIMMa-2), the co-primary endpoints of a 90% and >90% improvement in PASI were achieved in patients with moderate and severe psoriasis after 16 weeks of treatment with risankizumab (150mg). The response to risankizumab was significantly better compared to ustekinumab. This biologic also proved to be superior in comparison with the TNF-alpha antagonist adalimumab.

Tildrakizumab is a humanized, monoclonal IgG1/k antibody (produced in Chinese hamster ovary cells, CHO cells) with an anti-inflammatory and selective immunosuppressive effect. Tildrakizumab is used to treat plaque psoriasis. The effects are also based on the binding and inactivation of interleukin-23 (IL-23); the antibody also inhibits its interaction with the IL-23 receptor.

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