IL12B - interleukin 12B |Elisa - Clia - Antibody - Protein

Background

Interleukin-12 (IL-12) is a crucial cytokine in the regulation of immune responses, primarily produced by antigen-presenting cells such as macrophages, dendritic cells, and B cells. IL-12 is a heterodimeric cytokine composed of two distinct subunits: IL-12A (p35) and IL-12B (p40). While IL12A is necessary for biological activity, IL-12B plays a vital role in structural integrity and receptor binding. Together, they form the bioactive cytokine IL-12p70, which promotes the differentiation of naïve T cells into T-helper 1 (Th1) cells. This Th1 response is critical for cellular immunity, especially against intracellular pathogens such as viruses, certain bacteria, and protozoa.

In addition to forming IL-12p70, the IL12B subunit is also involved in the formation of IL-23, another key cytokine that drives Th17 cell differentiation and plays an important role in inflammatory and autoimmune responses. The pleiotropic roles of IL-12B in both IL-12 and IL-23 cytokine complexes highlight its essential contribution to both immune defense and the pathogenesis of immune-mediated diseases.

Protein Structure

The IL-12B protein, also referred to as p40, is a glycosylated protein with a molecular weight of approximately 40 kDa and is composed of 328 amino acids. It belongs to the type I cytokine receptor family and has structural features that are integral to its function in immune signaling.

Key Structural Features:

• Domain Organization: IL-12B comprises several important structural domains, including two fibronectin type III domains. These domains facilitate interactions with its receptor and with other cytokine subunits. The fibronectin domains also allow for the dimerization with IL-12A or p19 (the IL-23 subunit).
• Four-Helix Bundle: Like other members of the cytokine family, IL-12B adopts a four-helix bundle structure, which is crucial for its ability to bind to cytokine receptors. The four helices are organized in a characteristic "up-up-down-down" configuration, a common motif for cytokines involved in immune regulation.
• Glycosylation: IL-12B is extensively glycosylated at several asparagine residues, which is important for its stability, secretion, and receptor interactions. Glycosylation helps protect the protein from proteolytic degradation and assists in its proper folding.
• Dimerization: One of the most critical functions of IL-12B is its ability to dimerize with other subunits. In the case of IL-12p70, IL-12B (p40) forms a heterodimer with IL-12A (p35), whereas in IL-23, IL-12B dimerizes with p19. These dimerization events are essential for the biological activity of both cytokines.
• Receptor Binding: IL-12B primarily interacts with the IL-12 receptor beta 1 (IL-12Rβ1) subunit, which is shared between the IL-12 and IL-23 receptor complexes. IL-12B's binding to IL-12Rβ1 allows the subsequent recruitment of the IL-12 receptor beta 2 (IL-12Rβ2) subunit in the case of IL-12, or the IL-23 receptor in the case of IL-23, facilitating downstream signal transduction via the Jak-STAT pathway.

The three-dimensional structure of IL-12B, along with its ability to form heterodimers with other cytokine subunits, underpins its critical role in mediating immune responses and its involvement in various immune-related diseases.

Classification and Subtypes

IL-12B belongs to the IL-12 cytokine family, which includes IL-12, IL-23, IL-27, and IL-35. These cytokines share structural similarities and are involved in regulating immune responses, particularly in shaping T cell differentiation.

• IL-12p70: The canonical IL-12 heterodimer is composed of IL-12A (p35) and IL-12B (p40). This complex is responsible for promoting Th1 differentiation and stimulating IFN-γ production.
• IL-23: IL-12B also dimerizes with p19, another cytokine subunit, to form IL-23. IL-23 is distinct from IL-12 in its function, primarily promoting the differentiation and maintenance of Th17 cells, which are involved in inflammatory and autoimmune diseases.

IL-12B does not have any true subtypes, but its ability to combine with different cytokine subunits (p35 or p19) allows it to participate in multiple cytokine complexes with distinct immune-modulating functions.

Function and Biological Significance

IL-12B’s primary biological function is in the formation of the IL-12p70 and IL-23 cytokines. These cytokines play essential roles in immune responses, particularly in driving T cell differentiation, enhancing NK cell activity, and promoting pro-inflammatory responses.

Functions of IL-12B-Containing Cytokines:

IL-12p70 Functions:

• Th1 Differentiation: IL-12p70 is essential for the differentiation of naïve CD4+ T cells into Th1 cells, which are characterized by their production of IFN-γ. Th1 cells are critical for cell-mediated immunity, particularly in controlling intracellular pathogens.
• IFN-γ Production: IL-12p70 stimulates the production of IFN-γ by both T cells and NK cells. IFN-γ enhances the ability of macrophages to kill phagocytosed pathogens and boosts antigen presentation by upregulating MHC class I and II molecules.
• Cytotoxic Activity: IL-12p70 enhances the cytotoxic function of NK cells and cytotoxic T lymphocytes (CTLs), promoting the killing of infected or malignant cells. This activity is vital for controlling viral infections and tumor growth.
• Anti-Tumor Responses: IL-12p70 has potent anti-tumor effects due to its ability to stimulate Th1 responses and enhance cytotoxic immune cell activity. It has been investigated as a potential therapeutic agent in cancer immunotherapy.

IL-23 Functions:

• Th17 Differentiation: IL-23 is primarily responsible for the differentiation and maintenance of Th17 cells, a subset of T cells involved in mediating pro-inflammatory responses. Th17 cells are critical for controlling extracellular bacterial and fungal infections.
• Inflammatory Responses: IL-23 promotes the production of pro-inflammatory cytokines such as IL-17, which drives neutrophil recruitment to sites of infection or inflammation. IL-23 and IL-17 are key players in autoimmune and chronic inflammatory diseases.

Biological Significance:

The functional versatility of IL-12B-containing cytokines (IL-12 and IL-23) makes IL-12B a key player in various physiological and pathological contexts.

• Host Defense: IL-12p70 is critical for controlling infections caused by intracellular pathogens such as Mycobacterium tuberculosis, Listeria monocytogenes, and various viruses. IL-23, on the other hand, is essential for defending against extracellular bacteria and fungi, particularly at mucosal surfaces.
• Autoimmunity and Inflammation: Dysregulation of IL-12 or IL-23 can lead to autoimmune diseases. Excessive IL-12-driven Th1 responses contribute to conditions like type 1 diabetes and multiple sclerosis, whereas excessive IL-23/Th17 responses are associated with diseases such as psoriasis, Crohn’s disease, and rheumatoid arthritis.

Clinical Issues

Given its crucial role in immune regulation, IL-12B has been implicated in several clinical conditions. Both overproduction and deficiencies of IL-12B-containing cytokines are associated with immune-mediated diseases.

Overproduction of IL-12 or IL-23:

• Autoimmune Diseases: Increased levels of IL-12 or IL-23 are associated with autoimmune diseases. In Crohn’s disease, for example, elevated IL-12 and IL-23 levels promote excessive Th1 and Th17 activity, leading to chronic intestinal inflammation. Similarly, in psoriasis, IL-23 drives the activation of pathogenic Th17 cells, leading to skin inflammation and keratinocyte proliferation.
• Chronic Inflammatory Diseases: IL-23 has been strongly implicated in chronic inflammatory diseases, particularly those involving mucosal surfaces, such as ulcerative colitis. The IL-23/IL-17 axis is central to the pathology of these diseases.

Deficiency in IL-12 or IL-23:

• Increased Susceptibility to Infections: Deficiencies in IL-12B, either due to genetic mutations or impaired cytokine production, can result in primary immunodeficiency syndromes. Patients with mutations in the IL-12B gene or its receptor (IL-12Rβ1) suffer from recurrent infections, particularly by intracellular pathogens like Mycobacterium and Salmonella. These individuals have impaired Th1 and IFN-γ responses, leading to inadequate macrophage activation and pathogen clearance.

Therapeutic Applications:

• Autoimmune Disease Treatments: Given its role in autoimmune and chronic inflammatory diseases, targeting IL-12B or its receptor components has become a therapeutic strategy. The monoclonal antibody ustekinumab targets both IL-12 and IL-23 signaling by blocking the IL-12B subunit, and it has been approved for the treatment of psoriasis, psoriatic arthritis, and Crohn’s disease.
• Cancer Immunotherapy: IL-12 has shown promise in cancer immunotherapy due to its ability to promote anti-tumor immunity. However, its use has been limited by toxicity concerns, and researchers are exploring safer delivery methods, including gene therapy approaches.

Summary

IL-12B (p40) is a pivotal component of the IL-12 and IL-23 cytokine complexes, playing a central role in regulating immune responses. Its ability to promote Th1 and Th17 differentiation underpins its involvement in host defense mechanisms against intracellular and extracellular pathogens. Dysregulation of IL-12B-containing cytokines is associated with autoimmune diseases, chronic inflammatory conditions, and immune deficiencies. Targeting IL-12B with therapeutic interventions, such as monoclonal antibodies, holds great potential for treating autoimmune diseases and enhancing anti-tumor immunity. Ongoing research continues to explore the therapeutic possibilities of modulating IL-12 and IL-23 pathways to treat a range of diseases.