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IL4

Official Full Name
interleukin 4
Organism
Homo sapiens
GeneID
3565
Background
The protein encoded by this gene is a pleiotropic cytokine produced by activated T cells. This cytokine is a ligand for interleukin 4 receptor. The interleukin 4 receptor also binds to IL13, which may contribute to many overlapping functions of this cytokine and IL13. STAT6, a signal transducer and activator of transcription, has been shown to play a central role in mediating the immune regulatory signal of this cytokine. This gene, IL3, IL5, IL13, and CSF2 form a cytokine gene cluster on chromosome 5q, with this gene particularly close to IL13. This gene, IL13 and IL5 are found to be regulated coordinately by several long-range regulatory elements in an over 120 kilobase range on the chromosome. IL4 is considered an important cytokine for tissue repair, counterbalancing the effects of proinflammatory type 1 cytokines, however, it also promotes allergic airway inflammation. Moreover, IL-4, a type 2 cytokine, mediates and regulates a variety of human host responses such as allergic, anti-parasitic, wound healing, and acute inflammation. This cytokine has been reported to promote resolution of neutrophil-mediated acute lung injury. In an allergic response, IL-4 has an essential role in the production of allergen-specific immunoglobin (Ig) E. This pro-inflammatory cytokine has been observed to be increased in COVID-19 (Coronavirus disease 2019) patients, but is not necessarily associated with severe COVID-19 pathology. Two alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported. [provided by RefSeq, Aug 2020]
Synonyms
BSF1; IL-4; BCGF1; BSF-1; BCGF-1;
Bio Chemical Class
Cytokine: interleukin
Protein Sequence
MGLTSQLLPPLFFLLACAGNFVHGHKCDITLQEIIKTLNSLTEQKTLCTELTVTDIFAASKNTTEKETFCRAATVLRQFYSHHEKDTRCLGATAQQFHRHKQLIRFLKRLDRNLWGLAGLNSCPVKEANQSTLENFLERLKTIMREKYSKCSS
Open
Disease
Allergic/hypersensitivity disorder, Asthma, Atopic eczema, Idiopathic interstitial pneumonitis, Myeloproliferative neoplasm, Pulmonary eosinophilia, Systemic sclerosis
Approved Drug
0
Clinical Trial Drug
9 +
Discontinued Drug
0

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Detailed Information

Interleukin-4 (IL-4) is a pleiotropic cytokine encoded by the IL4 gene, primarily secreted by activated CD4⁺ Th2 cells, mast cells, basophils, eosinophils, and natural killer T cells (NKT cells). IL-4 plays a crucial role in regulating immune responses, tissue repair, anti-parasitic defense, and allergic inflammation among various physiological and pathological processes.

IL-4 Receptors and Signal Transduction Mechanisms

IL-4 binds to its specific receptor, IL-4 receptor α chain (IL-4Rα), forming two types of receptor complexes:

  • Type I IL-4 receptor: Composed of IL-4Rα and the common γ chain (γc), primarily expressed on hematopoietic cells.
  • Type II IL-4 receptor: Composed of IL-4Rα and IL-13Rα1, mainly present on non-hematopoietic cells.

After IL-4 binds to IL-4Rα, it induces conformational changes in the receptor, activating Janus kinase (JAK) family members JAK1 and JAK3, which subsequently phosphorylate signal transducer and activator of transcription 6 (STAT6). Phosphorylated STAT6 forms dimers that translocate to the nucleus, regulating the transcription of downstream target genes involved in the differentiation, proliferation, and function of immune cells.

Figure 1: Diagram depicting the distinct IL-4 signaling pathways in human monocytes/macrophages.Figure 1. Differential signaling pathways of IL-4 in human monocyte/macrophage alternative activation. (Bhattacharjee A, et al., 2013)

IL-4's Role in Immune Regulation

Promotion of Th2 Cell Differentiation: IL-4 is a key factor in Th2 cell differentiation. By activating the STAT6 signaling pathway, it induces naive CD4⁺ T cells to transform into the Th2 phenotype, enhancing the expression of cytokines such as IL-4, IL-5, and IL-13. This creates a positive feedback loop that further drives Th2-type immune responses.

Regulation of B Cell Function: IL-4 promotes B cell proliferation and differentiation, inducing immunoglobulin class switching, particularly to IgE and IgG1. Additionally, IL-4 upregulates the expression of CD23, the low-affinity IgE receptor, on the B cell surface, enhancing the B cell's ability to capture and present antigens.

Participation in Allergic Reactions: In allergic diseases, IL-4 contributes to the development of allergic symptoms by promoting IgE production and CD23 expression, enhancing the activation of mast cells and eosinophils, which release inflammatory mediators such as histamine.

Regulation of Macrophage Polarization: IL-4 induces macrophages to polarize toward the M2 phenotype. M2 macrophages possess anti-inflammatory and tissue repair functions, participating in the regulation of inflammatory responses and promoting tissue regeneration.

IL-4's Association with Diseases

Allergic Diseases: IL-4 plays a central role in the pathogenesis of allergic diseases such as asthma, allergic rhinitis, and atopic dermatitis. It contributes to airway hyperresponsiveness and exacerbation of inflammatory reactions by promoting IgE production and inflammatory cell activation.

Autoimmune Diseases: IL-4 demonstrates dual roles in certain autoimmune diseases. On one hand, IL-4 has anti-inflammatory effects by promoting Th2 responses and suppressing Th1-mediated inflammatory responses. On the other hand, excessive IL-4 signaling may lead to the breakdown of immune tolerance, promoting the occurrence of autoimmune reactions.

Tumor Immunity: In the tumor microenvironment, IL-4 helps tumor cells evade immune surveillance by inducing M2 macrophage polarization and activating immunosuppressive cells, thereby inhibiting anti-tumor immune responses. Furthermore, IL-4 can promote tumor cell proliferation and metastasis by regulating the expression of tumor-associated genes.

Therapeutic Applications of IL-4

Given IL-4's critical role in various diseases, therapeutic strategies targeting IL-4 or its receptors have become a research focus. For example, Dupilumab, a monoclonal antibody targeting IL-4Rα, has been approved for treating atopic dermatitis and asthma. Additionally, researchers are exploring the development of new immunotherapeutic approaches through modulating the IL-4 signaling pathway for treating autoimmune diseases and tumors.

In conclusion, IL-4, as a multifunctional cytokine, plays important roles in regulating immune responses, participating in allergic reactions, controlling inflammation, and tissue repair. In-depth research on IL-4's biological functions and signal transduction mechanisms helps reveal the pathogenesis of various diseases and provides a theoretical basis for developing new therapeutic strategies.

References

  1. Iwaszko M, Biały S, Bogunia-Kubik K. Significance of Interleukin (IL)-4 and IL-13 in Inflammatory Arthritis. Cells. 2021;10(11):3000.
  2. Bhattacharjee A, Shukla M, Yakubenko VP, et al. IL-4 and IL-13 employ discrete signaling pathways for target gene expression in alternatively activated monocytes/macrophages. Free Radic Biol Med. 2013;54:1-16.
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