IL-12 and IL-23 pathway inhibition in inflammatory bowel disease

Abstract

Interleukin-12 (IL-12) and interleukin-23 (IL-23), which belong to the IL-12 family of cytokines, have a key role in intestinal homeostasis and inflammation and are implicated in the pathogenesis of inflammatory bowel disease. Upon their secretion by antigen-presenting cells, they exert both pro-inflammatory and anti-inflammatory receptor-mediated effects. An increased understanding of these biological effects, particularly the pro-inflammatory effects mediated by IL-12 and IL-23, has led to the development of monoclonal antibodies that target a subunit common to IL-12 and IL-23 (p40; targeted by ustekinumab and briakinumab), or the IL-23-specific subunit (p19; targeted by risankizumab, guselkumab, brazikumab and mirikizumab). This Review provides a summary of the biology of the IL-12 family cytokines IL-12 and IL-23, discusses the role of these cytokines in intestinal homeostasis and inflammation, and highlights IL-12- and IL-23-directed drug development for the treatment of Crohn's disease and ulcerative colitis.

Fig. 1 |. Cellular sources, target cells, signalling and downstream effects of IL-12.

Interleukin-12 (IL-12) is a heterodimeric cytokine comprised of p40 (also part of the IL-23 dimer) and p35 subunits. It is produced by macrophages and dendritic cells. The receptor for IL-12 is composed of two different subunits, IL-12Rβ1 and IL-12Rβ2, which undergo conformational changes upon binding to IL-12 and bring into proximity two cytoplasmic tyrosine kinases, the Janus kinase 2 (JAK2) and tyrosine kinase 2 (TYK2), which are essential for downstream signalling of IL-12. JAKs trans/autophosphorylate each other and the receptor. Receptor phosphorylation enables binding and phosphorylation of signal transducers and activators of transcription (STATs), mainly STAT4. Phosphorylated STATs dimerize and translocate to the nucleus, where they regulate gene transcription. Different cell types express the IL-12 receptor on their membrane and are therefore targets for IL-12. Depending on the cell target, IL-12 exerts a variety of downstream effects. In naive CD4⁺ T cells, STAT4 signalling together with T-bet induce differentiation towards the T helper 1 (T_H1) cell phenotype and production of interferon-γ (IFNγ). In CD8⁺ T cells, natural killer (NK) cells and group 1 innate lymphoid cells (ILC1s), IL-12 induces IFNγ and tumour necrosis factor (TNF) release. Finally, IL-12 signalling on dendritic cells and macrophages amplifies the antibacterial response and T cell activation.

Fig. 2 |. Cellular sources, target cells, signalling and downstream effects of IL-23.

Interleukin-23 (IL-23) is a heterodimeric cytokine composed of p40 (also part of the IL-12 dimer) and p19 subunits. Like IL-12, and in response to similar stimuli (microbial signals, cytokines and co-stimulatory T cell ligands), IL-23 is produced by macrophages and dendritic cells. Some publications^– also show production of IL-23 by intestinal epithelial cells (dashed line, will need further confirmatory evidence). The IL-23 receptor is comprised of the IL-12Rβ1 and the IL-23R chains. Binding of IL-23 induces a conformational change that brings two cytoplasmic tyrosine kinases, Janus kinase 2 (JAK2) and tyrosine kinase 2 (TYK2), into proximity. JAKs trans/autophosphorylate each other and the receptor. Receptor phosphorylation enables binding and phosphorylation of signal transducers and activators of transcription (STATs), predominantly the STAT3 transcription factor. Phosphorylated STATs dimerize and translocate to the nucleus, where they regulate gene transcription. The IL-23 receptor is expressed on numerous cell types, including lymphoid cells, specifically CD4⁺ T helper 17 (T_H17) and CD8⁺ T cells. Innate lymphoid cells (ILCs), such as ILC3, also express the receptor and readily produce IL-22 and IL-17 cytokines in response to IL-23 stimulation. In IECs, IL-23 induces the expression of antimicrobial peptides. Furthermore, dendritic cells and macrophages respond to IL-23 stimulation by secreting a variety of cytokines. In addition, when the IL-23 receptor is engaged, dendritic cells demonstrate enhanced maturation and antigen presentation, and macrophages show an increased antibacterial response.