IL23 inhibitors in inflammatory bowel disease (Homo sapiens)

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"IL23 signaling in the intestinal mucosa. IL23 is a heterodimeric cytokine with distinct structure and physiological functions compared with IL12. IL23 was first discovered by the description of the novel p19 protein subunit interacting with p40, both of which were shown to activate the STAT4–JAK2 pathway.19 The principal cells producing IL23 include macrophages, neutrophils, and dendritic cells (DCs), on microbial stimulation in a Toll-like receptor 4 (TLR4)-dependent fashion. In addition, production by intestinal epithelial cells (IECs) has also been demonstrated. IL23 engages with the IL23 receptor consisting of 2 subunits: IL12 receptor β1 (right inset, red-colored, common to both IL12 and IL23 receptors, binding to the p40 subunit) and IL23Rα (right inset, orange-colored, binding to the p19 subunit). Binding of IL23 to its receptor leads to a conformational change, which triggers activation of JAK2 and TYK2, which phosphorylate each other, as well as the receptor itself. Subsequently, receptor phosphorylation leads to the binding of STATs, mainly STAT3. Phosphorylated STATs dimerize and migrate to the cell nucleus, where they activate the master transcription factor RORγt, resulting in the transcription of IL17-related genes in target cells (bottom left inset), especially (Th17) CD4+ helper T cells, but also CD8+ T cells, natural killer (NK) T cells, γδ T cells, innate lymphoid cells (ILCs), IECs (triggering the production of antimicrobial peptides [AMPs]), DCs, and macrophages. Concomitantly, IL17-associated cytokines, including IL17A/F, IL22, IL6, granulocyte and monocyte colony-stimulating factor (GM-CSF), and TNFα are produced. IL23 mainly contributes to perpetuating Th17 cell proliferation rather than differentiation because naïve T cells lack IL23 receptors." Inspired by figure 1 in https://www.gastrojournal.org/article/S0016-5085(24)05124-2/fulltext.