Details for: IL4

Gene ID: 3565

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: IL4

Ensembl ID: ENSG00000113520

Description: interleukin 4

Cell Significance Landscape

Associated with

  • Cytokine signaling in immune system
    (R-HSA-1280215)
  • Immune system
    (R-HSA-168256)
  • Interleukin-1 family signaling
    (R-HSA-446652)
  • Interleukin-4 and interleukin-13 signaling
    (R-HSA-6785807)
  • Interleukin-18 signaling
    (R-HSA-9012546)
  • Signaling by interleukins
    (R-HSA-449147)
  • B cell differentiation
    (GO:0030183)
  • Cell surface receptor signaling pathway via jak-stat
    (GO:0007259)
  • Cholesterol metabolic process
    (GO:0008203)
  • Cytokine activity
    (GO:0005125)
  • Dendritic cell differentiation
    (GO:0097028)
  • Extracellular region
    (GO:0005576)
  • Extracellular space
    (GO:0005615)
  • Growth factor activity
    (GO:0008083)
  • Immune response
    (GO:0006955)
  • Interleukin-4 receptor binding
    (GO:0005136)
  • Interleukin-4-mediated signaling pathway
    (GO:0035771)
  • Macrophage activation
    (GO:0042116)
  • Myeloid dendritic cell differentiation
    (GO:0043011)
  • Negative regulation of apoptotic process
    (GO:0043066)
  • Negative regulation of cellular response to transforming growth factor beta stimulus
    (GO:1903845)
  • Negative regulation of complement-dependent cytotoxicity
    (GO:1903660)
  • Negative regulation of dna-templated transcription
    (GO:0045892)
  • Negative regulation of endothelial cell apoptotic process
    (GO:2000352)
  • Negative regulation of epithelial cell migration
    (GO:0010633)
  • Negative regulation of inflammatory response
    (GO:0050728)
  • Negative regulation of neuroinflammatory response
    (GO:0150079)
  • Negative regulation of osteoclast differentiation
    (GO:0045671)
  • Negative regulation of transcription by rna polymerase ii
    (GO:0000122)
  • Negative regulation of tumor necrosis factor production
    (GO:0032720)
  • Neuroinflammatory response
    (GO:0150076)
  • Positive regulation of amyloid-beta clearance
    (GO:1900223)
  • Positive regulation of atp biosynthetic process
    (GO:2001171)
  • Positive regulation of b cell proliferation
    (GO:0030890)
  • Positive regulation of cell migration
    (GO:0030335)
  • Positive regulation of cell population proliferation
    (GO:0008284)
  • Positive regulation of cellular respiration
    (GO:1901857)
  • Positive regulation of cold-induced thermogenesis
    (GO:0120162)
  • Positive regulation of dna-templated transcription
    (GO:0045893)
  • Positive regulation of gene expression
    (GO:0010628)
  • Positive regulation of interleukin-10 production
    (GO:0032733)
  • Positive regulation of interleukin-13 production
    (GO:0032736)
  • Positive regulation of isotype switching to ige isotypes
    (GO:0048295)
  • Positive regulation of isotype switching to igg isotypes
    (GO:0048304)
  • Positive regulation of macroautophagy
    (GO:0016239)
  • Positive regulation of mhc class ii biosynthetic process
    (GO:0045348)
  • Positive regulation of receptor-mediated endocytosis
    (GO:0048260)
  • Positive regulation of t-helper 2 cell cytokine production
    (GO:2000553)
  • Positive regulation of t cell differentiation
    (GO:0045582)
  • Positive regulation of t cell proliferation
    (GO:0042102)
  • Positive regulation of transcription by rna polymerase ii
    (GO:0045944)
  • Protein binding
    (GO:0005515)
  • Regulation of immune response
    (GO:0050776)
  • Regulation of isotype switching
    (GO:0045191)
  • Regulation of phosphorylation
    (GO:0042325)
  • T cell activation
    (GO:0042110)
  • Type 2 immune response
    (GO:0042092)

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • granulocyte CL0000094
    CSI 3.09
    rCSI 4.72%
    PRS 99.92
  • group 2 innate lymphoid cell CL0001069
    CSI 0.74
    rCSI 3.98%
    PRS 99.94

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

Comma-separated if multiple.
Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [IL4](/details-gene/3565) (Interleukin-4) is a pleiotropic, secreted cytokine that functions as a central regulator of the immune system. Encoded on chromosome 5, it is a key signaling molecule in the differentiation of T-helper 2 ([Th2](/details-cell/CL0000546)) cells and the promotion of a **Type 2 immune response** ([GO:0042092](https://www.ebi.ac.uk/QuickGO/term/GO:0042092)). Its discovery was pivotal in understanding the regulation of B-cell and T-cell activity ([Link](https://pubmed.ncbi.nlm.nih.gov/3016727/)). The expression data highlights its significant role as a product of cells central to allergic and anti-helminth immunity, with particularly high significance in [granulocyte](/details-cell/CL0000094) populations and [group 2 innate lymphoid cell](/details-cell/CL0001069). Clinically, [IL4](/details-gene/3565) is strongly associated with atopic diseases ([147780](https://omim.org/entry/147780)). ## Cellular Roles and Expression Landscape **Overall**, the expression profile of [IL4](/details-gene/3565) underscores its role as a signature cytokine of Type 2 immunity. The provided data indicates its highest significance in [granulocyte](/details-cell/CL0000094) (CSI: 3.09), a category that includes basophils and eosinophils, which are potent sources and responders to [IL4](/details-gene/3565). This is complemented by its high significance in [group 2 innate lymphoid cell](/details-cell/CL0001069) (ILC2s), which are critical initiators of Type 2 responses in mucosal tissues. The co-expression in these cell types suggests a coordinated role where tissue-resident ILC2s may initiate an [IL4](/details-gene/3565)-driven response, which is then amplified by recruited granulocytes. This axis is fundamental to allergic inflammation and defense against extracellular parasites. The function of [IL4](/details-gene/3565) is not merely as a marker for these cells but as their key effector molecule, orchestrating the downstream immune cascade. ## Pathways and Molecular Function The molecular functions of [IL4](/details-gene/3565) are centered on its role as a cytokine ([GO:0005125](https://www.ebi.ac.uk/QuickGO/term/GO:0005125)) that binds to the interleukin-4 receptor ([GO:0005136](https://www.ebi.ac.uk/QuickGO/term/GO:0005136)). This interaction activates the JAK/STAT signaling pathway ([GO:0007259](https://www.ebi.ac.uk/QuickGO/term/GO:0007259)), as detailed in the Reactome pathway for [Interleukin-4 and interleukin-13 signaling](/details-cell/R-HSA-6785807). Biologically, [IL4](/details-gene/3565) exerts profound effects on multiple immune cell lineages. It is a critical factor for [B cell differentiation](/details-cell/GO:0030183) and proliferation ([GO:0030890](https://www.ebi.ac.uk/QuickGO/term/GO:0030890)), and it uniquely drives immunoglobulin class switching to IgE ([GO:0048295](https://www.ebi.ac.uk/QuickGO/term/GO:0048295)), a hallmark of atopic allergy. Furthermore, it promotes the alternative activation of macrophages ([GO:0042116](https://www.ebi.ac.uk/QuickGO/term/GO:0042116)), leading to a phenotype associated with tissue repair and immunoregulation. Its involvement in both pro-inflammatory ([neuroinflammatory response](/details-cell/GO:0150076)) and anti-inflammatory processes ([negative regulation of inflammatory response](/details-cell/GO:0050728)) highlights its context-dependent regulatory functions within the broader [immune system](/details-cell/R-HSA-168256). ## Research Directions Given its established role in Type 2 immunity, research on [IL4](/details-gene/3565) is increasingly focused on understanding the precise cellular circuits that regulate its expression and function in chronic inflammatory diseases. The context-dependent nature of its signaling presents a complex but critical area for investigation. **Testable Hypotheses:** 1. The high significance of [IL4](/details-gene/3565) in both [group 2 innate lymphoid cell](/details-cell/CL0001069)s and [granulocyte](/details-cell/CL0000094)s suggests a synergistic, feed-forward loop. We hypothesize that initial [IL4](/details-gene/3565) production by tissue-resident ILC2s in response to alarmins (e.g., IL-33) primes basophils, which are then recruited to the tissue and become the major source of amplifying [IL4](/details-gene/3565) during the peak of an allergic response. 2. Functional annotations indicate that [IL4](/details-gene/3565) is involved in both promoting and negatively regulating neuroinflammation. We hypothesize that the ultimate effect of [IL4](/details-gene/3565) in the central nervous system is cell-type specific, where it induces a pro-resolving, anti-inflammatory phenotype in microglia while potentially exacerbating pathology through its effects on astrocytes or other glial cells. **Proposed Experimental Approach:** To test the first hypothesis regarding the synergistic interplay between ILC2s and basophils, one could establish an *in vitro* co-culture system using primary human cells. Lung-resident ILC2s would be isolated and stimulated with IL-33 to initiate cytokine production. Peripheral blood basophils would then be co-cultured with the activated ILC2s or exposed to their conditioned medium. The expression of [IL4](/details-gene/3565) and other Type 2 cytokines would be quantified on a single-cell level using a combination of intracellular cytokine staining with flow cytometry and targeted transcriptomics to precisely determine which cell type is responsible for the amplification of the signal. **Therapeutic Potential:** [IL4](/details-gene/3565) is a highly validated therapeutic target for diseases driven by Type 2 inflammation, such as atopic dermatitis, asthma, and chronic rhinosinusitis with nasal polyps. As a secreted cytokine, it is readily accessible to biologic drugs. The therapeutic strategy is **inhibition** of its signaling pathway. This has been successfully realized with monoclonal antibodies targeting the IL-4 receptor alpha subunit (IL-4Rα), which is shared with the IL-13 receptor, effectively blocking the downstream signaling of both key cytokines. This approach has proven clinically effective, validating [IL4](/details-gene/3565) signaling as a critical pathogenic axis.

Genular Protein ID: 3735448967

Symbol: IL4_HUMAN

Name: Interleukin-4

UniProtKB Accession Codes:

P05112 Q14630 Q6NZ77

Database IDs:

ABCD 1 AGR 1 AlphaFoldDB 1 Antibodypedia 1 BMRB 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 2 CORUM 1 CTD 1 ChEMBL 1 ComplexPortal 2 DIP 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 3 DrugCentral 1 EMBL 8 Ensembl 2 EvolutionaryTrace 1 ExpressionAtlas 1 GO 51 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 4 KEGG 1 MANE-Select 1 MIM 3 MINT 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 29 PDBsum 29 PIR 1 PIRSF 1 PRINTS 1 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 2 RNAct 1 Reactome 2 RefSeq 2 SIGNOR 1 SMART 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 3016727

Title: Isolation and characterization of a human interleukin cDNA clone, homologous to mouse B-cell stimulatory factor 1, that expresses B-cell- and T-cell-stimulating activities.

PubMed ID: 3016727

DOI: 10.1073/pnas.83.16.5894

PubMed ID: 2535858

Title: Complete nucleotide sequence of the chromosomal gene for human IL-4 and its expression.

PubMed ID: 2535858

PubMed ID: 7806280

Title: An alternatively spliced interleukin 4 form in lymphoid cells.

PubMed ID: 7806280

DOI: 10.1007/bf00188440

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 3257560

Title: The 5' region of the human interleukin 4 gene: structure and potential regulatory elements.

PubMed ID: 3257560

DOI: 10.1093/nar/16.2.772

PubMed ID: 1993171

Title: Disulfide assignments in recombinant mouse and human interleukin 4.

PubMed ID: 1993171

DOI: 10.1021/bi00220a011

PubMed ID: 2521231

Title: Influence of recombinant IL-4, IFN-alpha, and IFN-gamma on the production of human IgE-binding factor (soluble CD23).

PubMed ID: 2521231

PubMed ID: 2971718

Title: Human recombinant IL-4 induces activated B lymphocytes to produce IgG and IgM.

PubMed ID: 2971718

PubMed ID: 7721895

Title: Activation of JAK3, but not JAK1, is critical to interleukin-4 (IL4) stimulated proliferation and requires a membrane-proximal region of IL4 receptor alpha.

PubMed ID: 7721895

DOI: 10.1074/jbc.270.16.9630

PubMed ID: 1946344

Title: Experimental and theoretical studies of the three-dimensional structure of human interleukin-4.

PubMed ID: 1946344

DOI: 10.1002/prot.340110204

PubMed ID: 1932028

Title: Secondary structure and topology of human interleukin 4 in solution.

PubMed ID: 1932028

DOI: 10.1021/bi00110a004

PubMed ID: 1400355

Title: Crystal structure of recombinant human interleukin-4.

PubMed ID: 1400355

DOI: 10.2210/pdb2int/pdb

PubMed ID: 1511746

Title: Crystal structure of human recombinant interleukin-4 at 2.25-A resolution.

PubMed ID: 1511746

DOI: 10.1016/0014-5793(92)80739-4

PubMed ID: 1569578

Title: Human interleukin 4. The solution structure of a four-helix bundle protein.

PubMed ID: 1569578

DOI: 10.1016/0022-2836(92)90457-u

PubMed ID: 1567880

Title: 1H, 15N, 13C, and 13CO assignments of human interleukin-4 using three-dimensional double- and triple-resonance heteronuclear magnetic resonance spectroscopy.

PubMed ID: 1567880

DOI: 10.1021/bi00132a026

PubMed ID: 1567881

Title: Determination of the secondary structure and folding topology of human interleukin-4 using three-dimensional heteronuclear magnetic resonance spectroscopy.

PubMed ID: 1567881

DOI: 10.1021/bi00132a027

PubMed ID: 1609277

Title: Three-dimensional solution structure of human interleukin-4 by multidimensional heteronuclear magnetic resonance spectroscopy.

PubMed ID: 1609277

DOI: 10.1126/science.256.5064.1673

PubMed ID: 8151703

Title: Aspects of receptor binding and signalling of interleukin-4 investigated by site-directed mutagenesis and NMR spectroscopy.

PubMed ID: 8151703

DOI: 10.1006/jmbi.1994.1245

PubMed ID: 7664036

Title: Comparison of four independently determined structures of human recombinant interleukin-4.

PubMed ID: 7664036

DOI: 10.1038/nsb0594-301

PubMed ID: 10219247

Title: Crystal structure of the interleukin-4/receptor alpha chain complex reveals a mosaic binding interface.

PubMed ID: 10219247

DOI: 10.1016/s0092-8674(00)80736-9

PubMed ID: 11526337

Title: Structure of interleukin 4 mutant E9A suggests polar steering in receptor-complex formation.

PubMed ID: 11526337

DOI: 10.1107/s0907444901009799

PubMed ID: 18243101

Title: Molecular and structural basis of cytokine receptor pleiotropy in the interleukin-4/13 system.

PubMed ID: 18243101

DOI: 10.1016/j.cell.2007.12.030

PubMed ID: 14681304

Title: Polymorphism in the P-selectin and interleukin-4 genes as determinants of stroke: a population-based, prospective genetic analysis.

PubMed ID: 14681304

DOI: 10.1093/hmg/ddh039

Sequence Information:

  • Length: 153
  • Mass: 17492
  • Checksum: 8725BF64B34D45F7
  • Sequence:
    • MGLTSQLLPP LFFLLACAGN FVHGHKCDIT LQEIIKTLNS LTEQKTLCTE LTVTDIFAAS 
KNTTEKETFC RAATVLRQFY SHHEKDTRCL GATAQQFHRH KQLIRFLKRL DRNLWGLAGL 
NSCPVKEANQ STLENFLERL KTIMREKYSK CSS

Genular Protein ID: 4236654227

Symbol: Q5FC01_HUMAN

Name: N/A

UniProtKB Accession Codes:

Q5FC01

Database IDs:

ARBA 5 AlphaFoldDB 1 Antibodypedia 1 BioGRID-ORCS 1 CTD 1 DNASU 1 DisGeNET 1 EMBL 4 ExpressionAtlas 1 GO 36 Gene3D 1 HOGENOM 1 InterPro 3 NCBI Taxonomy 1 OrthoDB 1 PANTHER 2 PIRNR 1 PIRSF 1 PIRSR 1 PRINTS 1 Pfam 1 PharmGKB 1 RefSeq 1 SAM 1 SMART 1 SMR 1 SUPFAM 1 UCSC 1 VEuPathDB 1

Citations:

PubMed ID: 11181995

Title: The sequence of the human genome.

PubMed ID: 11181995

DOI: 10.1126/science.1058040

Sequence Information:

  • Length: 137
  • Mass: 15797
  • Checksum: 3B621F60D0F0D261
  • Sequence:
    • MGLTSQLLPP LFFLLACAGN FVHGHKCDIT LQEIIKTLNS LTEQKNTTEK ETFCRAATVL 
RQFYSHHEKD TRCLGATAQQ FHRHKQLIRF LKRLDRNLWG LAGLNSCPVK EANQSTLENF 
LERLKTIMRE KYSKCSS