IL4

Summary

IL4 (interleukin 4, HGNC:6014) is a protein-coding gene on chromosome 5q31.1, encoding Interleukin-4 (P05112). Cytokine secreted primarily by mast cells, T-cells, eosinophils, and basophils that plays a role in regulating antibody production, hematopoiesis and inflammation, and the development of effector T-cell responses.

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.

Source: NCBI Gene 3565 — RefSeq curated summary.

At a glance

• GWAS associations: 18
• Clinical variants (ClinVar): 20 total
• Druggable target: yes
• MANE Select transcript: NM_000589

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6014
Approved symbol	IL4
Name	interleukin 4
Location	5q31.1
Locus type	gene with protein product
Status	Approved
Aliases	BSF1, IL-4, BCGF1, BCGF-1, MGC79402
Ensembl gene	ENSG00000113520
Ensembl biotype	protein_coding
OMIM	147780
Entrez	3565

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000231449, ENST00000350025, ENST00000495905, ENST00000622422

RefSeq mRNA: 3 — MANE Select: NM_000589 NM_000589, NM_001354990, NM_172348

CCDS: CCDS4158, CCDS4159, CCDS87322

Canonical transcript exons

ENST00000231449 — 4 exons

Exon	Start	End
ENSE00000763067	132679714	132679890
ENSE00000763068	132674459	132674506
ENSE00000854399	132682486	132682678
ENSE00003846528	132673989	132674185

Expression profiles

Bgee: expression breadth ubiquitous, 149 present calls, max score 92.11.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0404 / max 23.0524, expressed in 7 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
58492	0.0404	7

Top tissues by expression

264 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	92.11	gold quality
secondary oocyte	CL:0000655	84.52	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.92	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	78.53	gold quality
right uterine tube	UBERON:0001302	75.08	gold quality
monocyte	CL:0000576	67.89	gold quality
leukocyte	CL:0000738	67.18	gold quality
adenohypophysis	UBERON:0002196	65.00	gold quality
pituitary gland	UBERON:0000007	64.21	gold quality
right coronary artery	UBERON:0001625	61.85	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	61.12	gold quality
bone marrow cell	CL:0002092	59.10	silver quality
granulocyte	CL:0000094	59.08	gold quality
endocervix	UBERON:0000458	58.61	gold quality
cerebellar vermis	UBERON:0004720	57.31	gold quality
ascending aorta	UBERON:0001496	56.51	gold quality
thoracic aorta	UBERON:0001515	56.34	gold quality
paraflocculus	UBERON:0005351	56.01	gold quality
frontal pole	UBERON:0002795	55.48	gold quality
gall bladder	UBERON:0002110	54.22	gold quality
vermiform appendix	UBERON:0001154	54.19	gold quality
right testis	UBERON:0004534	52.95	gold quality
caecum	UBERON:0001153	52.28	gold quality
aorta	UBERON:0000947	52.19	gold quality
lower esophagus mucosa	UBERON:0035834	52.17	gold quality
right ovary	UBERON:0002118	51.90	gold quality
ectocervix	UBERON:0012249	51.74	gold quality
Brodmann (1909) area 10	UBERON:0013541	51.39	gold quality
right adrenal gland cortex	UBERON:0035827	51.35	gold quality
spleen	UBERON:0002106	51.03	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-HCAD-29	yes	6766.68
E-ANND-3	no	1.12

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

8 targets.

Target	Regulation
AICDA	Activation
ARG1	Activation
CCN2	Repression
CD36	Activation
IDE	Activation
MRC1	Activation
NFAT5	Activation
VTCN1	Repression

Upstream regulators (CollecTRI, top): AHR, AP1, AR, BATF, BCL6, BCL6B, BHLHE41, CEBPA, CEBPB, CEBPG, CIITA, CREBBP, CREM, CTCF, CUX1, EGR1, EGR2, EGR3, ELF1, ESR1, ETS1, EZH2, FOS, FOXP3, GATA1, GATA2, GATA3, GLI3, HAND1, HAND2, HIF1A, HMGA1, IKZF1, IRF1, IRF2, IRF4, IRF6, JUN, JUNB, KAT7

Literature-anchored findings (GeneRIF, showing 40)

• Increased IL-4 expression in Mycobacterium tuberculosis-activated lymphocytes promotes CD30 expression, which sensitizes the lymphocytes to TNF-alpha-mediated apoptosis via TRAF2 depletion. (PMID:11466338)
• expression in T cells up-regulated by CD30L (PMID:11728464)
• Incubation of cultured bronchial epithelium with IL-4 causes marked inhibition of the amiloride-sensitive Na+ channel, as well as up-regulation of the cyclic AMP-dependent current demonstrated by an increase in chloride secretion and CFTR mRNA level. (PMID:11777980)
• high-affinity interaction of human IL-4 and the receptor alpha chain is constituted by two independent binding clusters (PMID:11786020)
• Characterization of IL-4 receptor components expressed on monocytes and monocyte-derived macrophages: variation associated with differential signaling by IL-4 (PMID:11811777)
• role in regulation of Toll-like receptor surface expression in human peripheral blood monocytes and B cells (PMID:11841848)
• The acetylation state of histones associated with the IL-4 promoter is a key regulator of IL4 gene expression in T cells. (PMID:11842291)
• Oligonucleotide fishing for STAT6: cross-talk between IL-4 and chemokines. (PMID:11872954)
• IL-4 enhance cytotoxic T-Lymphocytes activity by inducing cell surface molecules expression and IL-2 secretion. (PMID:11877044)
• Interleukin (IL)-4 inhibits phorbol-ester induced HIV-1 expression in chronically infected U1 cells independently from the autocrine effect of endogenous tumour (PMID:11886168)
• The germinal center (GC) B cells in tonsils and colonic mucosa are a predominant source of IL-4 and demonstrate the reliance of IL-4-dependent Th2 differentiation in vivo on strong B cell participation and the development of GCs. (PMID:11907068)
• regulates CCR5 amd CD4 expression and HIV-1 replication in human macrophages and microglia (PMID:11920312)
• IL-4 interfered with the TGF-beta-induced transcriptional activation of the CTGF gene. (PMID:11967989)
• Polymorphisms for interleukin-4 (IL-4) -590 promoter, IL-4 intron3, and tumor necrosis factor alpha -308 promoter: non-association with endometriosis (PMID:11968047)
• CD45 controls interleukin-4-mediated IgE class switch recombination in human B cells (PMID:11994288)
• Acute cardiac transplant rejection is associated with low frequencies of interleukin-4 producing helper T-lymphocytes rather than with interleukin-4 promoter or splice variants. (PMID:12039414)
• Cysteinyl leukotrienes acting on human eosinophils can act as autocrine or paracrine mediators to stimulate the rapid, nonexocytotic release of preformed IL-4. (PMID:12063527)
• increased HIV replication in the thymus by inducing differentiation and expansion of mature CD27(+) thymocytes expressing CXCR4 or CCR5 (PMID:12072494)
• results indicate opposite effects of IFN-gamma and IL-4 on VEGF expression from normal and activated HF and HK (PMID:12102661)
• IL-4 was found to down-regulate IFN-gamma and tumor necrosis factor alpha, and HIV-1 p17 restored the ability of cells to produce both cytokines (PMID:12105273)
• data are consistent with a reduced capacity to make IL-4 promoted antibody responses to exogenous antigen in early pre-diabetes (PMID:12107748)
• Association of interleukin-4 and interleukin-1B gene variants with Larsen score progression in rheumatoid arthritis. (PMID:12115161)
• There is correlation between the Chinese ulcerative colitis patients and the gene polymorphisms of intron 3 of IL-4. (PMID:12133437)
• B-CLL patients with progressive disease had a significantly increased number of T cells spontaneously producing IL-2, IL-4 and GM-CSF, suggesting a role for T cells in the pathogenesis of B-CLL. (PMID:12144536)
• These results show that p38 MAPK provides a costimulatory signal for IL-4-induced gene responses by directly stimulating the transcriptional activation of STAT6. (PMID:12161424)
• During the latent phase of HSV-1 infection, IL-4 expression was significantly elevated in BALB/C mouse brains when compared with the uninfected controls. (PMID:12162874)
• DNA methylation around the IL-4 and IL-13 genes before and after T cell differentiation (PMID:12165514)
• Vitamin E inhibits IL-4 gene expression in peripheral blood T cells by blocking binding of transcription factors to two important IL-4 promoter binding sites for NF-kappaB and AP-1 and interfering with promoter activity upon T cell activation. (PMID:12207324)
• results suggest that in DG75 cells, TRAF3-induced MEK1 activation may be involved in CD40-mediated upregulation of IL-4-driven germline C epsilon transcription (PMID:12220533)
• expression of mRNA for IL-4, IL-5, TGF-beta1, IFN-gamma in patients with cicatricial pemphigoid (PMID:12366695)
• IL-4 induction requires c-jun N-terminal kinase (PMID:12368275)
• a common haplotype of the gene is associated with severe respiratory syncytial virus disease in Korean children (PMID:12402189)
• mediates STAT6 signaling; regulated by protein phosphatase 2a (PMID:12426308)
• IL-4 intron 3 polymorphism is not a useful marker for prediction of the susceptibility of febrile seizure and epilepsy of children. (PMID:12435565)
• lack of role in modulating thymus and activation-regulated chemokine/CCL17 and interferon-induced protein of 10kDA/CXCL10 release by tumor necrosis factor-alpha and interferon-gamma in HaCaT cell line (PMID:12441140)
• IL4 regulates differentiation and maturation of dendritic cells in cooperation with DC21 and IL-12 (PMID:12470598)
• IRF-1 and IRF-2 induced by IFN-gamma bind to three distinct IL-4 promoter sites and function as transcriptional repressors (PMID:12479817)
• Human IL-21 and IL-4 bind to partially overlapping epitopes of common gamma-chain. (PMID:12504082)
• Polymorphisms in the IL-4 gene did not reveal any association with increased risk of developing rheumatoid arthritis in Taiwan Chinese. (PMID:12508786)
• induces human germinal center-associated lymphoma gene (PMID:12509382)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Il4	ENSMUSG00000000869
rattus_norvegicus	Il4	ENSRNOG00000007624

Protein

Protein identifiers

Interleukin-4 — P05112 (reviewed: P05112)

Alternative names: B-cell stimulatory factor 1, Binetrakin, Lymphocyte stimulatory factor 1, Pitrakinra

All UniProt accessions (4): P05112, D4HNR6, Q5FC01, U3LVN1

UniProt curated annotations — full annotation on UniProt →

Function. Cytokine secreted primarily by mast cells, T-cells, eosinophils, and basophils that plays a role in regulating antibody production, hematopoiesis and inflammation, and the development of effector T-cell responses. Induces the expression of class II MHC molecules on resting B-cells. Enhances both secretion and cell surface expression of IgE and IgG1. Also regulates the expression of the low affinity Fc receptor for IgE (CD23) on both lymphocytes and monocytes. Positively regulates IL31RA expression in macrophages. Stimulates autophagy in dendritic cells by interfering with mTORC1 signaling and through the induction of RUFY4. In addition, plays a critical role in higher functions of the normal brain, such as memory and learning. Upon binding to IL4, IL4R receptor dimerizes either with the common IL2R gamma chain/IL2RG to produce the type 1 signaling complex, located mainly on hematopoietic cells, or with the IL13RA1 to produce the type 2 complex, which is also expressed on nonhematopoietic cells. Engagement of both types of receptors initiates JAK3 and to a lower extend JAK1 phosphorylation leading to activation of the signal transducer and activator of transcription 6/STAT6.

Subunit / interactions. Interacts with IL4R. Interacts with IL13RA1.

Subcellular location. Secreted.

Disease relevance. Ischemic stroke (ISCHSTR) [MIM:601367] A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. Ischemic strokes, resulting from vascular occlusion, is considered to be a highly complex disease consisting of a group of heterogeneous disorders with multiple genetic and environmental risk factors. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Similarity. Belongs to the IL-4/IL-13 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P05112-1	1, Long	yes
P05112-2	2, Short, IL-4delta2

RefSeq proteins (3): NP_000580, NP_001341919, NP_758858 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001325	IL-4/IL-13	Family
IPR002354	IL-4	Family
IPR009079	4_helix_cytokine-like_core	Homologous_superfamily
IPR018096	IL-4/IL-13_CS	Conserved_site

Pfam: PF00727

UniProt features (21 total): helix 7, turn 3, disulfide bond 3, strand 2, signal peptide 1, chain 1, glycosylation site 1, splice variant 1, sequence variant 1, mutagenesis site 1

Structure

Experimental structures (PDB)

29 structures.

PDB	Method	Resolution (Å)
2D48	X-RAY DIFFRACTION	1.65
2B8X	X-RAY DIFFRACTION	1.7
2B8U	X-RAY DIFFRACTION	1.8
2B8Y	X-RAY DIFFRACTION	1.8
2B91	X-RAY DIFFRACTION	2
4YDY	X-RAY DIFFRACTION	2
1HZI	X-RAY DIFFRACTION	2.05
2B90	X-RAY DIFFRACTION	2.1
1RCB	X-RAY DIFFRACTION	2.25
1IAR	X-RAY DIFFRACTION	2.3
2INT	X-RAY DIFFRACTION	2.35
2B8Z	X-RAY DIFFRACTION	2.5
5FHX	X-RAY DIFFRACTION	2.55
1HIK	X-RAY DIFFRACTION	2.6
3BPL	X-RAY DIFFRACTION	2.93
1HIJ	X-RAY DIFFRACTION	3
3BPN	X-RAY DIFFRACTION	3.02
6OEL	X-RAY DIFFRACTION	3.1
3QB7	X-RAY DIFFRACTION	3.25
1BBN	SOLUTION NMR
1BCN	SOLUTION NMR
1CYL	SOLUTION NMR
1ITI	SOLUTION NMR
1ITL	SOLUTION NMR
1ITM	SOLUTION NMR
2CYK	SOLUTION NMR
8A4F	SOLUTION NMR
8CGF	SOLUTION NMR
8CH7	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P05112-F1	87.49	0.72

Antibody-complex structures (SAbDab): 2 — 5FHX, 6OEL

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (3): 27–151, 48–89, 70–123

Glycosylation sites (1): 62

Mutagenesis-validated functional residues (1):

Position	Phenotype
33	about 500-fold lower interaction with il4r than wt.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-6785807	Interleukin-4 and Interleukin-13 signaling
R-HSA-9012546	Interleukin-18 signaling
R-HSA-9976102	Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)
R-HSA-9942503	Differentiation of naive CD4+ T cells to T helper 1 cells (Th1 cells)

MSigDB gene sets: 501 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_DNA_RECOMBINATION, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_DENDRITIC_CELL_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_REGULATION_OF_OSTEOCLAST_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, CCAWYNNGAAR_UNKNOWN, GOBP_REGULATION_OF_PHOSPHORYLATION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM

GO Biological Process (49): negative regulation of transcription by RNA polymerase II (GO:0000122), immune response (GO:0006955), cell surface receptor signaling pathway via JAK-STAT (GO:0007259), cholesterol metabolic process (GO:0008203), positive regulation of cell population proliferation (GO:0008284), positive regulation of gene expression (GO:0010628), negative regulation of epithelial cell migration (GO:0010633), positive regulation of macroautophagy (GO:0016239), B cell differentiation (GO:0030183), positive regulation of cell migration (GO:0030335), positive regulation of B cell proliferation (GO:0030890), negative regulation of tumor necrosis factor production (GO:0032720), positive regulation of interleukin-10 production (GO:0032733), positive regulation of interleukin-13 production (GO:0032736), interleukin-4-mediated signaling pathway (GO:0035771), type 2 immune response (GO:0042092), positive regulation of T cell proliferation (GO:0042102), T cell activation (GO:0042110), macrophage activation (GO:0042116), myeloid dendritic cell differentiation (GO:0043011), negative regulation of apoptotic process (GO:0043066), regulation of isotype switching (GO:0045191), positive regulation of MHC class II biosynthetic process (GO:0045348), positive regulation of T cell differentiation (GO:0045582), negative regulation of osteoclast differentiation (GO:0045671), negative regulation of DNA-templated transcription (GO:0045892), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of receptor-mediated endocytosis (GO:0048260), positive regulation of isotype switching to IgE isotypes (GO:0048295), positive regulation of isotype switching to IgG isotypes (GO:0048304), negative regulation of inflammatory response (GO:0050728), regulation of immune response (GO:0050776), dendritic cell differentiation (GO:0097028), positive regulation of cold-induced thermogenesis (GO:0120162), neuroinflammatory response (GO:0150076), negative regulation of neuroinflammatory response (GO:0150079), positive regulation of amyloid-beta clearance (GO:1900223), positive regulation of cellular respiration (GO:1901857), negative regulation of complement-dependent cytotoxicity (GO:1903660)

GO Molecular Function (5): cytokine activity (GO:0005125), interleukin-4 receptor binding (GO:0005136), growth factor activity (GO:0008083), cytokine receptor binding (GO:0005126), protein binding (GO:0005515)

GO Cellular Component (2): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Differentiation of T cells	2
Signaling by Interleukins	1
Interleukin-1 family signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
positive regulation of lymphocyte proliferation	2
positive regulation of cytokine production	2
receptor ligand activity	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
immune system process	1
response to stimulus	1
cell surface receptor signaling pathway via STAT	1
sterol metabolic process	1
secondary alcohol metabolic process	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
epithelial cell migration	1
regulation of epithelial cell migration	1
negative regulation of cell migration	1
negative regulation of multicellular organismal process	1
positive regulation of autophagy	1
macroautophagy	1
regulation of macroautophagy	1
lymphocyte differentiation	1
B cell activation	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
regulation of B cell proliferation	1
B cell proliferation	1
positive regulation of B cell activation	1
tumor necrosis factor production	1
regulation of tumor necrosis factor production	1
negative regulation of tumor necrosis factor superfamily cytokine production	1
interleukin-10 production	1
regulation of interleukin-10 production	1
interleukin-13 production	1
regulation of interleukin-13 production	1
cytokine-mediated signaling pathway	1

Protein interactions and networks

STRING

4899 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IL4	IL2	P01585	999
IL4	IL4R	P24394	999
IL4	IL1B	P01584	998
IL4	IL7	P13232	998
IL4	IL13RA1	P78552	997
IL4	CXCL8	P10145	996
IL4	IL9	P15248	996
IL4	IL2RG	P31785	996
IL4	STAT6	P42226	995
IL4	IL1A	P01583	993
IL4	IL13	P35225	991
IL4	IFNG	P01579	990
IL4	IL10	P22301	987
IL4	JAK3	P52333	986
IL4	IL5	P05113	983

IntAct

14 interactions, top by confidence:

A	B	Type	Score
IL4	IL4R	psi-mi:“MI:0407”(direct interaction)	0.810
IL4R	IL4	psi-mi:“MI:0915”(physical association)	0.810
IL4R	IL4	psi-mi:“MI:0914”(association)	0.810
IL4	IL4R	psi-mi:“MI:0915”(physical association)	0.810
IL2RG	IL4	psi-mi:“MI:0407”(direct interaction)	0.670
IL2RG	IL4	psi-mi:“MI:0914”(association)	0.670
IL13RA1	IL4	psi-mi:“MI:0407”(direct interaction)	0.610
IL4	IL13RA1	psi-mi:“MI:0915”(physical association)	0.610

BioGRID (3): IL4 (Biochemical Activity), IL4R (Co-crystal Structure), IL4 (Reconstituted Complex)

ESM2 similar proteins: A3QPB9, H2N2P1, O02699, O62757, O77515, O77762, P04401, P05112, P05113, P07750, P20096, P30367, P30368, P42202, P46652, P46685, P47966, P48093, P51492, P51744, P52173, P55030, P79155, P79339, Q04745, Q08125, Q28586, Q2PE74, Q3S4V6, Q588F8, Q588G0, Q60440, Q62575, Q6L7I9, Q76LU5, Q76LU6, Q7YS71, Q865W5, Q865X3, Q865X5

Diamond homologs: O77762, P05112, P07750, P20096, P30367, P30368, P42202, P46652, P47966, P51492, P51744, P55030, P79155, P79339, Q04745, Q2PE74, Q3S4V6, Q58M18, Q60440, Q7YS71, Q865X5, Q865Y0, Q8HYB1, Q9MZR8, Q9XS58

SIGNOR signaling

20 interactions.

A	Effect	B	Mechanism
IL4	up-regulates	IL13RA1	binding
IL4	up-regulates	IL4R	binding
IL4	up-regulates	IL2RG	binding
IL4	“up-regulates activity”	IL4R	binding
TBX21	down-regulates	IL4	“transcriptional regulation”
NfKb-p65/p50	“up-regulates quantity by expression”	IL4	“transcriptional regulation”
NFATC1	“up-regulates quantity by expression”	IL4	“transcriptional regulation”
CIITA	down-regulates	IL4	“transcriptional regulation”
GATA3	“up-regulates quantity by expression”	IL4	“transcriptional regulation”
IRF4	“up-regulates quantity by expression”	IL4	“transcriptional regulation”
NFATC2	“up-regulates quantity by expression”	IL4	“transcriptional regulation”
JUNB	“up-regulates quantity by expression”	IL4	“transcriptional regulation”
LEF1	“down-regulates quantity by repression”	IL4	“transcriptional regulation”
POU2F1	“down-regulates quantity by repression”	IL4	“transcriptional regulation”
NFATC2	up-regulates	IL4	“transcriptional regulation”
Inflammation	up-regulates	IL4
PTGS2	up-regulates	IL4
M2_polarization	up-regulates	IL4
IL4	up-regulates	Myoblast_fusion

Disease & clinical

Clinical variants and AI predictions

ClinVar

20 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	16
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

291 predictions. Top by Δscore:

Variant	Effect	Δscore
5:132674186:GTG:G	donor_loss	1.0000
5:132674446:T:TA	acceptor_gain	1.0000
5:132679866:G:GT	donor_gain	1.0000
5:132679867:A:T	donor_gain	1.0000
5:132679886:GCTTG:G	donor_gain	1.0000
5:132679887:CTTGG:C	donor_loss	1.0000
5:132679888:TTGG:T	donor_loss	1.0000
5:132679889:TGGTA:T	donor_loss	1.0000
5:132679891:G:GG	donor_gain	1.0000
5:132682481:TGCA:T	acceptor_loss	1.0000
5:132682483:CAGA:C	acceptor_loss	1.0000
5:132682484:A:AG	acceptor_gain	1.0000
5:132682484:AGA:A	acceptor_loss	1.0000
5:132682485:G:GT	acceptor_gain	1.0000
5:132682485:GA:G	acceptor_gain	1.0000
5:132682485:GAA:G	acceptor_gain	1.0000
5:132682485:GAAT:G	acceptor_gain	1.0000
5:132682485:GAATT:G	acceptor_gain	1.0000
5:132674182:GAAG:G	donor_gain	0.9900
5:132674186:G:GG	donor_gain	0.9900
5:132674187:T:G	donor_loss	0.9900
5:132674441:A:AG	acceptor_gain	0.9900
5:132674442:T:G	acceptor_gain	0.9900
5:132674450:T:TA	acceptor_gain	0.9900
5:132674451:G:A	acceptor_gain	0.9900
5:132679708:TTCCA:T	acceptor_loss	0.9900
5:132679710:CCAGA:C	acceptor_loss	0.9900
5:132679711:CAGAA:C	acceptor_loss	0.9900
5:132679712:A:AG	acceptor_gain	0.9900
5:132679712:A:T	acceptor_loss	0.9900

AlphaMissense

1004 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:132682544:T:C	L140P	0.955
5:132679757:T:A	L76H	0.953
5:132679745:C:A	A72D	0.938
5:132679757:T:C	L76P	0.935
5:132679738:T:A	C70S	0.932
5:132679739:G:C	C70S	0.932
5:132679744:G:C	A72P	0.931
5:132679740:C:G	C70W	0.923
5:132679871:T:C	L114P	0.923
5:132674163:T:G	L38W	0.919
5:132679757:T:G	L76R	0.909
5:132682523:T:C	L133S	0.909
5:132682535:T:C	L137S	0.909
5:132679760:G:C	R77P	0.907
5:132679738:T:C	C70R	0.906
5:132679739:G:A	C70Y	0.906
5:132679871:T:A	L114H	0.906
5:132679747:G:C	A73P	0.905
5:132679859:T:A	L110H	0.900
5:132674163:T:C	L38S	0.896
5:132674465:T:A	C48S	0.888
5:132674466:G:C	C48S	0.888
5:132679859:T:C	L110P	0.887
5:132682492:T:C	C123R	0.880
5:132682492:T:A	C123S	0.877
5:132682493:G:C	C123S	0.877
5:132679850:T:C	L107P	0.876
5:132674465:T:C	C48R	0.863
5:132674148:A:T	E33V	0.855
5:132682532:T:C	F136S	0.849

dbSNP variants (sampled 300 via entrez): RS1000510871 (5:132676663 G>A), RS1000533509 (5:132677138 T>G), RS1000670746 (5:132682872 G>A), RS1000743818 (5:132681196 T>C), RS1001000682 (5:132672668 G>A,T), RS1001125550 (5:132682583 G>A), RS1001155721 (5:132679949 C>T), RS1001362103 (5:132671988 G>A), RS1002179967 (5:132678209 G>A), RS1002235805 (5:132677950 C>A,T), RS1002242628 (5:132678802 T>C), RS1002254558 (5:132672579 C>A,T), RS1002826064 (5:132681583 G>A,C), RS1002920405 (5:132675294 T>C), RS1003314987 (5:132675070 G>A,T)

Disease associations

OMIM: gene MIM:147780 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

18 associations (top):

Study	Trait	p-value
GCST001725_83	Inflammatory bowel disease	1.000000e-52
GCST002737_2	Atopic dermatitis	5.000000e-09
GCST002738_12	Psoriasis	5.000000e-06
GCST003180_4	Atopic march	5.000000e-08
GCST003268_16	Psoriasis vulgaris	3.000000e-14
GCST005212_28	Asthma	5.000000e-16
GCST005213_2	Asthma (childhood onset)	2.000000e-09
GCST005527_7	Psoriasis	3.000000e-10
GCST006862_12	Asthma	1.000000e-14
GCST007564_19	Asthma or allergic disease (pleiotropy)	2.000000e-10
GCST007995_20	Asthma (childhood onset)	3.000000e-22
GCST008916_112	Asthma	2.000000e-11
GCST008916_34	Asthma	2.000000e-09
GCST008916_48	Asthma	1.000000e-11
GCST008916_99	Asthma	6.000000e-32
GCST009798_39	Asthma	5.000000e-29
GCST009798_75	Asthma	9.000000e-24
GCST010002_38	Refractive error	3.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007755	atopic march
EFO:1001494	psoriasis vulgaris

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3712894 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2243250	Toxicity	3	aspirin	Asthma

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2243250	IL4	3	1.75	1	aspirin

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.75	Kd	1800	nM	CHEMBL5266734
5.51	EC50	3100	nM	CHEMBL5266734

PubChem BioAssay actives

2 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-amino-4-(3,4-dihydroxyphenyl)-6-(4-fluorophenyl)pyridine-3-carbonitrile	1924943: Inhibition of IL-4 (unknown origin) assessed as dissociation constant by SPR analysis	kd	1.8000	uM

CTD chemical–gene interactions

280 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Lipopolysaccharides	affects cotreatment, affects expression, decreases expression, increases reaction, affects activity (+6 more)	13
Tetradecanoylphorbol Acetate	affects cotreatment, affects reaction, increases secretion, decreases reaction, increases expression (+5 more)	13
Particulate Matter	affects methylation, increases abundance, decreases expression, decreases secretion, affects cotreatment (+3 more)	8
Calcimycin	affects cotreatment, increases expression, decreases reaction, affects response to substance, increases metabolic processing (+1 more)	7
Dexamethasone	decreases expression, decreases response to substance, affects reaction, decreases secretion, affects cotreatment (+3 more)	7
Ionomycin	affects reaction, increases secretion, decreases reaction, increases expression, decreases expression (+2 more)	7
Vehicle Emissions	decreases expression, decreases reaction, increases expression, affects cotreatment, increases secretion	6
Poly I-C	decreases secretion, increases secretion, increases response to substance, affects cotreatment, increases reaction (+3 more)	5
Tretinoin	decreases activity, affects reaction, increases secretion, decreases reaction, increases expression	5
bisphenol A	decreases expression, decreases methylation, decreases secretion, increases expression, decreases reaction (+1 more)	4
Ketoconazole	decreases expression, decreases secretion, affects cotreatment, increases expression, increases chemical synthesis (+4 more)	4
Mercuric Chloride	decreases reaction, increases secretion, decreases expression, increases expression	4
Plant Extracts	decreases reaction, increases expression, decreases expression, decreases secretion	4
Dinoprostone	increases reaction, increases secretion, increases expression, decreases secretion, affects cotreatment	4
Terbinafine	decreases secretion, affects cotreatment, increases degradation, increases secretion, increases reaction (+3 more)	3
Air Pollutants	affects methylation, increases abundance, increases methylation, decreases methylation	3
Aspirin	increases reaction, decreases secretion, decreases reaction, increases activity, increases phosphorylation (+3 more)	3
Ribavirin	increases secretion, decreases expression, decreases secretion, increases reaction	3
Dronabinol	increases expression, increases secretion, decreases reaction, increases phosphorylation, affects reaction	3
Itraconazole	increases expression, decreases expression, decreases reaction, decreases secretion, affects cotreatment (+3 more)	3
fisetin	affects cotreatment, decreases reaction, increases expression, decreases expression	2
sodium arsenite	decreases reaction, increases expression	2
bioallethrin	affects expression, affects cotreatment, increases expression	2
Amb a I protein, Ambrosia artemisiifolia	affects cotreatment, increases expression, decreases reaction	2
nickel sulfate	increases expression, increases secretion	2
N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide	increases expression, decreases expression, decreases secretion, decreases reaction	2
SB 203580	increases expression, decreases expression, decreases reaction	2
(+)-JQ1 compound	decreases expression	2
Arsenic Trioxide	affects expression, decreases expression	2
Leflunomide	increases expression, affects activity, affects cotreatment, affects expression, decreases reaction	2

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5228027	Binding	Inhibition of IL-4 (unknown origin) assessed as dissociation constant by SPR analysis	Small molecule approaches to treat autoimmune and inflammatory diseases (Part III): Targeting cytokines and cytokine receptor complexes. — Bioorg Med Chem Lett

Cellosaurus cell lines

5 cell lines: 4 transformed cell line, 1 hybrid cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_6345	1G2 [Human hybrid]	Hybrid cell line
CVCL_E3RG	HS5-IL4	Transformed cell line	Male
CVCL_E3RI	HS5-CD40L-IL4	Transformed cell line	Male
CVCL_E3RJ	HS5-CD40L(LOW)-IL4	Transformed cell line	Male
CVCL_E3RK	HS5-CD40L-IL4-IL21	Transformed cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.