IL4R - interleukin 4 receptor | Elisa - Clia - Antibody - Protein

Background

The IL4R gene encodes the interleukin-4 receptor alpha (IL-4Rα) subunit, which plays a critical role in the immune system, especially in the regulation of T-helper cell responses. IL-4Rα serves as the receptor for two important cytokines, interleukin-4 (IL-4) and interleukin-13 (IL-13), both of which influence various aspects of immune and inflammatory responses, including antibody production and the polarization of T-helper cells towards the Th2 phenotype. IL-4R signaling is essential in allergic responses, asthma, and other conditions associated with elevated IgE levels and eosinophilia. IL4Rα exists in both membrane-bound and soluble forms, with the soluble form inhibiting the actions of IL-4 by acting as a decoy receptor.

IL4Rα is expressed across several cell types, including T and B lymphocytes, monocytes, macrophages, eosinophils, and endothelial cells. This widespread expression reflects the receptor’s importance in orchestrating responses to pathogens, allergens, and other environmental challenges. Given its central role in modulating immune responses, IL4R has become a target of therapeutic interest, particularly in conditions such as allergic asthma, atopic dermatitis, and certain autoimmune diseases.

Protein Structure

The IL4R protein has a well-defined structural organization that includes domains responsible for ligand binding, signal transduction, and receptor dimerization. The protein is a type I transmembrane glycoprotein and can be divided into three primary domains:

Extracellular Domain (ECD):

• The ECD of IL4R, which includes 232 amino acids, contains the ligand-binding sites for IL-4 and IL-13. Within this domain, two fibronectin type III (FNIII)-like domains facilitate the specific binding of IL-4 or IL-13 to IL4Rα, and a four-helix bundle characteristic of type I cytokine receptors is essential for ligand recognition.
• The ECD also includes conserved cysteine residues and N-linked glycosylation sites that contribute to receptor stability, structural integrity, and ligand binding affinity. The glycosylation sites enhance the stability and proper folding of the receptor, maintaining it in an optimal conformation for binding IL-4 or IL-13.

Transmembrane Domain (TMD):

• The TMD anchors IL4Rα to the cell membrane, composed of a single alpha-helical structure. This domain acts as a bridge between the ECD and intracellular domain, playing a crucial role in stabilizing receptor-ligand complexes and facilitating receptor dimerization.

Intracellular Domain (ICD):

• The ICD contains several phosphorylation sites crucial for initiating downstream signaling upon receptor activation. This domain lacks intrinsic kinase activity but recruits and activates Janus kinases (JAK1 and JAK3), which phosphorylate specific tyrosine residues on the ICD. This phosphorylation event subsequently recruits STAT6, a transcription factor central to Th2 differentiation, and initiates transcriptional changes that drive immune responses.
• The ICD also has interaction sites for other signaling molecules, including IRS-1 and IRS-2 (insulin receptor substrates), which link IL-4R signaling to metabolic and cellular growth pathways.

Classification and Subtypes

IL4Rα is classified within the type I cytokine receptor family, specifically the hematopoietin receptor superfamily, which includes receptors involved in growth, differentiation, and immune modulation. There are two primary types of receptor complexes that involve IL4Rα:

1. Type I IL-4 Receptor: Formed by the dimerization of IL4Rα with the common gamma chain (γc). This receptor complex is specifically responsive to IL-4 and is primarily found on hematopoietic cells, such as T and B cells.
2. Type II IL-4/IL-13 Receptor: Formed by the dimerization of IL4Rα with IL-13Rα1. This receptor is responsive to both IL-4 and IL-13 and is expressed on non-hematopoietic cells, including fibroblasts, epithelial cells, and smooth muscle cells. This receptor type is central to IL-13-driven responses in allergic inflammation and asthma.

Function and Biological Significance

IL4R has diverse and critical functions in immune modulation, inflammation, and cell differentiation. The binding of IL-4 or IL-13 to IL4Rα initiates signaling cascades that influence immune responses, promote allergic inflammation, and regulate metabolic pathways:

Th2 Differentiation and Immunoglobulin Class Switching:

• IL-4 is a key driver of Th2 differentiation, and IL4R signaling is essential in polarizing naïve T cells to a Th2 phenotype. This shift promotes the production of cytokines like IL-4, IL-5, and IL-13, which are characteristic of Th2 responses and play crucial roles in allergy and asthma pathophysiology.
• IL-4R signaling is also critical in immunoglobulin (Ig) class switching, particularly promoting the switch to IgE production in B cells. Elevated IgE levels are a hallmark of allergic conditions and are influenced by IL4R activation on B cells.

Inflammatory Response and Cell Recruitment:

• IL4R activation on eosinophils, mast cells, and basophils contributes to inflammatory responses associated with asthma, atopic dermatitis, and other allergic conditions. IL4R signaling promotes the recruitment of eosinophils and other inflammatory cells to the site of allergen exposure, leading to tissue inflammation and hypersensitivity.
• IL4R also influences the production of matrix metalloproteinases (MMPs) and other molecules that contribute to tissue remodeling and fibrosis, particularly in chronic inflammatory conditions.

Anti-Parasitic Immunity:

• IL-4 and IL-13 signaling through IL4R are essential in mounting effective immune responses against parasitic infections. IL4R activation promotes the production of mucus and the activation of immune cells, such as eosinophils, which target parasitic organisms.

Metabolic Regulation:

• IL4R signaling is linked to metabolic pathways through IRS proteins. Activation of IL4R influences glucose metabolism, lipid storage, and insulin sensitivity, indicating a role in linking immune responses with metabolic health.

Clinical Issues

Given its central role in immune responses, IL4R is implicated in several diseases, particularly allergic, inflammatory, and autoimmune conditions:

Asthma and Allergic Diseases:

• IL4R plays a prominent role in allergic asthma, with increased IL4Rα expression correlating with disease severity. IL4R signaling contributes to airway inflammation, mucus production, and hyperresponsiveness in asthma. Blocking IL4Rα, particularly with biologics like dupilumab, has shown efficacy in reducing asthma symptoms by inhibiting both IL-4 and IL-13 signaling.
• In addition to asthma, IL4R is involved in atopic dermatitis, allergic rhinitis, and food allergies. Targeting IL4R in these conditions reduces IgE production, inflammatory cytokines, and allergen-driven inflammation.

Autoimmune Diseases:

• IL4R signaling has been implicated in autoimmune conditions where a dysregulated Th2 response contributes to pathogenesis. Conditions like systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) show elevated IL4Rα levels, although IL4R-targeted therapies are still under investigation for these diseases.

Cancer:

• IL4R is overexpressed in several cancers, particularly in the tumor microenvironment, where it may contribute to immunosuppression and cancer cell survival. Targeting IL4R in cancers such as pancreatic cancer, breast cancer, and glioblastoma is being explored to inhibit tumor progression and enhance anti-tumor immunity.

Parasitic Infections:

• IL4R is vital in combating parasitic infections, and individuals with mutations in IL4R may have an altered immune response to parasitic organisms. Such mutations can impact susceptibility to infections like Schistosomiasis and Leishmaniasis.

Summary

The interleukin-4 receptor alpha (IL4Rα) plays a central role in immune modulation, orchestrating responses to allergens, parasites, and certain inflammatory conditions. Structurally, IL4Rα is a type I transmembrane protein that associates with either the common gamma chain (γc) in type I receptors or IL-13Rα1 in type II receptors. These complexes enable IL4R to mediate responses to IL-4 and IL-13, driving Th2 polarization, IgE production, and inflammatory responses.

IL4R signaling has significant implications in allergic diseases, asthma, autoimmune conditions, and parasitic immunity. In allergic asthma, atopic dermatitis, and other IgE-mediated responses, IL4R promotes cell recruitment and cytokine release, which exacerbate inflammation. IL4R-targeting therapies, such as the monoclonal antibody dupilumab, show promising results by blocking IL4R signaling and reducing disease symptoms. In cancer, IL4R contributes to an immunosuppressive tumor microenvironment, and ongoing research explores its potential as a therapeutic target in oncology.

Overall, IL4R is critical to the regulation of immune responses, and its modulation holds potential for treating a range of inflammatory, allergic, autoimmune, and malignant diseases.