IL18

Summary

IL18 (interleukin 18, HGNC:5986) is a protein-coding gene on chromosome 11q23.1, encoding Interleukin-18 (Q14116). Pro-inflammatory cytokine primarily involved in epithelial barrier repair, polarized T-helper 1 (Th1) cell and natural killer (NK) cell immune responses.

The protein encoded by this gene is a proinflammatory cytokine of the IL-1 family that is constitutively found as a precursor within the cytoplasm of a variety of cells including macrophages and keratinocytes. The inactive IL-18 precursor is processed to its active form by caspase-1, and is capable of stimulating interferon gamma production, and of regulating both T helper (Th) 1 and Th2 responses. This cytokine has been implicated in the injury of different organs, and in potentially fatal conditions characterized by a cytokine storm. In humans, IL-18 gene is located on chromosome 11. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 3606 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 18 total — 1 pathogenic
• Druggable target: yes
• MANE Select transcript: NM_001562

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5986
Approved symbol	IL18
Name	interleukin 18
Location	11q23.1
Locus type	gene with protein product
Status	Approved
Aliases	IGIF, IL1F4, IL-1g, IL-18
Ensembl gene	ENSG00000150782
Ensembl biotype	protein_coding
OMIM	600953
Entrez	3606

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 8 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000280357, ENST00000524595, ENST00000525547, ENST00000528832, ENST00000533858, ENST00000534225, ENST00000945845, ENST00000945846, ENST00000945847, ENST00000945848, ENST00000945849

RefSeq mRNA: 3 — MANE Select: NM_001562 NM_001243211, NM_001386420, NM_001562

CCDS: CCDS44731, CCDS58180

Canonical transcript exons

ENST00000280357 — 6 exons

Exon	Start	End
ENSE00001370484	112163906	112164094
ENSE00002192330	112143260	112143817
ENSE00002447536	112153592	112153603
ENSE00003467558	112154975	112155061
ENSE00003630513	112150072	112150206
ENSE00003655142	112148603	112148736

Expression profiles

Bgee: expression breadth ubiquitous, 254 present calls, max score 99.02.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.4235 / max 983.0078, expressed in 1080 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
122319	20.6556	1042
122318	2.9687	393
122320	2.0915	536
122317	1.1022	299
122323	0.2438	79
122322	0.2071	77
122321	0.1546	65

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	99.02	gold quality
skin of abdomen	UBERON:0001416	97.75	gold quality
skin of leg	UBERON:0001511	97.42	gold quality
esophagus mucosa	UBERON:0002469	96.94	gold quality
esophagus squamous epithelium	UBERON:0006920	96.75	gold quality
zone of skin	UBERON:0000014	96.50	gold quality
epithelium of esophagus	UBERON:0001976	95.65	gold quality
rectum	UBERON:0001052	95.18	gold quality
upper leg skin	UBERON:0004262	94.23	gold quality
gall bladder	UBERON:0002110	93.84	gold quality
mucosa of transverse colon	UBERON:0004991	93.70	gold quality
squamous epithelium	UBERON:0006914	93.54	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	93.46	gold quality
germinal epithelium of ovary	UBERON:0001304	93.41	gold quality
penis	UBERON:0000989	93.28	gold quality
oral cavity	UBERON:0000167	93.05	gold quality
vagina	UBERON:0000996	92.46	gold quality
upper arm skin	UBERON:0004263	92.44	gold quality
transverse colon	UBERON:0001157	91.30	gold quality
monocyte	CL:0000576	91.26	gold quality
cervix squamous epithelium	UBERON:0006922	91.09	gold quality
metanephros cortex	UBERON:0010533	91.01	gold quality
mammalian vulva	UBERON:0000997	90.80	gold quality
spleen	UBERON:0002106	90.68	gold quality
mononuclear cell	CL:0000842	90.50	gold quality
gingiva	UBERON:0001828	90.49	gold quality
skin of hip	UBERON:0001554	90.42	gold quality
lymph node	UBERON:0000029	90.37	gold quality
leukocyte	CL:0000738	90.08	gold quality
gingival epithelium	UBERON:0001949	90.08	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-GEOD-83139	yes	174.44
E-MTAB-8142	yes	100.11
E-CURD-119	yes	36.37
E-GEOD-125970	yes	22.46
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
IFNG	Unknown
THBS1	Activation

Upstream regulators (CollecTRI, top): AP1, AR, ATF2, ATF4, BCL6, FOS, FOXO1, GLI2, HAND1, HDAC9, IRF1, IRF8, JUN, NFKB1, NFKB, RELA, SPI1, STAT5A

miRNA regulators (miRDB)

12 targeting IL18, 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-6778-3P	99.96	67.29	2693
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-143-3P	99.49	69.05	1457
HSA-MIR-4770	99.49	69.09	1451
HSA-MIR-6088	99.29	68.45	1284
HSA-MIR-6506-5P	99.04	65.66	1386
HSA-MIR-619-5P	98.57	64.97	1988
HSA-MIR-744-3P	97.99	67.76	637
HSA-MIR-6787-3P	97.75	66.17	1233
HSA-MIR-6869-5P	97.17	67.06	634
HSA-MIR-1226-5P	96.50	65.28	643

Literature-anchored findings (GeneRIF, showing 40)

• IL-18 is an angiogenesis mediator that induces microvascular endothelial cell migration, promotes endothelial cell tube formation in vitro and in vivo, and contributes to rheumatoid arthritis synovial fluid-induced endothelial cell migration. (PMID:11466388)
• a novel function for IL-18 as an angiogenic factor in RA and may elucidate a potential therapeutic target for angiogenesis-directed diseases. (PMID:11466388)
• Bioactive IL-18 exhibiting IFN-gamma-inducing activity is detected in the supernatant of cultured gingival epithelial cells on costimulation with neutrophil proteinase 3 and LPS after IFN-gamma-priming. (PMID:11714826)
• IL-18 production may discriminate between gram-positive and gram-negative sepsis, and increased IL-18 appearance may be associated with an adverse outcome in septic patients. (PMID:11770036)
• activation of by Staphylococcus aureus in peripheral blood mononuclear cells (PMID:11781190)
• identification of amino acid residues critical for biological activity (PMID:11790772)
• IL-18 might be a positive regulation factor for the proliferation of J6-1 cells after in an autocrine model. (PMID:11798931)
• The expression of functional IL-18 on human atheroma-associated ECs, SMCs, and MPhi, and its unexpected ability to induce IFN-gamma expression in SMCs, suggests a novel paracrine proinflammatory pathway operating during atherogenesis (PMID:11805151)
• There was little serum IL-18 bioactivity as measured by interferon gamma production in 3 leukemia patients, although both serum IL-18 and leukemia cell IL-18 mrna levels were high. (PMID:11855785)
• Cushing’s syndrome patients have markedly elevated levels of the proinflammatory cytokine IL-18 (PMID:11888846)
• review: Immunoregulatory functions of interleukin 18 and its role in defense against bacterial pathogens. (PMID:11894141)
• presence of high levels of IL-18 in the cord blood of the pre-term infants is correlated with the incidence of periventricular leukomalacia and cerebral palsy and may provide a prognostic marker applicable at birth (PMID:11895335)
• critically involved in regulation of IgE production in vivo, providing a potential therapeutic target for allergic disorders. (PMID:11905033)
• role in Candida albicans-induced interferon-gamma production in human whole- blood cultures (PMID:11920321)
• Effect of diesel exhaust on Il-18 protein and mrna expression levels in alveolar macrophage cells and a macrophage cell line in the absence and presence of Mycobacterium bovis appeared to have little effect, in contrast to other cytokines. (PMID:11936774)
• IL-18 is involved in the inflammatory response and the initiation of the multiorgan dysfunctions following cardiopulmonary bypass (PMID:11958300)
• IL-18 is linked to raised IFN-gamma in multiple sclerosis and is induced by activated CD4(+) T cells via CD40-CD40 ligand interactions. (PMID:11960649)
• signal transduction pathways involved in rheumatoid arthritis synovial fibroblast interleukin-18-induced vascular cell adhesion molecule-1 expression (PMID:12105209)
• Physiological levels of interleukin-18 stimulate multiple neutrophil functions through p38 MAP kinase activation. (PMID:12149432)
• Results show increased levels of interleukin-18 in human cerebrospinal fluid following traumatic brain injury, and that administration of the IL-18 inhibitor, IL-18-binding protein, enhances neurological recovery. (PMID:12172382)
• Short-chain fatty acids up-regulate IL-18 protein expression in intestinal epithelial cells, suggesting a potential regulatory contribution of these luminal constituents to T cell mediated inflammatory and neoplastic intestinal conditions. (PMID:12207348)
• The polymorphisms of the IL-18 gene may play a possible role in expression regulation of the gene in sarcoidosis. (PMID:12366781)
• activation and release of IL-18 induced by bacterial virulence factors may represent one component of innate immunity against the intracellular bacteria (PMID:12377944)
• after binding to IL-18BP, IL-1F7b forms a complex with IL-18Rbeta, depriving the beta-chain of forming a functional receptor complex with IL-18Ralpha and thus inhibiting IL-18 activity (PMID:12381835)
• The enhanced IL-18 production by ultraviolet B irradiation requires reactive oxygen intermediates and activator protein-1. signaling in keratinocytes. (PMID:12387830)
• interleukin-18 production is increased in patients with lupus nephritis (PMID:12390326)
• promoter is polymorphic in type 1 diabetes (PMID:12401730)
• produced by oral epithelial cells in response to exposure to Candida albicans or lipopolysaccharide stimulation (PMID:12438388)
• elevated IL-18 and IL-12, and related pro-inflammatory activity, may be associated with aberrant matrix metalloproteinase activity (PMID:12456593)
• The influence of IL-18 on the IL-6 production by PMN appears to indicate a potential role of IL-18 in the early steps of the inflammatory cascade and other immune reactions mediated by IL-6. (PMID:12472176)
• IL-18 production is elevated in pulmonary and pleural tuberculosis. (PMID:12472673)
• IL-18 has chemoattractant properties in vitro and in vivo operating in particular upon human Th1 cells, and may have an role in promoting recruitment of memory Th1 cells to an inflammatory lesion. (PMID:12517977)
• IL-8 expression is negatively linked to ER status of breast and ovarian cancer cells.IL-8 expression is associated with a higher invasiveness potential of cancer cells in vitro, which suggests that IL-8 could be a novel marker of tumor aggressiveness. (PMID:12527894)
• IL-18 is a primary proinflammatory cytokine in RA that drives the local production of IL-1beta and TNFalpha. (PMID:12571842)
• Interleukin 18 is probably one of several genes that determine susceptibility to Crohn’s disease. (PMID:12572878)
• Increased expression of DC-SIGN+IL-12+IL-18+ and CD83+IL-12-IL-18- dendritic cell populations in the colonic mucosa of patients with Crohn’s disease (PMID:12594843)
• plasma level correlates with severity of malaria falciparum disease, and production coregulated together with Il-12 production (PMID:12654091)
• IL-18 and TNF-alpha function both as apoptosis-promoting factors and as apoptosis-inhibiting factors in acute liver failure (PMID:12679613)
• In the severe malarial anemia group the IL-18 response rate declined to 30% from 70% for uncomplicated malaria , supporting the hypothesis that impairment of IL-18 response may contribute to the development of severe malarial anemia. (PMID:12738632)
• IL-18 levels were similar in controls and preeclamptic women. IL-18 was not associated with gestational age. (PMID:12748489)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Il18	ENSMUSG00000039217
rattus_norvegicus	Il18	ENSRNOG00000009848

Protein

Protein identifiers

Interleukin-18 — Q14116 (reviewed: Q14116)

Alternative names: Iboctadekin, Interferon gamma-inducing factor, Interleukin-1 gamma

All UniProt accessions (1): Q14116

UniProt curated annotations — full annotation on UniProt →

Function. Pro-inflammatory cytokine primarily involved in epithelial barrier repair, polarized T-helper 1 (Th1) cell and natural killer (NK) cell immune responses. Upon binding to IL18R1 and IL18RAP, forms a signaling ternary complex which activates NF-kappa-B, triggering synthesis of inflammatory mediators. Synergizes with IL12/interleukin-12 to induce IFNG synthesis from T-helper 1 (Th1) cells and natural killer (NK) cells. Involved in transduction of inflammation downstream of pyroptosis: its mature form is specifically released in the extracellular milieu by passing through the gasdermin-D (GSDMD) pore.

Subunit / interactions. Forms a ternary complex with ligand-binding receptor subunit IL18R1 and signaling receptor subunit IL18RAP at the plasma membrane. Mature IL18 first binds to IL18R1 forming a low affinity binary complex, which then interacts with IL18RAP to form a high affinity ternary complex that signals inside the cell. Interacts with cargo receptor TMED10; the interaction mediates the translocation from the cytoplasm into the ERGIC (endoplasmic reticulum-Golgi intermediate compartment) and thereby secretion.

Subcellular location. Cytoplasm. Cytosol. Secreted.

Tissue specificity. Expressed in ovarian carcinoma but undetectable in normal ovarian epithelial cells. Resistant to proteolytic activation by caspase-1 and -4.

Post-translational modifications. The pro-IL-18 precursor is processed by CASP1, CASP4 or CASP5 to yield its mature, active form. The pro-IL-18 precursor features autoinhibitory interactions between the propeptide and the post-cleavage-site region, preventing recognition by the IL18R1 receptor. Processing by CASP1, CASP4 or CASP5 induces conformational changes to generate critical receptor-binding sites. The mature form is then secreted and released in the extracellular milieu by passing through the gasdermin-D (GSDMD) pore. In contrast, cleavage by CASP3 inactivates IL18.

Induction. In macrophages, release is increased by endocannabinoid anandamide/AEA.

Similarity. Belongs to the IL-1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q14116-1	1	yes
Q14116-2	2, Delta3pro-IL-18

RefSeq proteins (3): NP_001230140, NP_001373349, NP_001553* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000975	IL-1_fam	Family
IPR008996	IL1/FGF	Homologous_superfamily
IPR015529	IL-18	Family

Pfam: PF00340

UniProt features (57 total): mutagenesis site 29, strand 14, sequence conflict 3, helix 3, turn 3, site 2, propeptide 1, chain 1, splice variant 1

Structure

Experimental structures (PDB)

20 structures.

PDB	Method	Resolution (Å)
2VXT	X-RAY DIFFRACTION	1.49
9OD9	X-RAY DIFFRACTION	1.6
4EKX	X-RAY DIFFRACTION	1.75
7AL7	X-RAY DIFFRACTION	1.8
9OD7	X-RAY DIFFRACTION	1.9
4XFS	X-RAY DIFFRACTION	1.91
3F62	X-RAY DIFFRACTION	2
4XFT	X-RAY DIFFRACTION	2
4HJJ	X-RAY DIFFRACTION	2.1
3WO2	X-RAY DIFFRACTION	2.33
4EEE	X-RAY DIFFRACTION	2.71
4R6U	X-RAY DIFFRACTION	2.8
4XFU	X-RAY DIFFRACTION	2.85
3WO3	X-RAY DIFFRACTION	3.1
3WO4	X-RAY DIFFRACTION	3.1
8J6K	X-RAY DIFFRACTION	3.12
8SPB	ELECTRON MICROSCOPY	3.2
8SV1	ELECTRON MICROSCOPY	3.5
1J0S	SOLUTION NMR
8URV	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14116-F1	89.24	0.69

Antibody-complex structures (SAbDab): 2 — 2VXT, 4HJJ

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 (2): 36–37 (cleavage; by casp1, casp4 and casp5); 71–72 (cleavage; by casp3)

Mutagenesis-validated functional residues (29):

Position	Phenotype
38	abolished ability to bind the il18r1 receptor without affecting its processing by casp4.
40	reduces binding to il18r1 and the ability to induce ifng production.
41	impairs binding to il18r1 and the ability to induce ifng production.
44	reduces binding to il18r1 and the ability to induce ifng production.
47–48	decreased binding to casp4.
49	reduces binding to il18r1 and the ability to induce ifng production.
53	reduces binding to il18r1 and the ability to induce ifng production.
69	impairs binding to il18r1 and the ability to induce ifng production.
70–77	abolished ability to bind the il18r1 receptor without affecting its processing by casp4.
71	impairs binding to il18r1 and the ability to induce ifng production. abolished cleavage by casp3.
94	impairs binding to il18r1 and the ability to induce ifng production.
96	impairs binding to il18r1 and the ability to induce ifng production.
115	reduces binding of the preformed binary complex of il18 and il18r1 to il18rap resulting in impaired ifng production.
120	reduces binding of the preformed binary complex of il18 and il18r1 to il18rap resulting in impaired ifng production.
134	reduces binding of the preformed binary complex of il18 and il18r1 to il18rap resulting in impaired ifng production.
140	reduces binding to il18r1 and the ability to induce ifng production.
144	abolishes binding of the preformed binary complex of il18 and il18r1 to il18rap.
145	abolishes binding of the preformed binary complex of il18 and il18r1 to il18rap.
146	reduces binding of the preformed binary complex of il18 and il18r1 to il18rap.
148	abolishes binding of the preformed binary complex of il18 and il18r1 to il18rap.
168	reduces binding to il18r1 and the ability to induce ifng production.
183	reduces binding of the preformed binary complex of il18 and il18r1 to il18rap.
186	reduces binding of the preformed binary complex of il18 and il18r1 to il18rap.
192–193	decreased binding to casp4/casp11.
12	strongly decreased processing by casp4 or casp5; when associated with a-28.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-448706	Interleukin-1 processing
R-HSA-5620971	Pyroptosis
R-HSA-6783783	Interleukin-10 signaling
R-HSA-6785807	Interleukin-4 and Interleukin-13 signaling
R-HSA-9012546	Interleukin-18 signaling
R-HSA-9660826	Purinergic signaling in leishmaniasis infection
R-HSA-9960519	CASP4-mediated substrate cleavage
R-HSA-9960525	CASP5-mediated substrate cleavage

MSigDB gene sets: 565 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_ACYLGLYCEROL_HOMEOSTASIS, MODULE_92, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, MODULE_516, GOBP_EPITHELIUM_DEVELOPMENT, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, HNF3ALPHA_Q6, GOBP_REGULATION_OF_ALPHA_BETA_T_CELL_ACTIVATION, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, GOBP_REGULATION_OF_PHOSPHORYLATION, SWEET_KRAS_ONCOGENIC_SIGNATURE, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM

GO Biological Process (43): angiogenesis (GO:0001525), inflammatory response (GO:0006954), immune response (GO:0006955), cell-cell signaling (GO:0007267), cell population proliferation (GO:0008283), positive regulation of macrophage derived foam cell differentiation (GO:0010744), cytokine-mediated signaling pathway (GO:0019221), natural killer cell activation (GO:0030101), regulation of cell adhesion (GO:0030155), sleep (GO:0030431), positive regulation of chemokine production (GO:0032722), positive regulation of granulocyte macrophage colony-stimulating factor production (GO:0032725), positive regulation of type II interferon production (GO:0032729), positive regulation of interleukin-13 production (GO:0032736), positive regulation of interleukin-17 production (GO:0032740), positive regulation of natural killer cell proliferation (GO:0032819), positive regulation of tissue remodeling (GO:0034105), interleukin-18-mediated signaling pathway (GO:0035655), T-helper 1 type immune response (GO:0042088), type 2 immune response (GO:0042092), positive regulation of activated T cell proliferation (GO:0042104), neutrophil activation (GO:0042119), natural killer cell mediated cytotoxicity (GO:0042267), positive regulation of tyrosine phosphorylation of STAT protein (GO:0042531), cholesterol homeostasis (GO:0042632), positive regulation of T-helper 2 cell differentiation (GO:0045630), negative regulation of myoblast differentiation (GO:0045662), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of smooth muscle cell proliferation (GO:0048661), positive regulation of inflammatory response (GO:0050729), defense response to Gram-positive bacterium (GO:0050830), obsolete positive regulation of NF-kappaB transcription factor activity (GO:0051092), positive regulation of NK T cell proliferation (GO:0051142), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), establishment of skin barrier (GO:0061436), triglyceride homeostasis (GO:0070328), cellular response to lipopolysaccharide (GO:0071222), positive regulation of cold-induced thermogenesis (GO:0120162), positive regulation of neuroinflammatory response (GO:0150078), positive regulation of non-canonical NF-kappaB signal transduction (GO:1901224)

GO Molecular Function (4): cytokine activity (GO:0005125), interleukin-18 receptor binding (GO:0045515), protein binding (GO:0005515), receptor ligand activity (GO:0048018)

GO Cellular Component (4): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), cytosol (GO:0005829), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Interleukin-1 family signaling	2
Signaling by Interleukins	2
Non-canonical inflammasome activation	2
Regulated Necrosis	1
Cell recruitment (pro-inflammatory response)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
positive regulation of cytokine production	5
cellular anatomical structure	3
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
defense response	1
immune system process	1
response to stimulus	1
cell communication	1
signaling	1
cellular process	1
macrophage derived foam cell differentiation	1
regulation of macrophage derived foam cell differentiation	1
positive regulation of cell differentiation	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
lymphocyte activation	1
cell adhesion	1
regulation of cellular process	1
multicellular organismal process	1
chemokine production	1
regulation of chemokine production	1
granulocyte macrophage colony-stimulating factor production	1
regulation of granulocyte macrophage colony-stimulating factor production	1
positive regulation of protein metabolic process	1
type II interferon production	1
regulation of type II interferon production	1
interleukin-13 production	1
regulation of interleukin-13 production	1
interleukin-17 production	1
regulation of interleukin-17 production	1
natural killer cell proliferation	1
positive regulation of natural killer cell activation	1
regulation of natural killer cell proliferation	1
positive regulation of lymphocyte proliferation	1
regulation of tissue remodeling	1
tissue remodeling	1
positive regulation of multicellular organismal process	1
cytokine-mediated signaling pathway	1
cellular response to interleukin-18	1
adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains	1

Protein interactions and networks

STRING

3808 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IL18	IL18BP	O95998	998
IL18	IL18R1	Q13478	998
IL18	IL18RAP	O95256	996
IL18	IL1A	P01583	995
IL18	CASP1	P29466	979
IL18	IL1B	P01584	973
IL18	IL1R1	P14778	965
IL18	MYD88	P78397	961
IL18	IL6	P05231	953
IL18	IFNG	P01579	946
IL18	NLRP3	Q96P20	946
IL18	PYCARD	Q9ULZ3	940
IL18	NLRC4	Q9NPP4	940
IL18	TNF	P01375	937
IL18	MEFV	O15553	928

IntAct

25 interactions, top by confidence:

A	B	Type	Score
RAC1	RAP1GDS1	psi-mi:“MI:0914”(association)	0.800
CRIPTO	AIP	psi-mi:“MI:0914”(association)	0.640
IL18	SERPINB4	psi-mi:“MI:0915”(physical association)	0.590
IL18		psi-mi:“MI:0407”(direct interaction)	0.560
IL18	ADIRF	psi-mi:“MI:0915”(physical association)	0.560
IL18	IL18R1	psi-mi:“MI:0407”(direct interaction)	0.560
IL18R1	IL18	psi-mi:“MI:0407”(direct interaction)	0.560
WASHC3	WASH3P	psi-mi:“MI:0914”(association)	0.530
IL18	GPX4	psi-mi:“MI:0915”(physical association)	0.400
IL18	E6	psi-mi:“MI:0915”(physical association)	0.370
IL18	CASK	psi-mi:“MI:0915”(physical association)	0.370
Cul1	GPS1	psi-mi:“MI:0914”(association)	0.350
CDK15	A2ML1	psi-mi:“MI:0914”(association)	0.350
ZNF747	TRIM28	psi-mi:“MI:0914”(association)	0.350
FAM24B	SHTN1	psi-mi:“MI:0914”(association)	0.350
STX17	A2ML1	psi-mi:“MI:0914”(association)	0.350
IL18	ADIRF	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (39): IL18 (Affinity Capture-RNA), IL18 (Affinity Capture-MS), IL18 (Affinity Capture-MS), IL18 (Affinity Capture-MS), IL18 (Affinity Capture-MS), IL18 (Affinity Capture-MS), SERPINB4 (Affinity Capture-MS), IL18 (Affinity Capture-MS), IL18 (Two-hybrid), IL18BP (Reconstituted Complex), IL18 (Affinity Capture-MS), IL18 (Affinity Capture-MS), IL18 (Affinity Capture-MS), IL18 (Affinity Capture-MS), IL18 (Biochemical Activity)

ESM2 similar proteins: A4UYK8, G1SRW8, O18999, O77482, P01584, P03969, P0C7P3, P10749, P13109, P14628, P15655, P18510, P20003, P25085, P25086, P26889, P26890, P41687, P46648, P48090, P48800, P51493, P70380, P79182, P97636, Q14116, Q28292, Q28386, Q29056, Q2HZH0, Q63264, Q6PUD2, Q6R2X3, Q865X8, Q866R8, Q8IXQ6, Q8QFQ8, Q8R460, Q8WNR2, Q9BEH0

Diamond homologs: O19073, P70380, P97636, Q14116, Q3ZT29, Q5I931, Q95M33, Q9TU73, Q9XSQ7, Q9XSR0, Q8QFQ8

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
“Caspase 1 complex”	“up-regulates activity”	IL18	cleavage
“Caspase 3 complex”	“up-regulates activity”	IL18	cleavage
IL18	“up-regulates quantity by expression”	IFNG	“transcriptional regulation”
Macrophage_activation	“up-regulates quantity”	IL18
IL18	up-regulates	T_cell_activation
IL18	up-regulates	IL18R1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	7
Likely benign	4
Benign	4

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3391916	GRCh37/hg19 11q23.1(chr11:111957826-112026707)x1	Pathogenic

SpliceAI

902 predictions. Top by Δscore:

Variant	Effect	Δscore
11:112148597:TCTTA:T	donor_loss	1.0000
11:112148598:CTTA:C	donor_loss	1.0000
11:112148599:TTA:T	donor_loss	1.0000
11:112148600:TACCT:T	donor_loss	1.0000
11:112148602:CC:C	donor_loss	1.0000
11:112155730:T:TA	donor_gain	1.0000
11:112163902:TTACC:T	donor_loss	1.0000
11:112163903:TA:T	donor_loss	1.0000
11:112163905:CCTG:C	donor_gain	1.0000
11:112143814:TTTCC:T	acceptor_loss	0.9900
11:112143816:TCCT:T	acceptor_loss	0.9900
11:112143818:C:CG	acceptor_loss	0.9900
11:112143819:T:A	acceptor_loss	0.9900
11:112148733:TTAT:T	acceptor_gain	0.9900
11:112148733:TTATC:T	acceptor_loss	0.9900
11:112148736:TC:T	acceptor_loss	0.9900
11:112148737:C:CA	acceptor_loss	0.9900
11:112148737:C:CC	acceptor_gain	0.9900
11:112148738:T:G	acceptor_loss	0.9900
11:112148742:A:AC	acceptor_gain	0.9900
11:112150095:T:C	donor_gain	0.9900
11:112150207:C:CC	acceptor_gain	0.9900
11:112155723:AAAT:A	donor_gain	0.9900
11:112163904:A:AC	donor_gain	0.9900
11:112163905:C:CC	donor_gain	0.9900
11:112148734:TAT:T	acceptor_gain	0.9800
11:112150067:AATAC:A	donor_loss	0.9800
11:112150068:ATAC:A	donor_loss	0.9800
11:112150069:TA:T	donor_loss	0.9800
11:112150070:AC:A	donor_loss	0.9800

AlphaMissense

1318 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:112143726:A:G	F151S	0.992
11:112143618:A:G	F187S	0.990
11:112143696:A:T	L161Q	0.989
11:112143768:A:G	F137S	0.988
11:112143725:A:C	F151L	0.987
11:112143725:A:T	F151L	0.987
11:112143727:A:G	F151L	0.987
11:112143771:A:T	I136K	0.987
11:112143694:C:G	A162P	0.986
11:112143767:G:C	F137L	0.982
11:112143767:G:T	F137L	0.982
11:112143769:A:G	F137L	0.982
11:112148634:A:T	L110H	0.982
11:112143657:A:G	L174S	0.981
11:112148701:A:C	Y88D	0.981
11:112150131:A:T	L56H	0.981
11:112143696:A:C	L161R	0.980
11:112143617:G:C	F187L	0.979
11:112143617:G:T	F187L	0.979
11:112143619:A:G	F187L	0.979
11:112143771:A:C	I136R	0.979
11:112143696:A:G	L161P	0.978
11:112148673:G:T	A97D	0.978
11:112150131:A:C	L56R	0.978
11:112143663:A:T	L172H	0.976
11:112148634:A:C	L110R	0.976
11:112143764:A:C	F138L	0.975
11:112143764:A:T	F138L	0.975
11:112143766:A:G	F138L	0.975
11:112143663:A:G	L172P	0.974

dbSNP variants (sampled 300 via entrez): RS1000120984 (11:112145765 A>G,T), RS1000157208 (11:112151016 T>G), RS1000352535 (11:112160072 C>T), RS1000372405 (11:112144531 G>A), RS1000722644 (11:112144350 A>C,T), RS1000764470 (11:112144234 CT>C), RS1000777729 (11:112159633 A>T), RS1000781321 (11:112149464 G>T), RS1000833833 (11:112149869 C>A), RS1000853060 (11:112165269 A>T), RS1000910022 (11:112164946 T>C), RS1000943879 (11:112157645 G>C), RS1001115507 (11:112165457 C>T), RS1001397860 (11:112157908 A>G), RS1001420517 (11:112157041 A>G)

Disease associations

OMIM: gene MIM:600953 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST000189_22	Protein quantitative trait loci	7.000000e-13
GCST002255_1	Inflammatory biomarkers	2.000000e-32
GCST004441_43	Interleukin-18 levels	4.000000e-22
GCST009731_67	Blood protein levels in cardiovascular risk	4.000000e-33
GCST009736_1	Interleukin-18 levels	2.000000e-32

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004581	interleukin 18 measurement
EFO:0004812	interleukin-1 beta measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1741305 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

4 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs187238	Efficacy	3	interferons;ribavirin	Chronic hepatitis C virus infection
rs1946518	Efficacy	3	interferons;ribavirin	Chronic hepatitis C virus infection
rs1946518	Metabolism/PK	3	tacrolimus	Kidney Transplantation;Lung transplantation
rs5744247	Metabolism/PK	3	tacrolimus	Transplantation

PharmGKB variants

4 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs187238	IL18, TEX12	3	2.50	1	interferons;ribavirin
rs1946518	IL18, TEX12	3	3.25	2	tacrolimus;interferons;ribavirin
rs5744247	IL18, TEX12	3	2.25	1	tacrolimus
rs1946519	IL18		0.00	0

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
6.60	EC50	250	nM	CHEMBL1304177

PubChem BioAssay actives

1 with measured affinity, of 1 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
1-(4-cyanophenyl)-3-[4-[4-[(4-cyanophenyl)carbamoylamino]phenoxy]phenyl]urea	1924935: Inhibition of human IL-18 expressed in Escherichia coli BL21(DE3) cells incubated for 18 hrs	ec50	0.2500	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Lipopolysaccharides	affects expression, affects binding, increases cleavage, increases expression, increases secretion (+4 more)	27
Particulate Matter	increases abundance, increases cleavage, affects expression, increases secretion, affects cotreatment (+4 more)	10
Acetylcysteine	decreases reaction, increases expression, increases reaction, increases abundance, increases secretion (+1 more)	9
Adenosine Triphosphate	increases reaction, affects cotreatment, increases secretion, increases expression, decreases reaction (+1 more)	8
sodium arsenite	affects cotreatment, increases expression, increases reaction, affects reaction, decreases reaction (+1 more)	6
Air Pollutants	increases abundance, increases expression, decreases expression	5
Glucose	affects cotreatment, decreases reaction, increases secretion, increases expression, affects reaction (+1 more)	5
Cadmium Chloride	affects reaction, decreases reaction, increases abundance, increases expression, increases secretion	5
Ethanol	increases expression, affects response to substance, increases reaction, affects cotreatment, decreases reaction	4
Benzo(a)pyrene	affects cotreatment, increases expression, affects methylation, decreases methylation, decreases reaction	4
Cadmium	increases abundance, increases expression, increases secretion, affects reaction, decreases reaction	4
Hydrogen Peroxide	decreases expression, affects expression, decreases reaction, increases secretion	4
Asbestos, Crocidolite	decreases expression, increases secretion, decreases reaction	4
N-(1,2,3,5,6,7-hexahydro-S-indacen-4-ylcarbamoyl)-4-(2-hydroxy-2-propanyl)-2-furansulfonamide	decreases reaction, increases expression, increases cleavage, increases reaction	3
bisphenol A	decreases methylation, increases expression, increases secretion, affects expression, decreases reaction	3
arsenite	decreases reaction, affects binding, increases reaction, decreases expression, increases expression (+1 more)	3
lipopolysaccharide, E coli O55-B5	affects cotreatment, increases expression, decreases reaction, increases secretion, affects reaction	3
Cisplatin	affects cotreatment, increases expression, decreases expression	3
Dinitrochlorobenzene	increases expression, increases reaction	3
Estradiol	decreases expression, increases expression, affects expression	3
Folic Acid	increases methylation, affects cotreatment, increases expression	3
Histamine	decreases expression, decreases reaction, increases expression, affects binding, affects reaction	3
Tobacco Smoke Pollution	affects expression, increases expression, increases reaction, decreases reaction, increases secretion	3
Famotidine	decreases expression, affects binding, decreases reaction, increases expression	3
ruscogenin	decreases reaction, increases expression, increases secretion	2
cinnamaldehyde	increases expression	2
zinc protoporphyrin	increases expression, decreases response to substance, decreases reaction	2
cinnamyl alcohol	increases expression	2
4-methylhistamine	affects binding, decreases expression, decreases reaction, increases expression	2
3-methyladenine	decreases reaction, increases expression, affects cotreatment, increases reaction	2

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5228019	Binding	Inhibition of human IL-18 expressed in Escherichia coli BL21(DE3) cells incubated for 18 hrs	Small molecule approaches to treat autoimmune and inflammatory diseases (Part III): Targeting cytokines and cytokine receptor complexes. — Bioorg Med Chem Lett

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1UE	Abcam HeLa IL18 KO	Cancer cell line	Female
CVCL_B8I9	Abcam HCT 116 IL18 KO	Cancer cell line	Male
CVCL_B8X9	Abcam MCF-7 IL18 KO	Cancer cell line	Female
CVCL_B9KI	Abcam A-549 IL18 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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