Interleukin-23

Interleukins (from Latin/Greek inter = between; leukos = white; kinein = to move) is the name given to a group of endogenous, short-chain regulatory proteins (cytokines) of the immune system (IL1-IL38). Interleukins are mediators for induction, progression, and control of T-cell-mediated cytotoxic immune responses as well as B-cell activation (antibody production). They are predominantly produced and secreted by stimulated leukocytes, monocytes and macrophages. To date, about 38 different interleukins have been clearly identified. Each cytokine of the interleukin group is nomenclatorically assigned a 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 participate in the fine regulation of immune responses, 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 2 subunits: the IL-12B subunit (this is identical to IL-12p40 a subunit of interleukin-12) and the IL23A subunit(IL-23p19). Interleukin-23 was discovered when experimental approaches revealed that another potent binding partner exists for the IL-12p40 subunit of interleukin-12.

Interleukin-23, like interleukin-12, is mainly produced by B lymphocytes after induction, mainly 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+ u. CD11b+ LPDC) or by activated synovial fibroblasts.

Experimental studies on autoimmune encephalomyelitis showed Hyears ago that not interleukin-12 as originally assumed 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 models of inflammation, such as arthritis, inflammatory bowel disease, and psoriasis confirmed the hypothesis of dual use 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. IL23- functions can be considered part of the response of the innate and adaptive immune system to infection of peripheral tissues.

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. Upon binding to its receptor, there is activation of the JAK/STAT signaling cascade and triggering of phosphoinositide 3-kinase ( PI3K ) of RAC-alpha serine/threonine kinase (AKT) and NF-kappaB.

IL23 is jointly responsible for inflammatory processes in autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, psoriasis, Crohn's disease, nephritis in systemic lupus erythematosus. Furthermore, the cytokine 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 tumor development by suppressing tumor-destructive effects of interleukin-12.

Interleukin-23 inhibitively regulates interleukin-10 production, but activates interleukin-12 and interleukin-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, respectively, and their release of TNF-α and IFN-γ. Ustekinumab inhibits T-cell differentiation and the release of proinflammatory cytokines and is highly effective in psoriasis and psoriatic arthritis.

Guselkumab, a fully humanized monoclonal antibody binds to interleukin-23 and proved 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, an interleukin-23 inhibitor in clinical trials. In 2 pivotal, randomized, placebo-controlled, double-blind trials (ultIMMa-1/ ultIMMa-2), the co-primary endpoints of improving PASI by 90 and >90%, respectively, were achieved in patients with moderate-to-severe psoriasis after 16 weeks of treatment with risankizumab (150mg). Response to risankizumab was significantly better compared to ustekinumab. This biologic also proved superior when compared to the TNF-alpha antagonist adalimumab.

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

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