IL23 inhibitors in inflammatory bowel disease (Homo sapiens)

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IL-23 plays a crucial role in immune responses, especially in the intestinal mucosa. Unlike IL-12, IL-23 has distinct structural and functional properties. It has a novel p19 protein subunit, which interacts with the p40 subunit. This interaction activates the STAT4-JAK2 pathway. Major cells producing IL-23 include macrophages, neutrophils, and dendritic cells, particularly in response to microbial stimuli via Toll-like receptor 4 (TLR4). Intestinal epithelial cells (IECs) can also produce IL-23.

IL-23 binds to its receptor, which consists of two subunits: IL12 receptor β1 (common to both IL-12 and IL-23 receptors) and IL23Rα. The binding triggers a conformational change in the receptor, activating the JAK2 and TYK2 kinases, which then phosphorylate each other and the receptor itself. This phosphorylation allows for the binding of STAT proteins, mainly STAT3. These phosphorylated STATs dimerize and translocate to the nucleus, where they activate RORγt, a master transcription factor that drives the expression of IL-17-related genes.

This signaling pathway primarily promotes the proliferation of Th17 cells, rather than their differentiation, since naïve T cells lack IL-23 receptors. The activation also induces the production of various cytokines, including IL-17A/F, IL-22, IL-6, GM-CSF, TNFα, and antimicrobial peptides (AMPs) by IECs. In addition to Th17 cells, other immune cells, such as CD8+ T cells, natural killer T cells, γδ T cells, innate lymphoid cells (ILCs), and DCs, are also involved in this IL-23-driven immune response.

Inspired by [figure 1, Bourgonje 2025](https://www.gastrojournal.org/article/S0016-5085(24)05124-2/fulltext).