IL23A - interleukin 23 subunit alpha |Elisa - Clia - Antibody - Protein

Background

Interleukin 23A (IL-23A), also referred to as IL-23, is a heterodimeric cytokine that plays a pivotal role in immune regulation, inflammation, and host defense. It is a member of the IL-12 cytokine family, which is integral to bridging the innate and adaptive immune systems. IL-23 is predominantly produced by antigen-presenting cells (such as dendritic cells and macrophages) and acts mainly on T cells, specifically promoting the differentiation, expansion, and maintenance of Th17 cells. IL-23 is essential for chronic inflammation and has been implicated in several autoimmune and inflammatory diseases, including psoriasis, rheumatoid arthritis (RA), Crohn’s disease, and multiple sclerosis (MS).

Unlike its close relative IL-12, which promotes Th1 responses and interferon-γ (IFN-γ) production, IL-23 plays a critical role in the IL-23/Th17 axis, influencing the production of IL-17 and other pro-inflammatory cytokines that contribute to tissue inflammation. Its functions underscore its significance in immune pathology, where dysregulated IL-23 signaling contributes to the onset and persistence of chronic inflammatory disorders.

Protein Structure

IL-23 is a heterodimeric cytokine, composed of two distinct subunits:

1. p19 subunit (IL-23A) – This subunit is unique to IL-23 and is encoded by the IL23A gene.
2. p40 subunit – This is shared with IL-12 and is encoded by the IL12B gene.

Primary Structure:

• The p19 subunit of IL-23 consists of 189 amino acids, while the p40 subunit consists of 328 amino acids.
• The p19 subunit contains several key structural domains required for receptor binding, and the p40 subunit provides stability and enhances the overall signaling potency of the heterodimer.

Secondary and Tertiary Structure:

• The p19 subunit adopts a four α-helix bundle configuration, typical of cytokine structures. This enables its interaction with specific receptor components.
• The p40 subunit comprises two domains, one of which includes immunoglobulin (Ig)-like folds, which contribute to receptor binding and cytokine function.
• The two subunits (p19 and p40) are non-covalently associated, and the functional cytokine is only active when both subunits are present.

Receptor Interaction:

IL-23 signals through a heterodimeric receptor complex composed of:

1. IL-23 receptor (IL-23R) – Specific for the p19 subunit of IL-23.
2. IL-12 receptor β1 (IL-12Rβ1) – Shared with IL-12 and responsible for binding the p40 subunit.

IL-23's interaction with its receptor initiates a cascade of intracellular signaling events, predominantly through the JAK-STAT pathway, primarily activating STAT3, with additional involvement of STAT4 in certain contexts. This signaling promotes the survival, expansion, and effector functions of Th17 cells, which are central to the production of pro-inflammatory cytokines like IL-17, IL-22, and TNF-α.

Classification and Subtypes

IL-23 belongs to the IL-12 cytokine family, which includes IL-12, IL-27, and IL-35. Cytokines in this family share structural similarities and receptor components (notably the shared p40 subunit between IL-12 and IL-23). However, IL-23 is unique in that it specifically promotes Th17 cell differentiation rather than Th1 responses, as seen with IL-12.

• Subunit Composition: The heterodimeric nature of IL-23 (p19 and p40 subunits) distinguishes it from other IL-12 family members, which are also composed of two subunits, though in different combinations.
• Receptor Usage: IL-23 binds to the IL-23R/IL-12Rβ1 receptor complex, whereas other family members have distinct receptor complexes (e.g., IL-12 binds IL-12Rβ1 and IL-12Rβ2).

Function and Biological Significance

IL-23's primary function is to regulate immune responses, particularly by influencing the Th17 cell subset of CD4+ T cells. Th17 cells produce a distinct set of cytokines, notably IL-17, which is involved in recruiting neutrophils and promoting inflammatory responses.

Major Functions:

Th17 Cell Differentiation and Expansion:

• IL-23 is essential for the maintenance and expansion of Th17 cells, a subset of helper T cells that produce IL-17. While TGF-β and IL-6 initiate Th17 differentiation, IL-23 is crucial for their stabilization and effector functions, particularly in chronic inflammatory settings.

Inflammatory Response:

• IL-23 promotes inflammation by inducing Th17 cells to secrete IL-17, IL-22, IL-6, and TNF-α, which recruit and activate immune cells, including neutrophils. This is particularly important in defense against extracellular pathogens (such as bacteria and fungi), but also contributes to pathological inflammation in autoimmune diseases.

Innate Immunity:

• Beyond its role in adaptive immunity, IL-23 also affects innate immune responses. It enhances the production of antimicrobial peptides (e.g., defensins) by epithelial cells, providing a protective barrier at mucosal surfaces, such as the skin, lungs, and gastrointestinal tract.

Tissue-Specific Roles:

• IL-23 is essential in maintaining the balance of immune responses in tissues like the gut, skin, and lungs. In the gastrointestinal tract, for example, IL-23 promotes the defense against gut pathogens but also contributes to intestinal inflammation in diseases like Crohn’s disease.

Chronic Inflammation and Autoimmunity:

• Dysregulated IL-23 signaling is a key driver of chronic inflammation and autoimmune diseases. The IL-23/Th17 axis has been implicated in the pathogenesis of conditions such as psoriasis, rheumatoid arthritis, multiple sclerosis, and inflammatory bowel diseases (Crohn’s disease and ulcerative colitis). IL-23 promotes sustained Th17 responses, which are associated with tissue damage in these diseases.

Clinical Issues

The role of IL-23 in promoting chronic inflammation has made it a key therapeutic target in autoimmune and inflammatory diseases. Elevated levels of IL-23 and overactivation of the IL-23/Th17 pathway are associated with several clinical conditions.

Diseases Associated with IL-23:

Psoriasis:

• IL-23 is highly implicated in the pathogenesis of psoriasis, a chronic inflammatory skin disease characterized by keratinocyte hyperproliferation and immune infiltration. IL-23 promotes the differentiation and activation of Th17 cells, which produce IL-17 and drive skin inflammation and lesion formation.

Inflammatory Bowel Disease (IBD)

• IL-23 plays a central role in Crohn’s disease, a type of inflammatory bowel disease characterized by chronic inflammation of the gastrointestinal tract. IL-23 contributes to the maintenance of pathogenic Th17 cells, which produce pro-inflammatory cytokines that promote intestinal inflammation and tissue damage.

Rheumatoid Arthritis (RA):

• In rheumatoid arthritis, elevated IL-23 levels are associated with increased Th17 responses, which contribute to joint inflammation and destruction. Targeting IL-23 has shown promise in reducing joint inflammation and slowing disease progression.

Multiple Sclerosis (MS):

• IL-23 is also involved in the pathogenesis of multiple sclerosis, where Th17 cells mediate neuroinflammation and contribute to the demyelination seen in the central nervous system.

Therapeutic Targeting of IL-23:

The recognition of IL-23’s role in these diseases has led to the development of therapeutic inhibitors targeting the IL-23 pathway. Monoclonal antibodies that specifically neutralize the IL-23 p19 subunit (without affecting IL-12) have shown efficacy in treating inflammatory diseases like psoriasis and Crohn’s disease. These therapies include:

• Ustekinumab: Targets both IL-12 and IL-23 by neutralizing the shared p40 subunit.
• Guselkumab, Tildrakizumab, and Risankizumab: Specifically target the IL-23 p19 subunit, providing selective inhibition of IL-23 without affecting IL-12, leading to improved therapeutic outcomes in autoimmune diseases.

Summary

IL-23A, as part of the IL-23 heterodimer, is a critical cytokine involved in immune regulation, particularly through its role in promoting Th17 cell responses. While essential for host defense against extracellular pathogens and maintaining mucosal barriers, dysregulated IL-23 signaling is a key driver of chronic inflammation and autoimmune diseases such as psoriasis, Crohn’s disease, and rheumatoid arthritis. The heterodimeric structure of IL-23, comprising the unique p19 subunit and the shared p40 subunit, allows for specific therapeutic targeting, which has already proven effective in treating several inflammatory conditions. Understanding the complex biology of IL-23 continues to guide the development of new therapies aimed at modulating immune responses in chronic diseases.