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Inspiring Target:Interleukin 4 Receptor

Schematic diagram of IL-4/IL-4R signaling pathway
Fig 1. Schematic diagram of IL-4/IL-4R signaling pathway.

Interleukin-4Rα (IL-4Rα), the key receptor of IL-4, has emerged as an ‘inspiring’ target for innovative therapies aimed at treating various inflammatory and oncological diseases. IL-4Rα is a type I transmembrane protein that plays a key role in the molecular pathway that drives a specific immune pattern called type II inflammations.

This pathway is driven by two cytokines: interleukin-4 (IL-4) and interleukin-13 (IL-13). Both cytokines have diverse biological and immunological effects on lymphocytes, dendritic cells and fibroblasts adjustment function. Specifically, these cytokines bind to IL-4Rα to initiate the type II inflammation pathway that includes differentiation of Th2 cells, airway inflammation and mucus production.

Clinical Application

IL-4R and cytokines IL-4 and IL-13 are key regulators in humoral and adaptive immunity. This means that an imbalance in either receptor expression or circulating signaling cytokines can be clinically observed. The resultant immune overreaction is initiated by an initial imbalance of TH1 and TH2 differentiation that drives an abnormal secretion of cytokines. Activated Th2 cells release cytokines including IL-4, 13, and 31, which activate downstream B cells to transform and produce immunoglobulin E (IgE) antibodies. In turn, mast cells and basophils are recruited to degranulate and produce inflammatory factors. Simultaneously, the secreted IL-4 and 13 continue to bind to its respective receptors (e. g. IL-4R) that repeatedly promotes TH2 differentiation and subsequent inflammation. This effect is observed through several autoimmune diseases including asthma, eczema, and hay fever, as well as in metastatic tumors.

Asthma
Asthma
Asthma is a complex, persistent, and lifelong inflammatory disease. Dupilumab is a human monoclonal antibody targeting IL-4Rα. Its mechanism of action is to specifically block the type II IL-4R/IL-13R signaling pathway while inhibiting the intracellular activity of IL-4 and IL-13 with STAT6. By preventing cytokine signaling at the source, the Th2 inflammatory response is minimized.
Eczema
Eczema
Eczema, otherwise known as atopic dermatitis, is a disease characterized by skin inflammation, dry skin, rashes, and blisters. Recent studies have begun to emphasize that eczema may stem from overexpression of IL-13/IL-4 signaling in specific individuals. Thus, development of therapies targeting the IL-13/IL-4 /IL-4R and its intracellular signaling pathway is a promising innovative strategy.
Hay Fever
Hay Fever
Hay fever, also known as allergic rhinitis, is a common chronic disease that is driven by an IgE mediated inflammatory response in the nasal mucosa and cause a variety of complications. In a recent study, inhibition of the IL-4/STAT6/GATA3 signaling pathway can reduce IL-4 secretion, serum IgE and airway mucus production, effectively improving symptoms due to hay fever.
Metastatic Tumors
Metastatic Tumors
Beyond autoimmune diseases, IL-4R is also overexpressed in many epithelial cancers. Whereas the intracellular signaling of IL-4/ IL-4R in lymphocytes drives the type II inflammation pathway. As such, overexpression of IL-4R drives metastasis and tumor growth, revealing IL-4R inhibitory drugs as a potential therapeutic tool for metastatic tumors.

Product Features

Native conformation, free protocol shared

High biological activity verified by ELISA/SPR/ BLI

Authentic structure verified by SEC-MALS

Comprehensive products with various tags and species

High purity verified by SDS-PAGE

Product List

IL-4 R alpha
IL-4
IL-13 R alpha 1
IL-13 R alpha 2
IL-4 R alpha & IL-13 R alpha 1
Cat. No.Product DescriptionSpeciesOrder Now
Human
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Human
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Human
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Rabbit
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Rat
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Human
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Human
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Human
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Human
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Mouse
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Mouse
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Mouse
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Mouse
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Cynomolgus
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Cynomolgus
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Cynomolgus
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Verification Data

High purity (>95%) verified by SDS-PAGE
ILR-H5253

HumanI IL-4 R alpha, Fc Tag (Cat. No. ILR-H5253）on SDS-PAGE under reducing (R) condition. The gel was stained overnight with Coomassie Blue. The purity of the protein is greater than 95%

High structural homogeneity (>90%) verified by SEC-MALS
IL4-C5259

The purity of Cynomolgus IL-4, Fc Tag (Cat. No. IL4-C5259) is more than90%and the molecular weight of this protein is around85-115 kDaverified by SEC-MALS.

High biological activity verified by ELISA

IL4-H4218

Immobilized ActiveMax® Human IL-4, Tag Free (Cat. No. IL4-H4218)at 5 μL/mL (100 μL/well) can bind Biotinylated Human IL-4 R alpha, Avitag,His Tag (Cat. No. ILR-H82E9) with a linear range of 2-78 ng/mL.

IL4-H4218

Immobilized ActiveMax® Human IL-4, Tag Free(Cat. No. IL4-H4218)at 5 μg/mL (100 μL/well) can bind Human IL-4 R alpha, Fc Tag (Cat. No. ILR-H5253) with a linear range of 1-20 ng/mL.

Affinity verified by SPR and BLI

IL1-H82E8

Biotinylated Human IL-13 R alpha 1 Protein, His,Avitag (Cat. No. IL1-H82E8) immobilized on SA Chip can bind Human IL-13 Protein, His Tag, premium grade (Cat. No. IL3-H52H3) with an affinity constant of 13.8 nM as determined in a SPR assay (Biacore 8K) (Routinely tested).

IL3-H82E5

Loaded Biotinylated Human IL-13, His,Avitag (Cat. No. IL3-H82E5) on SA Biosensor, can bind Human IL-13 R alpha 2, His Tag (Cat. No.IL2-H52H5) with an affinity constant of 6.31 nM as determined in BLI assay (ForteBio Octet Red96e).

Related Information

>>> [Inspiring Target] IL-4R Alpha, a Potential Drug Target Worth over $10 Billion

Related References

  • [1] Weng, S. Y., Wang, X., Vijayan, S., Tang, Y., Kim, Y. O., Padberg, K., ... & Schuppan, D. (2018). IL-4 receptor alpha signaling through macrophages differentially regulates liver fibrosis progression and reversal. EBioMedicine, 29, 92-103.https://doi.org/10.1016/j.ebiom.2018.01.028.

  • [2] Husna, S. M. N., Shukri, N. M., Ashari, N. S. M., & Wong, K. K. (2022). IL-4/IL-13 axis as therapeutic targets in allergic rhinitis and asthma. PeerJ, https://doi.org/10, e13444.10.7717/peerj.13444.

  • [3] Liang, K. L., Yu, S. J., Huang, W. C., & Yen, H. R. (2020). Luteolin attenuates allergic nasal inflammation via inhibition of interleukin-4 in an allergic rhinitis mouse model and peripheral blood from human subjects with allergic rhinitis. Frontiers in pharmacology, 11,291.https://doi.org/10.3389/fphar.2020.00291.

  • [4] Bankaitis, K. V., & Fingleton, B. (2015). Targeting IL4/IL4R for the treatment of epithelial cancer metastasis. Clinical & experimental metastasis, 32(8), 847-856.https://doi.org/10.1007/s10585-015-9747-9.

  • [5] Moran, A., & Pavord, I. D. (2020). Anti-IL-4/IL-13 for the treatment of asthma: The story so far. Expert Opinion on Biological Therapy, 20(3), 283-294.

  • https://doi.org/10.1080/14712598.2020.1714027.

  • [6] Furue, M. (2020). Regulation of skin barrier function via competition between AHR axis versus IL-13/IL-4‒JAK‒STAT6/STAT3 axis: pathogenic and therapeutic implications in atopic dermatitis. Journal of Clinical Medicine, 9(11), 3741.https://doi.org/10.3390/jcm9113741.

  • [7] Pelaia, C., Pelaia, G., Crimi, C., Maglio, A., Armentaro, G., Calabrese, C., ... & Vatrella, A.(2022). Biological Therapy of Severe Asthma with Dupilumab, a Dual Receptor Antagonist of Interleukins 4 and 13. Vaccines, 10(6), 974.https://doi.org/10.3390/vaccines10060974.

FAQ

Q

Why is IL-4Rα an important target for simultaneously modulating IL-4- and IL-13-mediated type 2 inflammation?

IL-4Rα is shared by the type I IL-4 receptor and the type II IL-4/IL-13 receptor. Blocking IL-4Rα can therefore inhibit signaling initiated by both IL-4 and IL-13, affecting Th2 differentiation, IgE-associated responses, airway inflammation, and tissue remodeling. This broad pathway coverage is a major reason IL-4Rα is therapeutically relevant, but it also means candidates should be evaluated for effects on both receptor configurations.
Q

Why should type I and type II IL-4 receptors be distinguished when screening therapeutics?

The type I receptor contains IL-4Rα and the common γ-chain and responds to IL-4, mainly in hematopoietic cells. The type II receptor contains IL-4Rα and IL-13Rα1 and responds to both IL-4 and IL-13 in many hematopoietic and nonhematopoietic cells. A candidate may block ligand binding, second-subunit recruitment, or one receptor configuration more effectively than the other. Testing both formats helps define mechanism and receptor selectivity.
Q

How do IL-13Rα1 and IL-13Rα2 differ, and why should they be evaluated separately?

IL-13Rα1 partners with IL-4Rα to form the signaling-competent type II receptor. IL-13Rα2 binds IL-13 with high affinity and can act as a ligand sink, but it may also mediate context-dependent signaling in fibrosis and cancer. Antibodies or engineered ligands can therefore show different binding and functional profiles against the two receptors. Separate testing distinguishes inhibition of type II receptor signaling from effects on the IL-13Rα2 axis.
Q

How does IL-4Rα blockade differ from selective IL-4 or IL-13 neutralization?

IL-4Rα blockade can inhibit both IL-4- and IL-13-driven signaling through the type II receptor and also blocks IL-4 signaling through the type I receptor. Selective IL-4 or IL-13 neutralization preserves more of the complementary pathway and may therefore produce a different efficacy and safety profile. Comparative assays should examine both ligands and the relevant receptor complexes to confirm the actual pathway coverage of each candidate.
Q

How should recombinant proteins and cellular tools be combined for IL-4/IL-13 drug screening?

Individual ligands and receptor subunits are useful for defining direct binding and competition. Dual-subunit receptor products better represent the extracellular composition of the type II receptor, while stable or reporter cell lines confirm signaling inhibition in a cellular context. A practical workflow moves from molecular binding to receptor-complex selectivity and then to cellular function. Protein format and tag should be selected to avoid interference with the chosen capture or detection system.
  • Introduction
  • Clinical Application
  • Product Features
  • Product List
  • Verification Data
  • Related References
  • FAQ