Interleukin 23Edit

Interleukin 23 (IL-23) is a cytokine of the immune system that sits at a pivotal junction between defense and inflammation. It is a heterodimer in the IL-12 family, composed of a p19 subunit paired with a p40 subunit that it shares with IL-12. IL-23 is produced mainly by activated antigen-presenting cells such as Dendritic cells and Macrophages in response to microbial stimuli, and it signals through a receptor complex made up of IL-23R and IL-12Rβ1 on target cells. Through this signaling axis, IL-23 promotes the maintenance and expansion of TH17 cells, a lineage of helper T cells that secrete inflammatory cytokines such as Interleukin-17 and Interleukin-22, thereby shaping both protective immunity at barrier sites and pathogenic inflammation when dysregulated. In health, the IL-23/TH17 axis contributes to mucosal defense and tissue homeostasis; in disease, overactivity of this axis has been linked to several autoimmune and inflammatory conditions, making IL-23 a central target in modern immunotherapy.

Biology and function

Structure and signaling

IL-23 is a heterodimer formed by a p19 subunit and a p40 subunit; the p40 subunit is shared with IL-12, a related cytokine that drives TH1 responses. The gene encoding p40 is IL12B, and the dual specificity of IL-12 and IL-23 is a key feature that has influenced therapeutic development. IL-23 engages the receptor complex comprised of IL-23 receptor and IL-12 receptor beta 1 on various Immune cell, including TH17 cells and innate lymphoid cells. Signal transduction proceeds through the JAK-STAT pathway, with STAT3 as a central transcriptional mediator, leading to transcription of cytokines such as Interleukin-17 and Interleukin-22 among others. This signaling network links extracellular detection of microbial cues to the amplification of pro-inflammatory programs.

Cellular targets and roles

The principal cellular targets of IL-23 include TH17 cells, but several other cell types, including innate lymphoid cells (especially ILC3) and γδ T cells, respond to IL-23. By sustaining TH17 cells, IL-23 promotes the production of IL-17A, IL-17F, and IL-22, cytokines that help recruit neutrophils and bolster mucosal defenses. At the same time, inappropriate or chronic activation of this axis can fuel tissue-destructive inflammation. The IL-23/TH17 axis interacts with other inflammatory pathways, and its activity is modulated by signals from the microbiota, barrier integrity, and other cytokines such as IL-6 and IL-1β. For a broader view of the cytokine network, see Cytokine signaling and the IL-12 family Interleukin-12.

Normal physiology and host defense

In healthy individuals, IL-23 contributes to rapid, localized responses to microbial invasion at barrier surfaces like the skin and gut. It helps coordinate defense against extracellular pathogens and supports the maintenance of barrier-associated immune cells. This role is particularly evident in mucosal tissues, where IL-23 helps balance protective responses with the risk of collateral tissue damage. Disruption of this balance, whether by genetics, environmental factors, or chronic infection, can tilt toward chronic inflammation and disease.

Role in health and disease

Autoimmune and inflammatory diseases

Because IL-23 drives TH17-mediated inflammation, it has been implicated in a range of conditions characterized by persistent tissue inflammation. Notable diseases in which the IL-23 axis features prominently include psoriasis, psoriatic arthritis, and various forms of inflammatory bowel disease such as Crohn's disease and ulcerative colitis. Other inflammatory diseases, including ankylosing spondylitis and some forms of arthritis, have also been linked to IL-23–driven pathways. The common thread across these diseases is an inflammatory milieu in which IL-23 sustains TH17 cells and their effector cytokines.

Differences from IL-12 and the broader cytokine milieu

Historically, IL-12 and TH1 responses were considered central to many inflammatory conditions. The discovery of IL-23 revealed a distinct pathway that can drive inflammation independently of, or in concert with, TH1 responses. Therapeutic strategies that target IL-23 or its receptor can modulate disease activity while preserving some aspects of host defense, reflecting a nuanced balance between dampening pathology and maintaining protection. In this context, therapies that specifically target IL-23 or its p19 subunit can differ in effect from those that block both IL-12 and IL-23 (which target the shared p40 subunit), with implications for efficacy and safety in various diseases.

Therapeutic targeting

IL-23–directed therapies

The central role of IL-23 in many inflammatory diseases has spurred the development of targeted therapies, particularly monoclonal antibodies against the IL-23 axis. Antibodies that specifically block the p19 subunit (thereby inhibiting IL-23 while leaving IL-12 signaling intact) include Guselkumab (brand name Tremfya), Risankizumab (Skyrizi), and Tildrakizumab (Ilumya). These agents have demonstrated robust efficacy in plaque psoriasis and have expanded use in other IL-23–driven diseases such as psoriatic arthritis and axial spondyloarthritis, with ongoing evaluations in inflammatory bowel diseases.

A broader strategy blocks the shared p40 subunit, inhibiting both IL-12 and IL-23. Ustekinumab (Stelara) is a leading example, approved for multiple indications including plaque psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis. This dual blockade can confer benefits in conditions where IL-12 also contributes to pathology, but it may carry different safety and efficacy profiles compared to p19-selective inhibitors.

Clinical implications and safety

Clinical trials and real-world experience with IL-23 pathway inhibitors show meaningful improvements in skin, joint, and intestinal disease activity for many patients. Relative to some broader immunosuppressants, IL-23–targeted therapies often have favorable safety profiles, with lower rates of certain infections and malignancies in some populations, though long-term data continue to accumulate. Potential risks include infection, perturbations of mucosal immunity, and the possibility of diminished defense against opportunistic pathogens. Decisions about therapy are individualized, balancing disease burden, prior treatments, comorbidities, and patient preferences. See Biologic therapy and Monoclonal antibody for related concepts and examples of therapeutic modalities.

Controversies and debates

From a practical, policy-informed vantage, IL-23 biology sits at the intersection of medical innovation, patient access, and public health. Several debates commonly surface in clinical and policy discussions:

IL-23 vs IL-12/23 blockade and disease management There is ongoing dialogue about whether targeting IL-23 alone (p19 inhibitors) provides equal or superior outcomes compared with blocking both IL-12 and IL-23 (p40 inhibitors) across different diseases. Trials comparing these approaches suggestthat IL-23–specific therapies can achieve substantial disease control while potentially preserving some IL-12–driven protective responses. This nuance matters when selecting therapy for diseases where TH1 responses matter for protection, and it underlines the value of precision medicine within autoimmune conditions. See Interleukin-12 and Guselkumab for concrete examples.
Cost, access, and the economics of breakthrough biologics Biologic therapies targeting IL-23 are among the more expensive treatments in modern medicine. A common policy question is how to reconcile high upfront costs with long-term gains in quality of life, reduced disability, and decreased downstream healthcare spending. Advocates of market-based solutions argue that competition among agents, the introduction of biosimilars, and value-based pricing can lower costs without sacrificing innovation. Critics emphasize the need for broad access and argue that government interventions or price controls can dampen innovation. From a pragmatic standpoint, a balanced approach—protecting intellectual property to incentivize breakthroughs while promoting payer competition and transparent value assessments—tends to maximize patient access without sacrificing future research. See Biosimilar and Health economics.
Safety, long-term effects, and the defense of mucosal immunity Suppressing the IL-23 axis raises concerns about long-term immune competence, particularly at barrier surfaces. While IL-23 inhibitors have generally favorable safety records in the short to mid term, some critics worry about rare infections, cancer risk, or unintended immune consequences over many years of therapy. Proponents counter that targeted, pathway-specific therapies can reduce disease activity with less broad immunosuppression than older drugs, and that ongoing pharmacovigilance and real-world data help refine risk–benefit assessments. See Infection and Autoimmune disease for broader context on safety considerations.
The role of behavioral and lifestyle factors in autoimmune disease management A conservative framing of healthcare policy emphasizes evidence-based medical therapies alongside prevention, lifestyle modification, and early intervention. Critics of “do more with drugs” approaches argue for aggressive emphasis on lifestyle, diet, and preventive screening as cost-effective strategies. Supporters note that for many patients with established disease, targeted therapies such as IL-23 inhibitors can dramatically reduce symptoms and improve function, sometimes enabling reductions in other medications and improving work and daily living outcomes. See Clinical trial and Quality of life for related considerations.
The balance between innovation and access in a free-market framework The development of IL-23 inhibitors exemplifies a broader tension: protecting the incentives that drive breakthrough therapies while ensuring affordable access for patients who need them. Proponents of a market-driven framework argue that robust intellectual property protections and competitive pressures spur innovation and keep the pharmaceutical ecosystem dynamic. Critics may press for broader price negotiation, government funding, or direct-to-consumer policy changes. The practical stance often follows a middle path: maintain strong incentives for innovation, while employing targeted policies (such as subsidies or value-based pricing) to expand access for patients with high disease burden.