IL4RA

Detailed Information

Interleukin-4 receptor (IL-4R, also known as CD124 or IL-4Rα) is a type I transmembrane protein and a member of the interleukin receptor family. The full-length cDNA of IL-4Rα is 3.6 kb and contains an open reading frame encoding 825 amino acids. This includes a signal peptide (25 amino acids), an extracellular domain (207 amino acids in the ligand-binding region), a transmembrane region (24 amino acids), and a cytoplasmic domain (569 amino acids).

This gene encodes the α chain of the interleukin-4 receptor, a type I transmembrane protein capable of binding both IL-4 and IL-13 to regulate IgE production. The encoded protein can also bind IL-4 to promote the differentiation of Th2 cells. The membrane-bound protein may be proteolytically cleaved to generate a soluble form, which can inhibit IL-4-mediated cell proliferation and IL-5 upregulation in T cells.

There are three forms of human IL-4R:

• Type I: Composed of the high-affinity IL-4Rα chain and the IL-2Rγ chain.
• Type II: Composed of IL-4Rα and IL-13Rα chains.
• Type III: Composed of IL-4Rα, IL-13Rα, and IL-2Rγ chains.

The IL-4Rα chain has a high affinity for IL-4 and has been cloned and demonstrated to be biologically responsive to IL-4. Its extracellular domain contains a WSXWS motif, which is essential for the receptor's optimal conformation necessary for ligand binding. Upon ligand binding, tyrosine kinases associated with IL-4R are activated, initiating downstream signal transduction.

Expression and Function of IL-4R/IL-4Rα

IL-4Rα is the critical shared subunit among the three types of IL-4 receptor complexes and is often referred to simply as IL-4R. These receptor complexes are expressed differentially across cell types:

• Type I IL-4R complexes are primarily expressed on T lymphocytes, NK cells, basophils, and mast cells.
• Type II complexes are expressed on tumor cells of non-lymphoid origin.
• Type III complexes are mainly expressed on B cells and monocytes.

Upon binding to its ligands IL-4 and IL-13, IL-4R mediates various immunomodulatory effects, including the regulation of IgE antibody production in B cells, promotion of Th2 cell differentiation, and alternative activation of macrophages. Recent studies have linked IL-4R/IL-4Rα inhibition or knockout to susceptibility to rhinovirus (RV) infection. Furthermore, genetic polymorphisms in IL-4R/IL-4Rα and IL-4 have been associated with several autoimmune diseases such as asthma, rhinitis, and arthritis.

Figure 1. The mechanisms associated with IL-4R/IL-4Rα. (Suzuki A, et al., 2015)

Ligands of IL-4R/IL-4Rα

IL-4R/IL-4Rα exerts its biological functions mainly through binding with IL-4 and IL-13.

IL-4 is produced by activated Th2 cells, basophils, and mast cells. It suppresses inflammation by inhibiting the activation of monocyte-macrophage lineages and the production of Th1-type cytokines such as IL-1, TNF-α, and interferon-γ (IFN-γ). However, IL-4 can also exert pro-inflammatory effects depending on the immune context, making it a multifunctional cytokine.

IL-13 is produced by Th2 cells and shares approximately 25% amino acid sequence homology with IL-4. It promotes B cell differentiation and enhances their activity while suppressing the production of cytokines such as IL-1β, IL-8, TNF-α, and IL-6 in peripheral blood mononuclear cells. IL-4 and IL-13 exhibit highly similar biological activities, sharing key signal transduction components and demonstrating similarities in both gene localization and protein structure.

Signaling Mechanisms of IL-4R/IL-4Rα

IL-4 and IL-13 mediate signal transduction through type I IL-4Rα/γc and/or type II IL-4Rα/IL-13Rα complexes. IL-4 interacts with IL-4Rα and then with the γc chain to form the type I receptor, or with IL-13Rα1 to form the type II receptor complex.

The IL-4 receptor is a cell-surface dimer composed of α and γ subunits. IL-4Rα is the high-affinity subunit specific for IL-4, while the γ chain (γc), shared among several cytokine receptors (type I and III), enhances receptor function. IL-13Rα acts similarly to γc, augmenting the binding of IL-4 to IL-4Rα.

Upon IL-4 binding, the IL-4R and γc chain dimerize and activate protein tyrosine kinases (PTKs), leading to phosphorylation of intracellular substrates and initiating a signaling cascade. This activates four major signaling pathways:

• Phosphoinositide 3-kinase (PI-3K) pathway, involved in cell survival.
• Ras/mitogen-activated protein kinase (MAPK) pathway, associated with proliferation and gene transcription.
• Insulin receptor substrate 1/2 (IRS-1/2) pathway.
• Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathway, which governs transcriptional regulation.

IL-4Rα mainly signals via the JAK1/STAT6 pathway. JAK3 associates with the γc chain, and JAK2 associates with IL-13Rα1. STAT6 is crucial for IL-4-dependent expression of CD23, MHC class II ε chains, and IL-4Rα itself, and it plays a vital role in the secretion of Th2 cytokines.

IL-13 exerts its function through the type II receptor complex (via IL-13Rα1) or through IL-13Rα2. TNF-α upregulates IL-13Rα2 expression. Binding of IL-13 to IL-13Rα2 activates AP-1 and induces gene expression, along with the soluble secretion of TGF-β.

Role of IL-4R in Type 2 Inflammatory Pathways

Allergic diseases, which are primarily IgE-mediated type I hypersensitivity reactions—including allergic rhinitis (AR), allergic bronchial asthma, atopic dermatitis (AD), and food allergies—affect approximately 40% of the global population. It is estimated that 400 million people suffer from AR, 300 million from asthma, and 250 million from food allergies worldwide. In 2022, the global market for allergy immunotherapy was valued at USD 2.8 billion. By 2028, it is projected to reach USD 5.0 billion, with a compound annual growth rate (CAGR) of 10.15% from 2022 to 2028.

From a pathophysiological standpoint, the type 2 inflammatory pathway plays a central role in allergic disease development. This pathway involves Th2 cells (a subset of CD4+ T cells) secreting interleukins IL-4, IL-5, and IL-13, thereby stimulating type 2 immunity characterized by high levels of IgE and eosinophils.

Th2-derived IL-4, IL-13, and IL-5 act as the primary cytokines responsible for initiating and maintaining type 2 inflammation. IL-4 promotes the differentiation of naïve CD4+ T cells into Th2 cells and upregulates the expression of IgE by B cells, while IL-13 contributes to mucus hypersecretion and airway hyperresponsiveness, and IL-5 is involved in eosinophil growth and activation. Collectively, these cytokines are central to the pathophysiology of allergic diseases.

Among them, IL-4 and IL-13 share IL-4Rα as a common receptor subunit. Therefore, blocking IL-4Rα can simultaneously inhibit signaling pathways triggered by both IL-4 and IL-13, offering a highly efficient strategy for targeting type 2 inflammation. This is the mechanism of action underlying biologics like dupilumab—a fully human monoclonal antibody that binds to IL-4Rα and disrupts downstream signal transduction of both IL-4 and IL-13.

Clinical Applications and Therapeutic Advances Targeting IL-4R/IL-4Rα

IL-4Rα has emerged as a promising therapeutic target due to its pivotal role in type 2 immune responses and its involvement in numerous allergic and inflammatory diseases. Clinical interventions targeting IL-4Rα have been developed with the aim of neutralizing the effects of IL-4 and IL-13, thereby mitigating the symptoms and progression of conditions such as asthma, atopic dermatitis, and eosinophilic esophagitis.

One of the most notable therapeutics is dupilumab, an FDA-approved monoclonal antibody that targets IL-4Rα. By binding to IL-4Rα, dupilumab inhibits both IL-4 and IL-13 signaling, offering broad-spectrum suppression of type 2 inflammatory pathways. It is currently approved for the treatment of:

• Moderate-to-severe atopic dermatitis in adults and children aged 6 months and older
• Eosinophilic or oral corticosteroid-dependent asthma in patients aged 6 years and older
• Chronic rhinosinusitis with nasal polyps
• Eosinophilic esophagitis

Clinical trials have shown that dupilumab significantly improves symptoms, reduces disease exacerbations, and enhances quality of life in patients with severe allergic disease phenotypes. It also exhibits a favorable safety profile, making it a robust therapeutic option for long-term disease management.

In addition to dupilumab, a pipeline of IL-4R/IL-13Rα1/IL-4-targeting biologics is under development, with some already in clinical trials. These include monoclonal antibodies such as lebrikizumab and tralokinumab, which block IL-13 specifically but indirectly modulate IL-4R signaling by inhibiting downstream pathways.