Interleukin 4 receptor (IL-4R/IL-4Ra): a Multifunctional Target of Cytokines, Suggesting Diverse Potential in Asthma, Rhinitis, Viral, and Tumor Resea
On January 26, 2024, a pharmaceutical company license two promising products: an anti-TSLP monoclonal antibody and an anti-IL-4Ra monoclonal antibody. These aim to treat respiratory disorders like asthma and chronic obstructive pulmonary disease (COPD). Particularly noteworthy is the IL-4R/IL-4Rα, a versatile target with diverse research applications, is at the forefront. Over 10 drugs targeting IL-4R/IL-4Rα are in II/III clinical stage development globally. Its significance extends to viral and tumor pathogenesis, suggesting broad therapeutic potential. Further research into its mechanisms and clinical applications is vital. Let's explore the IL-4R/IL-4Ra further today!
1. What is the Interleukin-4 Receptor?
1.1 The Structure of IL-4R/IL-4Rα
Interleukin-4 receptor subunit alpha (IL4R), also known as CD124 or IL4Rα, encodes the alpha chain of interleukin-4 (IL-4), belonging to the interleukin family as a type I transmembrane protein. IL-4Rα is a pivotal subunit shared by all three types of IL-4R complexes, commonly abbreviated as IL-4R. The IL4Rα chain cDNA spans 3.6 kb, encoding 825 amino acids, including a signaling sequence (25 amino acids), an extracellular region (207 binding domain amino acids), a transmembrane region (24 amino acids), and an intracellular region (569 amino acids) (Figure 1) [1-3].
Three human IL4R types exist: type I, comprising a high-affinity IL-4Ra and an IL-2Rγ chain; type II, consisting of an IL-4Ra and an IL-13Ra chain; type III, featuring an IL-4Ra and IL-13Ra chain, and an IL-2Rγ chain. The IL-4Ra chain, with high IL-4 affinity, has been cloned and shown to respond to IL-4 biologically. Its extracellular structural domain houses the WSXWS module, crucial for cytokine receptor binding. Upon ligand binding, the tyrosine kinase linked to the IL-4R is activated, initiating signaling pathways [1-5].
1.2 The IL-4R/IL-4Rα Expression and Function
Type I IL4R complexes are predominantly found in T-lymphocytes, NK-cells, basophils, and mast cells; Type II complexes occur in non-lymphocyte-origin tumor cells; Type III complexes are mainly present in B-cells and monocytes. Upon binding interleukin 4 and interleukin 3 ligands, IL4R triggers various immunomodulatory effects, including regulating IgE antibody production in B cells, facilitating Th2 cell differentiation, and inducing alternative macrophage activation. Recent studies suggest that inhibiting or reducing IL-4R/IL-4Rα expression is linked to susceptibility to rhinovirus (RV) infection. Additionally, numerous studies have demonstrated strong associations between genetic variations in IL-4R/IL-4Rα and IL4 and various autoimmune diseases, including asthma, rhinitis, arthritis, and more [1-3, 6-7].
2. What are the Ligands for IL-4R/IL-4Rα?
IL-4R/IL-4Rα primarily functions by interacting with IL-4?and IL-13. IL-4 is produced by activated type II helper T cells, basophils, and mast cells. It plays a crucial role by inhibiting monocyte-macrophage activation and Th1 cytokines like IL-1, TNF-α, and IFN-γ?to dampen the inflammatory response. However, IL-4 also exhibits pro-inflammatory effects in various immune mechanisms, rendering it a multifunctional cytokine. On the other hand, IL-13, produced by Th2 cells, shares about 25% homology in amino acid sequences with IL-4. IL-13 promotes B-cell differentiation and activity while suppressing peripheral blood monocyte-macrophage production and the expression of IL-1β, IL-8, TNF-α, IL-6, and other cytokines. Despite their similar biological activities, IL-4 and IL-13 share a key signaling receptor component and exhibit some similarities in gene localization and protein composition [8-10].
3. How's the Mechanisms Associated with IL-4R/IL-4Rα?
The IL-4 receptor forms a cell surface dimerization complex comprising α and γ subunits. IL-4Rα serves as a highly sensitive and specific receptor for IL-4, while the γ chain, also known as the common gamma chain (γc chain), is shared by Type I and Type III cytokines. IL13Rα functions similarly to the γ chain, enhancing the binding between IL-4Rα and IL-4. IL-4 and IL-13, being pleiotropic cytokines with comparable biological activities, primarily activate the IL-4 receptor.
When IL-4 binds to the receptor, it triggers the formation of a dimer with the γc chain, activating tyrosine kinase (PTK). This initiates the phosphorylation of intracellular substrates, setting off a cascade of signaling events. Four major pathways are activated: the phosphatidylinositol 3 kinase associated with cell survival (PI-3K) pathway, the Ras/mitogen-activated protease associated with cell proliferation and gene transcription (MAPK) pathway, the insulin receptor substrate 1/2 (IRS-1/2) pathway, and the control of gene transcription by the Jak-STAT pathway. Additionally, Stat-6 positively regulates IL-4-dependent CD23, type II MHCε heavy chain, and IL-4α receptor expression, while also playing a critical role in Th2 lymphocyte factor secretion (Figure 2) [3, 11].
4. IL-4R/IL-4Rα Related Disease Research
Research indicates that genetic variations in the IL-4 receptor gene are linked to various diseases. Focus lies on polymorphic loci like lle50Val, Gln55 (576) Arg, and Ser503 (478) Pro within the IL-4 gene. Understanding how these variations affect disease susceptibility could aid in prevention and treatment strategies. Additionally, IL-4R/IL-4Rα may play crucial roles in viral infections and cancer, expanding its significance across different disease areas.
4.1 IL-4R/IL-4Rα and Asthma Research
IL-4, IL-4R/IL-4Rα, and IL-13 are pivotal in allergic reactions and asthma development. They significantly impact airway responsiveness, causing structural changes, inflammation, and muscle proliferation. IL-4 and IL-13 exert their effects by binding to IL-4R, potentially affecting the Th1/Th2 cell balance implicated in asthma pathogenesis. The relationship between IL-4 and IL-4R gene polymorphisms and asthma is under scrutiny, particularly regarding the IL-4Ra lle50Val variant. Studies report conflicting findings on its association with asthma. Additionally, the rs1805011 polymorphism in the IL-4R gene may heighten allergy risk and susceptibility to mild asthma and allergic dermatitis in Polish children [12-15].
4.2 IL-4R/IL-4Rα and Allergic Rhinitis Research
Missense mutations in IL-4R/IL-4Ra genes alter the amino acid structure, enhancing IL-4R signaling and modifying its biological function. Notably, the Q576R mutation in the IL-4Ra chain is a newly identified variant where guanine (G) at position 1902 is replaced by adenine (A), resulting in glutamic acid (Q) being replaced by arginine (R) at base 576 on IL-4R. Studies reveal elevated R576 expression in patients with metaplastic diseases, and suggest its role in promoting allergic asthma by modulating IL-4R signaling. Furthermore, R576 is closely linked to asthma severity, suggesting its potential as a clinical marker [17-20].
4.3 IL-4R/IL-4Rα and Systemic Lupus Erythematosus Research
The PCR-RFLP method was used to study lle50Val genotypes in SLE patients, showing a higher frequency of IL-4Ra chain lle50 in these patients. SLE pathogenesis involves reduced IL-2, IL-12, and IFN-1 production, with increased IL-6 and IL-10, leading to Th1/Th2 cytokine imbalance. Th2 responses prevail, mediated by IL-4 and IL-4R signaling, crucial in converting Th0 cells to Th2 cells. IL-4R Gln551Arg genotyping revealed a higher frequency of IL-4R chain Arg551 in SLE patients, suggesting a role in promoting the Th2 subtype and autoantibody production in response to other factors [21-22].
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4.4 IL-4R/IL-4Rα and Other Autoimmune Disease Research
Polymorphisms in IL-4R/IL-4Rα are associated with various autoimmune diseases. For instance, the IL-4Rα Q576R polymorphism is linked to increased Th2 cells in atopic dermatitis patients, commonly associated with allergic reactions [23]. Another study found that polymorphisms in the IL-4R gene at the rs1805013 locus may heighten the risk of developing osteoarthritis [24]. In Caucasian populations, 18 SNPs in the IL-13/IL-4/IL-4R system were investigated for their relation to hand joint susceptibility, revealing the IL-4/IL-13 system's importance in hand joint arthritis pathogenesis [25]. Additionally, the I75V locus of the IL-4Ra gene is elevated in myasthenia gravis patients, particularly in females and those positive for AChR antibodies, potentially affecting IL-4 signaling and immune response balance in myasthenia gravis development [26].
4.5 IL-4R/IL-4Rα and Virus Research
Host cell cytokine receptors, such as BMPR2, CCR5, CCR7, FGFR1, IL17RB, IL1R1, IL4R, PDGFRA, TLR2, and TNFRSF11B, are crucial for signaling and are often targeted by viruses. Recent studies indicate that inhibiting IL4R or suppressing IL4R gene expression can effectively prevent respiratory syncytial virus (RSV)-induced lung injury and rhinovirus (RV)-induced airway mucus secretion in neonatal mice [27-28]. Moreover, the HIV-1 tat gene was found to sustain its replication by enhancing IL4R transcription, highlighting the significance of IL-4R/IL-4Rα in various virus-induced diseases [29].
4.6 IL-4R/IL-4Rα and Cancer Research
IL-4R/IL-4Rα is implicated in cancer development and progression. In hepatoma tissues, IL4R expression is notably high and correlates with tumor differentiation status. Studies indicate that IL4R regulates hepatocellular carcinoma cell proliferation and metastasis by modulating JAK1/STAT6 and JNK/ERK1/2 signaling pathways [30]. IL-4 binding to IL4R induces programmed cell death in human breast cancer cells, suggesting a potential therapeutic role for the IL-4/IL4R signaling pathway in breast cancer [31]. Moreover, the IL-4/IL4R pathway inhibits the proliferation of acute lymphoblastic leukemia (B-CLL) cancer cells and prevents their progression into the G1 phase [32]. While these findings highlight the significance of IL-4R in cancer, further research is needed to elucidate its precise mechanisms.
5. The Prospects for Clinical Drug Research of IL-4R/IL-4Rα
Currently, there are up to 40 drugs in active development targeting IL-4R/IL-4Rα, with IL-4R/IL-4Rα monoclonal antibodies showing promising clinical prospects. The pioneering IL-4R monoclonal antibody, Dupilumab, co-developed by Sanofi and Regeneron, gained FDA approval in March 2017 for treating moderate-to-severe atopic dermatitis, asthma, and chronic rhinitis. With Dupilumab sales reaching €7.7 billion by 2023, Sanofi anticipates further growth, establishing it as a cornerstone in immunotherapy. In summary, IL-4R/IL-4Rα-targeting drugs offer broad potential, providing patients with diverse therapeutic options and renewed hope, particularly in autoimmune diseases like atopic dermatitis and asthma.
In Conclusion:
IL-4R/IL-4Rα is a key target in immune modulation and disease treatment. Genetic variations in IL-4R/IL-4Rα impact susceptibility to diseases like asthma and atopic dermatitis. Studies show its role in viral infections and cancer progression. Monoclonal antibodies, like Dupilumab, hold promise for treating these conditions. Continued research offers hope for improved therapies across various immune-related disorders.
6. CUSABIO IL-4R/IL-4Rα Recombinant Proteins for Research Use
In order to assist pharmaceutical companies in the research of IL-4R/IL-4Rα in asthma, rhinitis, arthritis, viruses, tumors, etc., CUSABIO launched IL-4R/IL-4Rα active protein products to help you in your research on the mechanism of IL-4R/IL-4Rα or its potential clinical value.
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CUSABIO IL-4R/IL-4Rα Protein
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