IL4 - interleukin 4 |Elisa - Clia - Antibody - Protein

Background

Interleukin-4 (IL-4) is a crucial cytokine in the immune system, primarily involved in the regulation of humoral (antibody-mediated) immune responses and the differentiation of immune cells. It is produced by several immune cells, including activated CD4+ T cells (specifically Th2 cells), mast cells, basophils, eosinophils, and, to a lesser extent, CD8+ T cells. IL-4 is a member of the interleukin family of cytokines and plays a key role in driving the differentiation of naïve helper T cells (Th0) into Th2 cells, which are central to the adaptive immune response. This cytokine is also vital in inducing B cell class switching to immunoglobulin E (IgE), a process essential for allergic reactions.

In addition to its immune-regulatory functions, IL-4 is heavily involved in allergic diseases such as asthma, allergic rhinitis, and atopic dermatitis. IL-4 mediates a wide range of biological effects that contribute to inflammation, allergy, and immune system modulation. It functions by binding to specific receptors on the surface of target cells, initiating intracellular signaling cascades that regulate gene expression and cellular functions.

Protein Structure

IL-4 is a small glycoprotein with a molecular weight of approximately 15–19 kDa, consisting of 129 amino acids in its mature form. The structure of IL-4 belongs to the four-helix bundle family of cytokines, characterized by four alpha-helices arranged in an up-up-down-down configuration, similar to other cytokines like IL-2, IL-3, and IL-5.

Key structural elements of IL-4 include:

• Four α-Helix Bundle: The four helices are the primary structural motifs of IL-4, forming a compact, globular structure. The helices are stabilized by hydrophobic interactions between residues in the core of the protein. The overall structure is highly conserved among members of the cytokine family.
• Disulfide Bonds: IL-4 contains three disulfide bonds (between cysteine residues), which are crucial for the stabilization of its tertiary structure. These bonds help maintain the functional conformation necessary for receptor binding and biological activity. The disulfide bonds bridge helices, providing the structural rigidity that enables proper receptor interaction.
• Receptor Binding: IL-4 interacts with its receptor, IL-4R, through well-defined regions on its surface. The IL-4 receptor is a heterodimer that consists of two subunits:

1. IL-4Rα: The IL-4-specific receptor chain.
2. γc (Common gamma chain): A shared subunit also used by other cytokines like IL-2, IL-7, and IL-9.

When IL-4 binds to the IL-4Rα chain, it induces receptor dimerization, activating downstream signaling cascades. In some cases, IL-4 can also signal through the type II receptor complex, which involves IL-4Rα and the IL-13Rα1 subunit (shared with IL-13).

• Glycosylation: IL-4 is glycosylated at one or more sites, depending on the species and the expression system. This post-translational modification is not necessary for its biological activity, but it may influence its stability and half-life in circulation.

Classification and Subtypes

IL-4 belongs to the larger family of class I cytokines, which are characterized by their four-helix bundle structure and interactions with receptors that include the common gamma chain (γc). It is classified as a Th2 cytokine, given its prominent role in the differentiation of Th2 cells and the mediation of humoral immune responses.

While IL-4 does not have direct subtypes, it is closely related to IL-13, another Th2 cytokine that shares many functional and structural similarities with IL-4. Both cytokines can bind to the same receptor complexes (IL-4Rα and IL-13Rα1) and often act redundantly in immune responses, particularly in allergic inflammation. IL-13, however, exerts its effects more prominently on epithelial cells and tissues, while IL-4 mainly acts on immune cells such as T cells and B cells.

Function and Biological Significance

IL-4 is a versatile cytokine with a broad range of biological functions, primarily centered on the immune system and the regulation of inflammation. Its most significant roles include:

1. T Cell Differentiation: IL-4 is essential for the differentiation of naïve CD4+ T cells into Th2 cells. This process occurs when IL-4, produced by mast cells, basophils, or other early immune cells, signals through its receptor on CD4+ T cells. Th2 cells, in turn, produce more IL-4, creating a feedback loop that amplifies the Th2 response. Th2 cells are important for the defense against extracellular parasites and the regulation of humoral (antibody-mediated) immunity.
2. B Cell Class Switching: One of IL-4’s most critical roles is in the promotion of B cell class switching, particularly the switch from IgM/IgG to IgE production. IgE is the immunoglobulin responsible for mediating allergic reactions by binding to high-affinity IgE receptors on mast cells and basophils. When these cells encounter an allergen, the crosslinking of IgE receptors triggers the release of histamines and other inflammatory mediators, leading to allergic symptoms.
3. Mucus Production: IL-4 promotes mucus secretion by epithelial cells, a function that is particularly relevant in the pathophysiology of allergic diseases such as asthma. By inducing mucus hypersecretion, IL-4 contributes to airway obstruction and hyperresponsiveness.
4. Inhibition of Macrophage Activation: IL-4 plays a suppressive role on macrophages, inhibiting their pro-inflammatory, "classical" activation (which is driven by cytokines like IFN-γ) and promoting an alternative activation pathway. IL-4-activated macrophages are involved in tissue repair, fibrosis, and the resolution of inflammation, but they can also contribute to chronic diseases when dysregulated.
5. Regulation of Inflammation: IL-4 can inhibit the production of pro-inflammatory cytokines such as IL-1, IL-6, and TNF-α, thus serving as a modulator of the immune response to limit excessive inflammation.

Clinical Issues

Due to its wide-ranging effects on immune cells and inflammatory pathways, IL-4 is implicated in several clinical conditions, particularly allergic diseases and disorders of immune regulation.

1. Allergic Diseases: IL-4 is central to the pathogenesis of allergic diseases such as asthma, allergic rhinitis, and atopic dermatitis. By driving the production of IgE and promoting Th2 responses, IL-4 facilitates the allergic inflammatory cascade. Elevated levels of IL-4 are often observed in patients with these conditions, and blocking IL-4 signaling (e.g., with receptor antagonists or monoclonal antibodies) has been a successful strategy in managing allergic diseases.
2. Asthma: In asthma, IL-4 contributes to airway hyperresponsiveness, eosinophil recruitment, and mucus production. Therapeutics targeting the IL-4/IL-13 axis, such as dupilumab (a monoclonal antibody that blocks IL-4Rα), have shown efficacy in reducing asthma exacerbations and improving lung function in patients with severe asthma.
3. Autoimmune Diseases: While IL-4 is mainly associated with Th2 responses, it also has regulatory roles in autoimmune diseases. For example, IL-4 can have a protective effect in conditions such as multiple sclerosis and type 1 diabetes, where Th1-mediated inflammation predominates. However, in some cases, excessive IL-4 activity may exacerbate disease, especially when Th2 responses are involved.
4. Cancer: IL-4 can play both pro- and anti-tumor roles in cancer. In certain malignancies, such as non-Hodgkin lymphoma, IL-4 promotes tumor cell survival and proliferation by activating anti-apoptotic signaling pathways. Targeting IL-4 in these cancers is being explored as a potential therapeutic strategy.

Summary

IL-4 is a critical cytokine with broad biological functions in immune regulation, inflammation, and allergic responses. Structurally, it belongs to the four-helix bundle cytokine family and binds to a receptor complex composed of IL-4Rα and the common gamma chain. Functionally, IL-4 drives Th2 differentiation, IgE class switching, and alternative macrophage activation, contributing to the regulation of both humoral immunity and inflammatory responses. Clinically, dysregulation of IL-4 is associated with allergic diseases like asthma, as well as autoimmune disorders and certain cancers. As a result, IL-4 has become a target for therapeutic intervention in various diseases where its signaling contributes to pathophysiology, with treatments like IL-4Rα blockers showing promise in managing allergic conditions. Understanding the precise roles and mechanisms of IL-4 continues to be of great importance in immunology and clinical research.