IL33

Summary

IL33 (interleukin 33, HGNC:16028) is a protein-coding gene on chromosome 9p24.1, encoding Interleukin-33 (O95760). Cytokine that binds to and signals through the IL1RL1/ST2 receptor which in turn activates NF-kappa-B and MAPK signaling pathways in target cells.

The protein encoded by this gene is a cytokine that binds to the IL1RL1/ST2 receptor. The encoded protein is involved in the maturation of Th2 cells and the activation of mast cells, basophils, eosinophils and natural killer cells. Several transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 90865 — RefSeq curated summary.

At a glance

• GWAS associations: 66
• Clinical variants (ClinVar): 64 total
• Druggable target: yes
• MANE Select transcript: NM_033439

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16028
Approved symbol	IL33
Name	interleukin 33
Location	9p24.1
Locus type	gene with protein product
Status	Approved
Aliases	DVS27, DKFZp586H0523, NF-HEV, IL1F11
Ensembl gene	ENSG00000137033
Ensembl biotype	protein_coding
OMIM	608678
Entrez	90865

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 24 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000381434, ENST00000417746, ENST00000456383, ENST00000463336, ENST00000611532, ENST00000682010, ENST00000893939, ENST00000893940, ENST00000893941, ENST00000893942, ENST00000893943, ENST00000893944, ENST00000893945, ENST00000893946, ENST00000893947, ENST00000893948, ENST00000893949, ENST00000893950, ENST00000893951, ENST00000893952, ENST00000893953, ENST00000948088, ENST00000948089, ENST00000948090, ENST00000948091

RefSeq mRNA: 9 — MANE Select: NM_033439 NM_001199640, NM_001199641, NM_001314044, NM_001314045, NM_001314046, NM_001314047, NM_001314048, NM_001353802, NM_033439

CCDS: CCDS56563, CCDS56564, CCDS6468, CCDS83341

Canonical transcript exons

ENST00000682010 — 8 exons

Exon	Start	End
ENSE00000927863	6250474	6250599
ENSE00000927864	6251140	6251265
ENSE00000927865	6252866	6252991
ENSE00000927866	6253552	6253602
ENSE00000927867	6254462	6254553
ENSE00001488607	6255968	6257983
ENSE00001778724	6241684	6241785
ENSE00003918877	6215807	6215852

Expression profiles

Bgee: expression breadth ubiquitous, 239 present calls, max score 96.66.

FANTOM5 (CAGE): breadth broad, TPM avg 15.8834 / max 946.2399, expressed in 624 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
95978	14.7507	577
95979	0.6658	124
95977	0.4094	188
95980	0.0575	22

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	96.66	gold quality
right coronary artery	UBERON:0001625	96.55	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	96.53	gold quality
smooth muscle tissue	UBERON:0001135	96.28	gold quality
left coronary artery	UBERON:0001626	95.32	gold quality
descending thoracic aorta	UBERON:0002345	95.12	gold quality
gall bladder	UBERON:0002110	94.27	gold quality
lower esophagus muscularis layer	UBERON:0035833	94.24	gold quality
lower esophagus	UBERON:0013473	94.20	gold quality
coronary artery	UBERON:0001621	94.18	gold quality
lymph node	UBERON:0000029	93.60	gold quality
thoracic aorta	UBERON:0001515	92.90	gold quality
ascending aorta	UBERON:0001496	92.75	gold quality
colonic epithelium	UBERON:0000397	92.62	gold quality
right atrium auricular region	UBERON:0006631	92.62	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	92.39	gold quality
body of stomach	UBERON:0001161	91.94	gold quality
superficial temporal artery	UBERON:0001614	91.94	gold quality
ventricular zone	UBERON:0003053	91.76	gold quality
omental fat pad	UBERON:0010414	91.53	gold quality
peritoneum	UBERON:0002358	91.48	gold quality
mucosa of stomach	UBERON:0001199	91.45	gold quality
cardiac atrium	UBERON:0002081	91.29	gold quality
nasal cavity mucosa	UBERON:0001826	91.25	gold quality
left uterine tube	UBERON:0001303	91.17	gold quality
mucosa of paranasal sinus	UBERON:0005030	91.05	gold quality
body of uterus	UBERON:0009853	91.00	gold quality
endocervix	UBERON:0000458	90.97	gold quality
adipose tissue of abdominal region	UBERON:0007808	90.92	gold quality
stomach	UBERON:0000945	90.57	gold quality

Single-cell (SCXA)

Detected in 13 experiment(s), a significant marker in 12.

Experiment	Marker?	Max mean expression
E-MTAB-6308	yes	760.94
E-MTAB-8559	yes	676.13
E-CURD-114	yes	272.67
E-MTAB-10553	yes	52.18
E-HCAD-1	yes	39.32
E-MTAB-6701	yes	28.31
E-HCAD-9	yes	20.74
E-MTAB-8410	yes	20.30
E-ANND-3	yes	18.08
E-MTAB-6678	yes	12.51
E-MTAB-7249	yes	8.74
E-GEOD-130148	yes	5.65
E-MTAB-6386	no	21.83

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

5 targets.

Target	Regulation
CD80	Activation
CD86	Activation
IL6	Activation
NOS2	Activation
TNF	Activation

Upstream regulators (CollecTRI, top): GATA4, GLI2, IRF7, NFIL3, RELA, TBX2, TNF

miRNA regulators (miRDB)

85 targeting IL33, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-548P	99.98	72.25	3784
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-8087	99.90	69.55	1351
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-95-5P	99.89	72.17	3973
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-4799-5P	99.82	70.60	2663

Literature-anchored findings (GeneRIF, showing 40)

• Results suggest that NF-HEV may be one of the key nuclear factors that controls the specialized phenotype of the lymphatic venule endothelium. (PMID:12819012)
• IL-33, which mediates its biological effects via IL-1 receptor ST 2, activates NF-kappaB and MAP kinases, and drives production of T(H)2-associated cytokines from in vitro polarized T(H)2 cells (PMID:16286016)
• IL-33 is a dual function protein that may function as both a proinflammatory cytokine and an intracellular nuclear factor with transcriptional regulatory properties. (PMID:17185418)
• ST2 reduced production of IL-4, IL-5, and IL-13 from IL-33-stimulated splenocytes. These results indicate that soluble ST2 acts as a negative regulator of Th2 cytokine production by the IL-33 signaling. (PMID:17623648)
• IL-33 may play an important role in mast cell-mediated inflammation (PMID:17675461)
• IL-33 may enhance mast cell function in allergic disorders and other settings, either in the presence or absence of co-stimulation of mast cells via IgE/antigen-FcepsilonRI signals. (PMID:17700564)
• IL-33 is a selective T helper (Th) type 2 cell chemoattractant that increases the proportion of human Th2 cells in polarized morphology in vitro and stimulates their subsequent invasion into collagen gels. (PMID:17853410)
• The ability of recombinant human IL-33 to induce type 2 T helper (Th2) cell responses has functional relevance in the context of helminth infection, particularly during the initiation of the response. (PMID:18250453)
• IL-33 and its receptor, ST2, may play important roles in eosinophil-mediated inflammation (PMID:18539196)
• Docks into the acidic pocket formed by the histone 2A-2B dimer at the nucleosomal surface. (PMID:18688256)
• Interleukin-33 enhances adhesion, CD11b expression and survival in human eosinophils (PMID:18762778)
• The proposed transcriptional repressor function of IL-33 may be involved in the control of endothelial cell activation. (PMID:18787100)
• New cytokine interleukin (IL)-33, in the presence of antigen, polarizes murine and human naive CD4-positive T cells into a population of T cells which produce mainly IL-5 but not IL-4. (PMID:18802081)
• As discussed in this Review, the interleukin (IL)-33/IL-1 receptor family member ST2 pathway may play a part in the progression of atherosclerotic vascular disease. (PMID:18827826)
• IL33 is constitutively expressed in the nucleus of endothelial cells and epithelial cells in vivo. (PMID:18836528)
• IL-33 potently induces several arrays of basophil functions such as basophil migration toward eotaxin, adhesiveness, activation, degranulation, and cytokine generation via a basophil receptor, suppression of tumorigenicity 2 (ST2). (PMID:18941187)
• basophils and eosinophils are the only direct target leukocytes for IL-33, suggesting that IL-33 promotes allergic inflammation and Th2 polarization (PMID:18955562)
• results support a role for IL-33 in the pathogenesis of Japanese cedar pollinosis. (PMID:19037964)
• SNPs at WDR36, IL33 and MYB that showed suggestive association with eosinophil counts were also associated with atopic asthma. (PMID:19198610)
• IL-33 is produced locally in inflamed joints, and neutralization of IL-33 signaling has a therapeutic effect on the course of arthritis. (PMID:19248109)
• IL-33 can contribute as a co-stimulatory factor to innate cellular immune responses. (PMID:19266498)
• results demonstrate that interleukin-33 and troponin I assays can be multiplexed and retain the necessary precision, reproducibility, and sensitivity to be applied to new candidate biomarkers for verification of low-abundance proteins in blood (PMID:19372185)
• Human adipocytes and preadipocytes express IL-33. (PMID:19393621)
• full-length IL-331-270 is biologically active; cleavage by caspase-1 does not occur at the site initially proposed but rather after residue Asp178 within the IL-1-like domain. (PMID:19439663)
• Results clearly show that caspase-1 cleavage is not required for pro-IL-33 secretion and bioactivity, highlighting major differences between IL-1beta and IL-33. (PMID:19465481)
• IL-33 is strongly associated with fibrosis in chronic liver injury and activated hepatic stellate cells are a source of IL-33. (PMID:19508382)
• IL-33 does not require proteolysis for activation, but rather, that IL-33 bioactivity is diminished through caspase-dependent proteolysis within apoptotic cells. (PMID:19559631)
• These results indicate that calpains play a critical role in pro-IL-33 processing in vivo. (PMID:19596270)
• ST2 gene expression is proliferation-dependent and its ligand, IL-33, induces inflammatory reaction in endothelial cells (PMID:19756962)
• these data propose IL-33 as a novel inflammatory marker of severe and refractory asthma. (PMID:19801525)
• IL-33/ST2 plays a significant role in the amplification of alternatively activated macrophages polarization and chemokine production which contribute to innate and Ag-induced airway inflammation. (PMID:19841166)
• We provide unprecedented genetic evidence suggesting a role for the IL33 pathway in the pathogenesis of nasal polyposis (PMID:19860791)
• near complete NMR backbone and side chain assignments of the human cytokine interleukin-33 (IL-33) in solution (PMID:19888696)
• The summarizes wide range of documented IL-33 activities on human cellular mediators of inflammation as well as genetic evidence that IL-33 contributes to disease. (PMID:19906013)
• upregulated in colonocytes of ulcerative colitis (PMID:19913053)
• Data show that IL-33 levels are elevated in sera and synovial fluid samples from patients with rheumatoid arthritis, and correlated with disease activity. (PMID:19918048)
• IL-33 markedly enhanced eosinophil survival and upregulated cell surface expression of the adhesion molecule intercellular adhesion molecule (ICAM)-1 on eosinophils, but it suppressed that of ICAM-3 and L-selectin. (PMID:20029461)
• Full length IL-33 and its N-terminal caspase 3 breakdown product translocate to the nucleus. (PMID:20035719)
• enhances IL-6 and IL-8 production in synoviocytes od rheuumatoid arthritis (PMID:20072851)
• This study sheds light on the relevance of further using IL-33 BALF levels and studying epithelial cells’ IL-33 expression as potential biomarkers in moderate and severe asthma (PMID:20153038)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Il33	ENSMUSG00000024810
rattus_norvegicus	Il33	ENSRNOG00000016456

Protein

Protein identifiers

Interleukin-33 — O95760 (reviewed: O95760)

Alternative names: Interleukin-1 family member 11, Nuclear factor from high endothelial venules

All UniProt accessions (2): A0A1I9RI50, O95760

UniProt curated annotations — full annotation on UniProt →

Function. Cytokine that binds to and signals through the IL1RL1/ST2 receptor which in turn activates NF-kappa-B and MAPK signaling pathways in target cells. Involved in the maturation of Th2 cells inducing the secretion of T-helper type 2-associated cytokines. Also involved in activation of mast cells, basophils, eosinophils and natural killer cells. Acts as an enhancer of polarization of alternatively activated macrophages. Acts as a chemoattractant for Th2 cells, and may function as an ‘alarmin’, that amplifies immune responses during tissue injury. Induces rapid UCP2-dependent mitochondrial rewiring that attenuates the generation of reactive oxygen species and preserves the integrity of Krebs cycle required for persistent production of itaconate and subsequent GATA3-dependent differentiation of inflammation-resolving alternatively activated macrophages. In quiescent endothelia the uncleaved form is constitutively and abundantly expressed, and acts as a chromatin-associated nuclear factor with transcriptional repressor properties, it may sequester nuclear NF-kappaB/RELA, lowering expression of its targets. This form is rapidely lost upon angiogenic or pro-inflammatory activation.

Subunit / interactions. Forms a 1:1:1 heterotrimeric complex with its primary high-affinity receptor IL1RL1 and the coreceptor IL1RAP. Interacts with cargo receptor TMED10; the interaction mediates the translocation from the cytoplasm into the ERGIC (endoplasmic reticulum-Golgi intermediate compartment) and thereby secretion. (Microbial infection) Interacts (in reduced form) with H.polygyrus ARI.

Subcellular location. Nucleus. Chromosome. Cytoplasm. Cytoplasmic vesicle. Secretory vesicle. Secreted.

Tissue specificity. Expressed at high level in high endothelial venules found in tonsils, Peyer patches and mesenteric lymph nodes. Almost undetectable in placenta.

Post-translational modifications. The full-length protein can be released from cells and is able to signal via the IL1RL1/ST2 receptor. However, proteolytic processing by CELA1, CSTG/cathepsin G and ELANE/neutrophil elastase produces C-terminal peptides that are more active than the unprocessed full length protein. May also be proteolytically processed by calpains. Proteolytic cleavage mediated by apoptotic caspases including CASP3 and CASP7 results in IL33 inactivation. In vitro proteolytic cleavage by CASP1 was reported but could not be confirmed in vivo suggesting that IL33 is probably not a direct substrate for that caspase.

Domain organisation. The homeodomain-like HTH domain mediates nuclear localization and heterochromatin association.

Induction. By infection with the parasite H.polygyrus.

Miscellaneous. Constitutively active.

Similarity. Belongs to the IL-1 family. Highly divergent.

Isoforms (4)

UniProt ID	Names	Canonical?
O95760-1	1	yes
O95760-2	2
O95760-3	3, spIL-33
O95760-4	4

RefSeq proteins (9): NP_001186569, NP_001186570, NP_001300973, NP_001300974, NP_001300975, NP_001300976, NP_001300977, NP_001340731, NP_254274* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR026145	IL-33	Family
IPR053902	IL33_C	Domain

Pfam: PF15095

UniProt features (38 total): strand 13, mutagenesis site 5, chain 4, splice variant 3, turn 3, site 3, helix 2, region of interest 2, propeptide 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
9X0J	ELECTRON MICROSCOPY	2.57
4KC3	X-RAY DIFFRACTION	3.27
9WWH	X-RAY DIFFRACTION	3.51
9X05	ELECTRON MICROSCOPY	3.64
2KLL	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95760-F1	66.91	0.33

Functional residue map

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

Catalytic / active sites (3): 94–95 (cleavage; by ctsg); 98–99 (cleavage; by elane); 108–109 (cleavage; by ctsg)

Mutagenesis-validated functional residues (5):

Position	Phenotype
144	decreases affinity for il1rl1.
148	7-fold decrease in affinity for il1rl1.
149	almost abolishes binding to il1rl1.
165	8-fold decrease in affinity for il1rl1.
244	decreases affinity for il1rl1.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-5689880	Ub-specific processing proteases
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-HSA-9014843	Interleukin-33 signaling

MSigDB gene sets: 334 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_POSITIVE_REGULATION_OF_MACROPHAGE_ACTIVATION, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_MACROPHAGE_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_PRODUCTION_OF_MOLECULAR_MEDIATOR_OF_IMMUNE_RESPONSE, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS

GO Biological Process (44): negative regulation of transcription by RNA polymerase II (GO:0000122), positive regulation of cytokine production (GO:0001819), microglial cell activation involved in immune response (GO:0002282), negative regulation of immunoglobulin production (GO:0002638), positive regulation of immunoglobulin production (GO:0002639), negative regulation of leukocyte migration (GO:0002686), negative regulation of T-helper 1 type immune response (GO:0002826), positive regulation of type 2 immune response (GO:0002830), protein import into nucleus (GO:0006606), response to wounding (GO:0009611), positive regulation of cellular defense response (GO:0010186), gene expression (GO:0010467), positive regulation of glycoprotein biosynthetic process (GO:0010560), positive regulation of gene expression (GO:0010628), macrophage differentiation (GO:0030225), positive regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032436), negative regulation of type II interferon production (GO:0032689), positive regulation of chemokine production (GO:0032722), positive regulation of interleukin-13 production (GO:0032736), positive regulation of interleukin-4 production (GO:0032753), positive regulation of interleukin-5 production (GO:0032754), positive regulation of interleukin-6 production (GO:0032755), positive regulation of tumor necrosis factor production (GO:0032760), interleukin-33-mediated signaling pathway (GO:0038172), type 2 immune response (GO:0042092), positive regulation of macrophage activation (GO:0043032), positive regulation of MHC class I biosynthetic process (GO:0045345), positive regulation of MHC class II biosynthetic process (GO:0045348), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of inflammatory response (GO:0050729), defense response to virus (GO:0051607), microglial cell proliferation (GO:0061518), extrinsic apoptotic signaling pathway (GO:0097191), negative regulation of inflammatory response to wounding (GO:0106015), negative regulation of macrophage proliferation (GO:0120042), antibacterial innate immune response (GO:0140367), positive regulation of neuroinflammatory response (GO:0150078), macrophage activation involved in immune response (GO:0002281), signal transduction (GO:0007165), phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0043491)

GO Molecular Function (3): interleukin-33 receptor binding (GO:0002112), cytokine activity (GO:0005125), protein binding (GO:0005515)

GO Cellular Component (8): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), nucleus (GO:0005634), nucleoplasm (GO:0005654), chromosome (GO:0005694), cytoplasm (GO:0005737), transport vesicle (GO:0030133), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Intracellular signaling by second messengers	1
Deubiquitination	1
Negative regulation of the PI3K/AKT network	1
Interleukin-1 family signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
positive regulation of cytokine production	3
cellular anatomical structure	3
immunoglobulin production	2
regulation of immunoglobulin production	2
positive regulation of macromolecule biosynthetic process	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
cytokine production	1
regulation of cytokine production	1
positive regulation of gene expression	1
positive regulation of multicellular organismal process	1
microglial cell activation	1
macrophage activation involved in immune response	1
immune response	1
negative regulation of production of molecular mediator of immune response	1
positive regulation of production of molecular mediator of immune response	1
negative regulation of immune system process	1
regulation of leukocyte migration	1
negative regulation of cell migration	1
leukocyte migration	1
negative regulation of adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains	1
regulation of T-helper 1 type immune response	1
T-helper 1 type immune response	1
regulation of type 2 immune response	1
type 2 immune response	1
positive regulation of immune response	1
intracellular protein transport	1
protein localization to nucleus	1
import into nucleus	1
establishment of protein localization to organelle	1
response to stress	1
cellular defense response	1
regulation of cellular defense response	1
positive regulation of defense response	1
macromolecule biosynthetic process	1
glycoprotein biosynthetic process	1
regulation of glycoprotein biosynthetic process	1
positive regulation of glycoprotein metabolic process	1
gene expression	1

Protein interactions and networks

STRING

2636 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IL33	IL1RL1	Q01638	999
IL33	IL1RAP	Q9NPH3	996
IL33	IL1R1	P14778	988
IL33	CRLF2	Q9HC73	946
IL33	IL13	P35225	938
IL33	IL5	P05113	936
IL33	IL17RB	Q9NRM6	931
IL33	TSLP	Q969D9	925
IL33	MYD88	P78397	912
IL33	IL4	P05112	904
IL33	IL18R1	Q13478	893
IL33	IL1B	P01584	886
IL33	IL18	Q14116	868
IL33	IL25	Q9H293	864
IL33	IL17A	Q16552	851

IntAct

10 interactions, top by confidence:

A	B	Type	Score
IL33	H2AC11	psi-mi:“MI:0914”(association)	0.500
IL33	H2AC11	psi-mi:“MI:0915”(physical association)	0.500
IL1RL1	IL33	psi-mi:“MI:0407”(direct interaction)	0.440
IL1RL1	IL33	psi-mi:“MI:0915”(physical association)	0.400
IL33	GALM	psi-mi:“MI:0915”(physical association)	0.400
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
IL33	CRMP1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (14): USP21 (Affinity Capture-Western), IL33 (Affinity Capture-Western), IL33 (Affinity Capture-MS), USP17L2 (Affinity Capture-Western), IL33 (Affinity Capture-Western), IL1RL1 (Reconstituted Complex), IL33 (Reconstituted Complex), GALM (Affinity Capture-MS), MDM2 (Affinity Capture-Western), IL33 (Affinity Capture-Western), IL33 (Biochemical Activity), HIST2H2AA3 (Reconstituted Complex), HIST2H2BE (Reconstituted Complex), IL33 (Biochemical Activity)

ESM2 similar proteins: A0A0R4IBK5, A4QNW7, A6QR20, D3ZSP7, O15050, O46612, O46613, O95760, O97863, P01582, P01583, P04822, P08831, P16598, P18430, P46647, P48089, P62932, P79161, P79340, Q0V9U8, Q0VD34, Q16533, Q1LVQ2, Q28385, Q28579, Q3HWU1, Q497M3, Q4R6W9, Q5R4I8, Q5RBY8, Q5RDG8, Q5U228, Q66H70, Q6AX58, Q6AXX9, Q6NU22, Q6NU51, Q6ZN28, Q865X7

Diamond homologs: O95760, O97863, Q5RDG8, Q66H70, Q8BVZ5

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
IL33	“up-regulates activity”	IL1RL1	binding
IL33	up-regulates	M2_polarization

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	45
Likely benign	5
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

1019 predictions. Top by Δscore:

Variant	Effect	Δscore
9:6241781:GGGAA:G	donor_gain	1.0000
9:6241782:GGAAG:G	donor_gain	1.0000
9:6241783:G:GT	donor_gain	1.0000
9:6241783:G:T	donor_gain	1.0000
9:6241786:G:GG	donor_gain	1.0000
9:6241791:GACT:G	donor_gain	1.0000
9:6254459:A:AG	acceptor_gain	1.0000
9:6254459:AAGGT:A	acceptor_gain	1.0000
9:6254460:A:G	acceptor_gain	1.0000
9:6241782:GGAA:G	donor_gain	0.9900
9:6241783:GAA:G	donor_gain	0.9900
9:6241794:T:G	donor_gain	0.9900
9:6241794:T:TG	donor_gain	0.9900
9:6241799:T:G	donor_gain	0.9900
9:6252883:GA:G	acceptor_gain	0.9900
9:6254453:A:AG	acceptor_gain	0.9900
9:6254458:TAAG:T	acceptor_loss	0.9900
9:6254459:AAG:A	acceptor_gain	0.9900
9:6254460:A:AG	acceptor_loss	0.9900
9:6254453:AATT:A	acceptor_gain	0.9800
9:6254454:A:G	acceptor_gain	0.9800
9:6254551:G:GT	donor_gain	0.9800
9:6256078:TGTA:T	donor_gain	0.9800
9:6250471:TAGA:T	acceptor_gain	0.9700
9:6250472:AGAA:A	acceptor_gain	0.9700
9:6252326:GCTA:G	acceptor_gain	0.9700
9:6254461:G:GG	acceptor_gain	0.9700
9:6254461:GGT:G	acceptor_gain	0.9700
9:6254549:TGGAG:T	donor_loss	0.9700
9:6254552:AGG:A	donor_loss	0.9700

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000038492 (9:6242726 C>T), RS1000144867 (9:6248538 T>G), RS1000184077 (9:6235141 G>A), RS1000225188 (9:6237327 C>G), RS1000312600 (9:6240665 T>C), RS1000407628 (9:6230975 A>G), RS1000428782 (9:6240390 G>C), RS1000589626 (9:6244413 T>C), RS1000648826 (9:6241843 A>C), RS1000660816 (9:6234919 C>T), RS1000744843 (9:6232598 A>T), RS1000763263 (9:6241615 T>C), RS1000765312 (9:6238801 G>C,T), RS1000828039 (9:6237572 A>G), RS1000840732 (9:6226770 C>T)

Disease associations

OMIM: gene MIM:608678 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): prostate cancer (MONDO:0008315)

Orphanet (1): Familial prostate cancer (Orphanet:1331)

HPO phenotypes

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

GWAS associations

66 associations (top):

Study	Trait	p-value
GCST000804_3	Asthma	9.000000e-10
GCST001182_3	Asthma	2.000000e-12
GCST001588_15	Periodontal microbiota	3.000000e-06
GCST001894_4	Endometriosis	9.000000e-07
GCST002083_24	Self-reported allergy	2.000000e-09
GCST002275_3	Asthma (childhood onset)	9.000000e-13
GCST002322_7	Asthma and hay fever	2.000000e-09
GCST003987_3	Asthma	1.000000e-31
GCST003990_13	Allergy	8.000000e-11
GCST004746_20	Small cell lung carcinoma	4.000000e-07
GCST005038_118	Allergic disease (asthma, hay fever or eczema)	1.000000e-35
GCST005038_71	Allergic disease (asthma, hay fever or eczema)	3.000000e-10
GCST005212_26	Asthma	7.000000e-20
GCST005213_5	Asthma (childhood onset)	3.000000e-08
GCST006409_43	Allergic rhinitis	2.000000e-14
GCST006862_14	Asthma	4.000000e-29
GCST006911_13	Asthma (moderate or severe)	2.000000e-20
GCST007443_15	Nasal polyps	7.000000e-32
GCST007444_2	Chronic rhinosinusitis	6.000000e-07
GCST007562_6	Asthma	7.000000e-23
GCST007563_22	Allergic disease (asthma, hay fever or eczema)	2.000000e-08
GCST007563_32	Allergic disease (asthma, hay fever or eczema)	4.000000e-08
GCST007564_32	Asthma or allergic disease (pleiotropy)	4.000000e-22
GCST007797_3	Asthma onset (childhood vs adult)	4.000000e-12
GCST007797_5	Asthma onset (childhood vs adult)	1.000000e-14
GCST007797_6	Asthma onset (childhood vs adult)	9.000000e-22
GCST007797_7	Asthma onset (childhood vs adult)	1.000000e-20
GCST007798_88	Asthma	3.000000e-43
GCST007798_89	Asthma	5.000000e-41
GCST007798_90	Asthma	3.000000e-72

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0004847	age at onset
EFO:1002011	adult onset asthma
EFO:0009941	Inhalant adrenergic use measurement
EFO:0009942	Glucocorticoid use measurement
EFO:0009943	Antihistamine use measurement
EFO:0007614	asthma exacerbation measurement
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes
EFO:0007990	neutrophil percentage of leukocytes

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4630890 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases reaction, increases abundance, increases expression, increases reaction	3
Estradiol	increases reaction, affects cotreatment, decreases expression, increases expression	3
Lipopolysaccharides	affects cotreatment, increases expression, increases secretion, increases reaction, affects response to substance	3
Particulate Matter	increases reaction, affects cotreatment, decreases reaction, increases abundance, increases expression	3
4,4’,4’’-(4-propyl-((1)H)-pyrazole-1,3,5-triyl) tris-phenol	affects cotreatment, increases expression, increases reaction	2
Acetaminophen	decreases expression, increases secretion, affects reaction, decreases phosphorylation	2
Air Pollutants	decreases reaction, increases abundance, increases expression, increases reaction, affects cotreatment (+1 more)	2
Progesterone	affects cotreatment, decreases expression	2
Silicon Dioxide	affects reaction, increases expression, affects expression	2
Tetrachlorodibenzodioxin	decreases reaction, increases expression, affects binding, increases reaction	2
Tobacco Smoke Pollution	increases reaction, increases secretion, decreases expression	2
Aflatoxin B1	decreases methylation, increases expression	2
Lactic Acid	decreases expression, increases expression	2
Antigens, Dermatophagoides	decreases expression, decreases reaction, increases expression, increases reaction	2
Soot	increases reaction, decreases reaction, decreases expression, increases abundance, increases expression	2
abemaciclib	increases expression	1
chicanine	decreases reaction, increases expression	1
bisphenol F	decreases methylation	1
NE-52-qq57	increases secretion, decreases reaction, increases expression	1
kaempferol	decreases reaction, increases expression	1
bisphenol A	decreases methylation	1
citral	decreases expression	1
5’-methylthioadenosine	decreases reaction, increases expression	1
terephthalic acid	increases expression	1
2,3-pentanedione	decreases expression	1
mono-(2-ethylhexyl)phthalate	decreases reaction, increases expression, increases reaction, increases abundance, increases secretion	1
3,4,5,3’,4’-pentachlorobiphenyl	increases expression	1
4-phenylenediamine	increases expression	1
hydroquinone	decreases expression	1
fumaric acid	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5228024	Binding	Inhibition of human IL-33 incubated for 1 hrs by AlphaLISA assay	Small molecule approaches to treat autoimmune and inflammatory diseases (Part III): Targeting cytokines and cytokine receptor complexes. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer