Recombinant human IL-4 protein - Bioactive cytokine

IL-4 background

IL-4, also known as B-cell stimulatory factor 1 or Lymphocyte stimulatory factor 1, is a cytokine that belongs to the IL-2/γc superfamily. IL-4 is produced as a secreted monomeric molecule by activated CD4+ T cells, Natural Killer T cells (NKT cells), group 2 innate lymphoid cells (ILC2s), macrophages, mast cells, basophils, or eosinophils [1].

IL-4 binds two types of heterodimeric receptors and exerts pleiotropic actions on multiple cell lineages. Type I receptors are composed of the IL-4Rα and the common γ chains. Type II receptors are composed of the IL-4Rα and IL-13Rα1 chains. The binding of IL-4 to its receptors triggers a signaling cascade leading to the activation of STAT6. Subsequent gene expression drives Th2 and Th9 helper cell differentiation and M2 macrophage polarization. In B cells, IL-4 promotes proliferation and IgE immunoglobulin class switching [1, 2]. In non-hematopoietic cells, the functions of IL-4 span from mucus hypersecretion in airway epithelial cells, extracellular matrix protein deposition by fibroblasts, and growth of endothelial cells [1]. Altogether, the downstream IL-4 effector functions participate in parasitic infection clearance and allergic reactions [2].

Relevance for therapeutics development

IL-4 is a key cytokine for controlling infections by extracellular parasites. However, along with IL-13, it also contributes to harmful allergic responses [2, 3]. As the prevalence of chronic allergic diseases such as asthma and atopic dermatitis is increasing worldwide, there has been a keen interest in the therapeutic blocking of IL-4 and IL-13 signaling.

Dupilumab is a fully human monoclonal antibody (mAb) that targets the IL-4Rα subunit [4]. It acts like a receptor antagonist and inhibits the signaling of both IL-4 and IL-13 [4]. Dupilimab was FDA-approved in 2017 for treating asthma, atopic dermatitis, and chronic sinusitis [4, 5]. Due to its favorable safety profile and established clinical use, Dupilumab holds significant promise for amending treatment options for many dermatologic conditions [6].

The development of engineered IL-4 cytokines has also been explored. For example, IL-4 "superkines" featuring a higher affinity for type I or type II receptors have been generated to target cells expressing lower second chain (γc or IL-13Rα1) numbers. To go further, engineered super-IL-4 fused to Pseudomonas toxin has been tested for targeted toxin delivery in tumor cells expressing IL-4 receptors [7].

References:

1. Keegan, A.D., et al., 2021. Recent advances in understanding the role of IL-4 signaling. Fac Rev. 10: 71.
2. Bernstein, Z.J., et al., 2023. Engineering the IL-4/IL-13 axis for targeted immune modulation. Immunol Rev. 320(1):29-57. 
3. Ogulur, I., et al., 2025. Type 2 immunity in allergic diseases. Cell & Mol Immunol, 22(3):211-242.
4. Harb, H. & Chatila, T.A., 2020. Mechanisms of Dupilumab. Clin Exp Allergy. 50(1):5-14.
5. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761055s040lbl.pdf
6. Olbrich, H., et al., 2023. Dupilumab in Inflammatory Skin Diseases: A Systematic Review. Biomolecules.13(4):634.
7. Leonard, W.J & Lin, J.X, 2023. Strategies to therapeutically modulate cytokine action. Nat Rev Drug Discov. 22(10):827-854.