Keywords: IL-23, IL-23R, Th17 differentiation, JAK-STAT signaling, autoimmunity, target biology

IL-23 is a key member of the IL-12 cytokine family and plays a central regulatory role in coordinating adaptive immune responses. Since its discovery in 2000, IL-23 and its receptor IL-23R have been identified as the dominant signals for Th17 cell differentiation and maintenance, making them strategic targets for drug development in autoimmune diseases such as psoriasis, inflammatory bowel disease, and ankylosing spondylitis. Unlike the downstream effector molecule IL-17A, IL-23 is located at the upstream node of the inflammatory cascade, and targeting it can achieve broader suppression of the Th17 pathway. This article systematically analyzes the biological basis of IL-23/IL-23R from four dimensions: molecular structure, receptor complex, signal transduction mechanisms, and target properties.

IL-23 is a heterodimeric cytokine composed of two covalently linked subunits: the p19 subunit and the p40 subunit. p19 (IL-23A) is the unique functional subunit of IL-23, consisting of approximately 189 amino acids and featuring a typical four-helix bundle cytokine structure. p40 (IL-12B) is shared with IL-12 and consists of approximately 328 amino acids, containing three immunoglobulin-like domains. p19 and p40 form a stable heterodimer via disulfide bonds, with p19 responsible for specific binding to IL-23R and p40 primarily involved in interactions with IL-12Rβ1.

The expression of the two subunits is independently regulated: p19 expression is mainly induced by Toll-like receptor signaling and inflammatory factors, limited to activated dendritic cells, macrophages, and monocytes; whereas p40 expression is more widespread and detectable in various antigen-presenting cells. This differential expression allows for finer regulation of IL-23 production.

The IL-23 receptor complex consists of two receptor chains: IL-23R (or IL-23Rα) and IL-12Rβ1. IL-23R is the unique receptor subunit for IL-23, composed of approximately 629 amino acids and containing an extracellular ligand-binding domain, a transmembrane region, and an intracellular signaling domain. IL-12Rβ1 is shared with IL-12 and consists of approximately 662 amino acids.

The binding of IL-23 to the receptor complex occurs sequentially: IL-23 first binds IL-23R with high affinity via the p19 subunit, inducing conformational changes that promote the interaction of the p40 subunit with IL-12Rβ1, ultimately forming a stable ternary complex. This sequential assembly mechanism is a hallmark of type I cytokine receptors and also provides multiple interface nodes for selective intervention.

Notably, the IL-23R gene has multiple splice variants encoding different isoforms of soluble IL-23R and membrane-bound IL-23R. Soluble IL-23R can act as a natural ligand trap, regulating the bioavailability of IL-23. Membrane-bound IL-23R is primarily expressed on the surface of immune cells such as memory T cells, Th17 cells, γδT cells, and ILC3.

Upon binding to the receptor complex, IL-23 induces the intracellular domains of IL-23R and IL-12Rβ1 to come into proximity, activating the non-covalently associated JAK kinases. Specifically, IL-23R couples with JAK2, while IL-12Rβ1 couples with TYK2. Receptor dimerization brings JAK2 and TYK2 into close proximity, leading to cross-phosphorylation and activation of their tyrosine kinase activity.

The activated JAK kinases then phosphorylate specific tyrosine residues on the intracellular tails of the receptors. For example, in IL-23R, phosphorylation of Tyr381, Tyr386, and other tyrosine sites creates docking sites for downstream signaling molecules containing SH2 domains. The most critical signaling molecule is STAT3. STAT3 binds to phosphorylated IL-23R via its SH2 domain and is subsequently phosphorylated by JAK2 at the Tyr705 residue. Phosphorylated STAT3 forms homodimers and translocates to the nucleus, where it binds to STAT3-responsive elements in the promoters of target genes, initiating a series of transcriptional programs.

In addition to STAT3, IL-23 signaling can weakly activate STAT4 and, in certain cell types, the PI3K-AKT and MAPK pathways. However, STAT3 is the dominant molecule mediating the biological functions of IL-23.

The core transcription factor activated by IL-23 signaling in T cells is STAT3, and its downstream target genes include:

RORC: encodes RORγt, the lineage-defining transcription factor for Th17 cells

IL-17A, IL-17F: effector cytokines of Th17 cells

IL-23R: autocrine positive feedback to enhance cellular sensitivity to IL-23

CCL20: a chemokine mediating Th17 cell migration to inflammatory sites

Thus, the functional integration of IL-23 includes: promoting the differentiation of naive CD4+ T cells into the Th17 phenotype, maintaining the survival and proliferation of differentiated Th17 cells, and enhancing the pathogenicity of Th17 cells (via upregulation of IL-23R and effector molecules). In non-T cells, IL-23 can activate innate lymphoid cells (ILC3) and γδT cells to produce IL-17A and IL-22.

As a drug target, IL-23 and its receptor exhibit the following key properties:

(1) Pathway node position: IL-23 is located upstream of the Th17 axis, and inhibiting IL-23 can block the production of multiple downstream effector molecules such as IL-17A, IL-17F, and IL-22, achieving broad-spectrum suppression. Compared to directly targeting IL-17A, upstream inhibition theoretically covers a more complex spectrum of pathogenic mediators.

(2) Cellular selectivity: IL-23R expression is limited to specific immune cell subsets (Th17, γδT, ILC3), with minimal impact on Th1, Th2, and other immune responses. This selectivity provides a relatively safe window for disease intervention.

(3) Targeting diversity: The IL-23 signaling axis can be targeted at multiple levels—neutralizing the ligand (anti-p19 or anti-p40 antibodies), blocking the receptor (anti-IL-23R antibodies or receptor antagonist peptides), interfering with intracellular kinases (JAK inhibitors), or transcription factors (RORγt inverse agonists). This offers a rich chemical and biological space for diverse drug development.

(4) Distinction from IL-12: Since IL-23 shares the p40 subunit with IL-12, early p40-targeting drugs (e.g., ustekinumab) simultaneously inhibited both pathways. The development of p19-selective inhibitors achieved specific blockade of IL-23 while preserving IL-12-mediated anti-infection and anti-tumor immune surveillance functions.

As the upstream command center of the Th17 immune response, the molecular structure, receptor assembly, and signal transduction mechanisms of IL-23/IL-23R have been thoroughly elucidated. The JAK2/TYK2-STAT3-RORγt-IL-17A signaling axis constitutes a complete pathway from extracellular ligands to nuclear transcriptional programs. Understanding the target biology of IL-23/IL-23R has directly driven the development of diverse drugs, including p19 monoclonal antibodies and oral receptor antagonist peptides.