Interleukin-23 (IL-23) is a naturally occurring protein found in the human body, serving as a messenger within the immune system. Classified as a cytokine, this protein plays a part in regulating various immune responses. IL-23 helps direct how immune cells communicate and react to different stimuli. Understanding this molecule offers insights into how the body manages its defenses.
Defining Interleukin-23
Interleukin-23 is characterized as a heterodimeric cytokine, meaning it is formed from two distinct protein subunits: p19 and p40. While the p40 subunit is also a component of another cytokine, IL-12, the presence of the unique p19 subunit gives IL-23 its specific functions, setting it apart from IL-12. The formation of a biologically active IL-23 requires both p19 and p40 subunits to be synthesized within the same cell.
Primary producers of IL-23 are specialized immune cells such as activated macrophages and dendritic cells, which are types of antigen-presenting cells often found in peripheral tissues like the skin, intestines, and lungs. Other immune cells, including monocytes, innate lymphoid cells, and certain T cells, also contribute to its production. The secretion of IL-23 is triggered by an antigen stimulus recognized by pattern recognition receptors.
The IL-23/Th17 Immune Pathway
IL-23’s primary function is promoting the survival and expansion of a specific group of immune cells known as T helper 17 cells (Th17). These Th17 cells are a specialized part of the immune response, playing a role in combating certain infections, particularly those caused by extracellular bacteria and fungi. When IL-23 binds to its receptor, it signals Th17 cells to become active. This binding activates specific signaling pathways, inducing the transcription of various genes related to Th17 cells.
Activated Th17 cells then produce their own inflammatory molecules, including IL-17A, IL-17F, IL-21, IL-22, and granulocyte-macrophage colony-stimulating factor (GM-CSF). These molecules amplify the inflammatory cascade and contribute to host defense mechanisms, especially at mucosal barriers and in the skin. IL-23 then stabilizes the Th17 phenotype, helping these cells to persist and continue their immune activities.
Role in Autoimmune Diseases
While the IL-23/Th17 pathway is beneficial for fighting infections, its overactivation can contribute to chronic inflammation and autoimmune diseases. Elevated levels of IL-23 are observed in the inflamed tissues of individuals with various autoimmune conditions. This sustained overproduction of IL-23 drives a continuous inflammatory cycle that underpins these diseases.
In psoriasis, a skin condition characterized by rapid skin cell growth, the IL-23/Th17 pathway is a driver of the disease. Increased IL-23 activates Th17 cells, which then produce IL-17 and other cytokines. These molecules promote the excessive proliferation of keratinocytes, the main cells of the skin, leading to the characteristic thickened, scaly plaques.
Psoriatic arthritis also involves the overactivity of the IL-23/Th17 axis. IL-23 directly affects the entheses and the synovium. This leads to bone changes and inflammation in the joints.
In inflammatory bowel diseases (IBD), such as Crohn’s disease and ulcerative colitis, IL-23 plays a part in gut lining inflammation. IL-23 promotes the differentiation and maintenance of Th17 cells in the intestinal lamina propria. These Th17 cells contribute to persistent inflammation and tissue damage by releasing pro-inflammatory cytokines like IL-17 and IL-22. Genetic variations in the IL-23 receptor gene have been linked to susceptibility or protection from IBD, reinforcing IL-23’s involvement in these conditions.
Therapeutic Inhibition of IL-23
Given IL-23’s role in autoimmune diseases, scientists have developed a class of targeted medications called IL-23 inhibitors. These drugs are monoclonal antibodies designed to neutralize IL-23. They work by binding to the p19 subunit of IL-23, preventing it from interacting with its receptor on immune cells.
By blocking IL-23, these inhibitors disrupt the inflammatory cascade upstream of Th17 cell activation, reducing the production of downstream inflammatory molecules like IL-17. This targeted approach helps to dampen the chronic inflammation that drives conditions such as psoriasis, psoriatic arthritis, and inflammatory bowel diseases, leading to improved symptoms and tissue healing. Examples of such inhibitors include guselkumab, risankizumab, and tildrakizumab, which are effective for these conditions.