Interleukin 23: Function, Role in Disease, and Treatment

Interleukin-23 is an immune signaling molecule that helps coordinate the body’s inflammatory response, and it has become one of the most important drug targets in modern medicine for autoimmune and inflammatory conditions. It is a two-part protein made up of a subunit called p19 paired with a subunit called p40, and it acts as a key driver of a branch of immunity linked to chronic inflammation in diseases like psoriasis, inflammatory bowel disease, and psoriatic arthritis.¹ Understanding what IL-23 does in the body, how it contributes to disease, and how blocking it can produce lasting remission reveals why this molecule has reshaped treatment for millions of people.

What IL-23 Is and How It Signals

IL-23 belongs to a family of immune messengers called cytokines. Its structure is a pairing of two protein chains: p19, which is unique to IL-23, and p40, which it shares with a related cytokine called IL-12. That shared p40 subunit is important because it means IL-12 and IL-23 overlap in some of their biology but drive very different downstream effects. IL-12 pushes the immune system toward one type of response (driven by Th1 cells), while IL-23 promotes a distinct inflammatory response (driven by Th17 cells).²

IL-23 is produced mainly by dendritic cells and macrophages, types of immune cells that serve as sentinels for infection. These cells release IL-23 when they detect microbial signals. For example, components of the tuberculosis bacterium trigger IL-23 production through specific pattern-recognition receptors, and yeast-derived molecules do the same through a receptor called dectin-1.³ The body also has built-in brakes. An enzyme called protein phosphatase 2A specifically dials down IL-23 production without affecting IL-12, which hints at how tightly the immune system tries to regulate these two related but functionally different signals.²

Once released, IL-23 binds to a receptor complex on the surface of target cells. That receptor is made of two pieces: the IL-23 receptor (IL-23R) and IL-12 receptor β1, which is another component shared with the IL-12 system.⁴ When IL-23 locks onto this receptor, it activates internal signaling pathways that turn on genes involved in inflammation. This signaling cascade has itself become a target for drug development, since interrupting it at various points can dampen the inflammatory chain reaction.

The Th17 Connection

The most well-known job of IL-23 in the immune system is sustaining a population of immune cells called Th17 cells. These cells produce inflammatory molecules, most famously IL-17, and are involved in defending against certain infections at barrier surfaces like the skin and gut. IL-23 was originally thought to be the cytokine that created Th17 cells from scratch, but the picture turned out to be more nuanced. Naïve immune cells that have never encountered a threat do not even have the receptor for IL-23, so they cannot respond to it. Other signals, particularly IL-6 and TGF-β, are the ones that initially push naïve cells toward the Th17 identity.⁵

Where IL-23 becomes essential is in keeping Th17 cells active and maintaining their inflammatory character over time. Without IL-23, Th17 cells are surprisingly unstable. They can be coaxed into abandoning their identity and switching to produce the cytokines of other immune cell types instead. IL-23, especially when working alongside another inflammatory signal called IL-1β, locks Th17 cells into their inflammatory program through repeated rounds of activation.⁶ This maintenance role is why IL-23 is so central to chronic inflammatory diseases: it keeps the inflammatory cells going long after the initial trigger has passed.

IL-23 also acts on cells beyond Th17. It activates a group of innate immune cells called innate lymphoid cells (ILCs), which can produce IL-22, IL-17, and other inflammatory mediators in tissues like the gut. In animal models, gut-specific IL-23 expanded these ILC populations and drove them to produce a cocktail of inflammatory molecules.⁷ This means IL-23’s inflammatory reach extends well beyond the Th17 cells it is best known for.

Host Defense Against Infection

Despite its reputation as a troublemaker in autoimmune disease, IL-23 plays a genuinely protective role when the body faces certain infections. This is especially clear in fungal infections. Mice that lack IL-23 are extremely vulnerable to systemic infection with the yeast Candida albicans. Research showed that without IL-23, immune cells called myeloid cells die off rapidly in the infected kidney, leading to unchecked fungal growth and severe tissue damage. Remarkably, this protective effect operates independently of the IL-17 pathway and does not require lymphocytes at all. IL-23 directly prevents myeloid cells from undergoing programmed cell death during infection.⁸

This finding matters for patients receiving drugs that block IL-23. While clinical safety data have been reassuring so far, the biology suggests that clinicians should remain attentive to fungal infections in people on long-term IL-23 blockade, particularly those with other risk factors for immune suppression.

IL-23 in Autoimmune and Inflammatory Disease

The diseases most strongly linked to IL-23 overactivity are psoriasis, inflammatory bowel disease, and spondyloarthritis (a group that includes psoriatic arthritis and ankylosing spondylitis). In each of these conditions, the IL-23/Th17 pathway is chronically overactive, driving tissue damage and persistent inflammation.⁹

In Crohn’s disease, a form of inflammatory bowel disease, levels of the IL-23 p19 subunit are markedly elevated in inflamed gut tissue. The degree of elevation tracks with how severe the intestinal damage looks on endoscopy.¹⁰ A genetic angle reinforces the connection: variants in the IL-23 receptor gene influence who gets inflammatory bowel disease. One variant, Arg381Gln, is strongly protective against Crohn’s disease. People who carry this variant have roughly two-and-a-half times lower odds of developing Crohn’s compared to those who do not, and a weaker but still measurable protective effect shows up in ulcerative colitis as well.¹¹ Variants in the same receptor gene are also linked to risk for psoriasis and ankylosing spondylitis.¹²

In psoriasis, the link runs through skin-resident memory Th17 cells. These cells linger in the skin even after a flare has cleared and are ready to reignite inflammation at the first provocation. Locally produced IL-23 is what keeps these memory cells alive, driving their proliferation directly within skin tissue. When researchers blocked the IL-23 receptor in both mice and human patients, these resident memory Th17 cells were depleted from the skin, which helps explain why anti-IL-23 treatments can produce durable remissions rather than just temporary symptom relief.¹³

IL-23 and Cancer

The relationship between IL-23 and cancer is counterintuitive if you know only its role in autoimmune disease. Where IL-12 (its molecular sibling) tends to promote antitumor immunity, IL-23 generally does the opposite. It appears to suppress the immune system’s ability to fight tumors and to promote tumor growth and spread.¹⁴ Animal studies have shown that IL-23 suppresses innate immune surveillance against tumors, and this effect is broader than just working through IL-17. IL-23 antagonizes antitumor responses primarily by dampening innate immunity, promoting both tumor development and metastasis independently of the Th17 axis.¹⁵

This creates an interesting therapeutic tension. Blocking IL-23 to treat autoimmune disease could, in theory, be beneficial from a cancer-surveillance standpoint by removing one brake on innate antitumor immunity. But the clinical data on cancer rates in patients taking IL-23 blockers has not shown a clear signal either way, which suggests that real-world human cancer biology involves many more variables than any single cytokine pathway.

Cardiovascular Disease

Elevated IL-23 levels have also been found in the bloodstream of people with atherosclerosis in the carotid arteries. In a study of patients with carotid plaques, IL-23 levels were significantly higher than in healthy controls, and the highest levels appeared in people with the most recent symptoms. The IL-23 receptor was also heavily expressed within the plaques themselves, localizing to macrophages embedded in the vessel wall. High plasma levels of IL-23 were associated with increased mortality during follow-up.¹⁶ More broadly, patients with cardiovascular disease tend to show elevated blood levels of several IL-12 family cytokines, including IL-23.¹⁷ Whether IL-23 is actively driving plaque instability or simply reflecting an inflammatory state remains an open question, but the association has drawn interest from cardiologists and immunologists alike.

Drugs That Block IL-23

The recognition that IL-23 drives chronic inflammation led to a wave of biologic drugs designed to neutralize it. These drugs fall into two categories based on which part of IL-23 they target.

The first drug in this space was ustekinumab, a monoclonal antibody that binds the p40 subunit shared by IL-12 and IL-23. By grabbing p40, ustekinumab blocks both cytokines from engaging their receptors. It is approved for moderate-to-severe psoriasis, psoriatic arthritis, and Crohn’s disease, and it proved effective in patients who had failed other treatments including methotrexate, cyclosporine, and phototherapy.¹⁸¹⁹

The second generation of drugs targets the p19 subunit, which is unique to IL-23. This means they block IL-23 while leaving IL-12 untouched. Three p19 inhibitors are now widely used: guselkumab, risankizumab, and tildrakizumab. Each is a monoclonal antibody given by injection.²⁰²¹ Head-to-head evaluations have found that drugs specifically targeting IL-23 or IL-17 tend to produce better clinical outcomes than older approaches that block both IL-12 and IL-23 together, or that block TNF.²²

Although these three p19 inhibitors all block the same subunit, they do it in structurally distinct ways. Structural analysis has shown that risankizumab grabs the largest patch of the p19 surface, while guselkumab’s binding site overlaps most heavily with the spot where the IL-23 receptor itself attaches. Tildrakizumab binds a smaller, non-overlapping area. Despite these differences, all three prevent IL-23 from activating its receptor, likely through a combination of directly competing for the receptor-binding site and physically blocking access to it.²³

Safety Profile of p19 Inhibitors

Given that IL-23 plays a real role in fighting infections and potentially in cancer surveillance, a natural concern is whether blocking it long-term causes problems. The clinical safety record has been reassuring. Across long-term trial data, rates of serious adverse events, serious infections, skin cancers, other malignancies, major cardiovascular events, and severe allergic reactions were not elevated with extended use of p19 inhibitors. Selective IL-23 blockade was also not associated with higher rates of opportunistic infections, tuberculosis reactivation, oral yeast infections, or new-onset inflammatory bowel disease.²⁴ This favorable profile is one reason p19 inhibitors have moved to the front of the treatment lineup for psoriasis and are gaining ground in other conditions.

In psoriatic arthritis specifically, a study emulating a head-to-head trial found that TNF inhibitors, IL-17 inhibitors, and IL-23 p19 inhibitors all performed comparably after twelve months, with the p19 inhibitors trending slightly better overall. The authors concluded that all three classes could be considered equally effective, which shifts the conversation toward matching the right drug to the right patient rather than picking a universally “best” class.²⁵

The Move Toward Oral IL-23 Blockade

All approved IL-23 blockers today are injectable antibodies, which is a barrier for some patients. A significant development in the pipeline is icotrokinra, the first oral drug designed to selectively block the IL-23 receptor. Rather than binding IL-23 itself (as the injectable antibodies do), icotrokinra is a small cyclic peptide that attaches to the IL-23 receptor on immune cells, preventing IL-23 from activating them.²⁶

In phase 3 trials for moderate-to-severe psoriasis, icotrokinra beat placebo at achieving clear or nearly clear skin and at least 90% improvement in psoriasis severity at sixteen weeks. It also outperformed deucravacitinib, an existing oral drug with a different mechanism, at twenty-four weeks. Sustained efficacy was observed through a year of treatment in extension studies, with a favorable safety profile and minimal potential for interactions with other medications.²⁷ If approved, icotrokinra would mark a meaningful shift in how IL-23-driven diseases are managed, giving patients a pill that achieves the kind of targeted immune modulation previously available only through injections.

Predicting Who Will Respond

Not everyone responds equally to IL-23-targeted therapy, and researchers are working to figure out why. One approach looks at blood biomarkers before treatment starts. In a study of guselkumab for psoriatic arthritis, patients who responded well had higher baseline levels of certain inflammatory markers, including IL-17A and a skin antimicrobial peptide called beta-defensin 2, compared to those who did not respond.²⁸ The logic is intuitive: patients whose disease is most heavily driven by the IL-23/IL-17 axis are the ones who benefit most when you block that axis.

In Crohn’s disease, researchers have taken a different approach, looking at gene expression patterns in gut tissue. A set of thirteen genes expressed in the intestinal lining predicted with high accuracy whether patients treated with ustekinumab would achieve mucosal healing. Two genes in particular, LCN2 and KDM5D, held up as effective predictive markers when tested in an independent group of patients.²⁹ These kinds of molecular readouts are still mostly research tools, but they point toward a future where the choice of biologic drug is informed by each patient’s specific biology rather than trial and error.

How Old Is This System

IL-23 is not a recent evolutionary invention, though different parts of its machinery appeared at very different times. A phylogenetic analysis across hundreds of species found that the receptors used by the IL-12 family of cytokines originated before the era of mollusks, somewhere between roughly 500 and 700 million years ago. The ligand subunit p19, which is the piece unique to IL-23, appeared much later, during the emergence of mammals and birds around 180 to 225 million years ago. The analysis also identified three structural motifs within the receptor that have remained essentially unchanged across vast evolutionary distances, suggesting they are critical for the receptor-ligand interaction to work properly.³⁰ The implication is that the receptor infrastructure was repurposed over hundreds of millions of years, with newer ligands like p19 being layered on top of ancient scaffolding to fine-tune immune responses in warm-blooded animals. It is a reminder that the immune pathways we now target with precision drugs were built by evolutionary tinkering on a timescale that dwarfs human medicine.