IL36B

Summary

IL36B (interleukin 36 beta, HGNC:15564) is a protein-coding gene on chromosome 2q14.1, encoding Interleukin-36 beta (Q9NZH7). Cytokine that binds to and signals through the IL1RL2/IL-36R receptor which in turn activates NF-kappa-B and MAPK signaling pathways in target cells linked to a pro-inflammatory response.

The protein encoded by this gene is a member of the interleukin 1 cytokine family. Protein structure modeling indicated that this cytokine may contain a 12-stranded beta-trefoil structure that is conserved between IL1A (IL-A alpha) and IL1B (IL-1 beta). This gene and eight other interleukin 1 family genes form a cytokine gene cluster on chromosome 2. Two alternatively spliced transcript variants encoding distinct isoforms have been reported.

Source: NCBI Gene 27177 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 16 total
• MANE Select transcript: NM_173178

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15564
Approved symbol	IL36B
Name	interleukin 36 beta
Location	2q14.1
Locus type	gene with protein product
Status	Approved
Aliases	FIL1, IL-1H2, IL-1F8, FILI-(ETA), IL1-ETA, IL1H2, MGC126880, MGC126882
Ensembl gene	ENSG00000136696
Ensembl biotype	protein_coding
OMIM	605508
Entrez	27177

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000259213, ENST00000327407

RefSeq mRNA: 2 — MANE Select: NM_173178 NM_014438, NM_173178

CCDS: CCDS2109, CCDS2110

Canonical transcript exons

ENST00000327407 — 5 exons

Exon	Start	End
ENSE00000856865	113028939	113029078
ENSE00001229508	113052817	113052867
ENSE00001308170	113031697	113031766
ENSE00001309406	113027433	113028115
ENSE00001330154	113031048	113031155

Expression profiles

Bgee: expression breadth broad, 34 present calls, max score 78.31.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skin of leg	UBERON:0001511	78.31	gold quality
skin of abdomen	UBERON:0001416	74.13	gold quality
zone of skin	UBERON:0000014	72.49	gold quality
buccal mucosa cell	CL:0002336	72.39	silver quality
lower esophagus mucosa	UBERON:0035834	64.92	gold quality
esophagus mucosa	UBERON:0002469	62.97	gold quality
tendon of biceps brachii	UBERON:0008188	49.39	gold quality
lower lobe of lung	UBERON:0008949	48.11	silver quality
islet of Langerhans	UBERON:0000006	47.90	gold quality
tonsil	UBERON:0002372	46.82	gold quality
stromal cell of endometrium	CL:0002255	46.38	gold quality
esophagus	UBERON:0001043	44.17	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
amniotic fluid	UBERON:0000173	43.19	gold quality
trigeminal ganglion	UBERON:0001675	43.04	gold quality
pylorus	UBERON:0001166	42.80	gold quality
middle temporal gyrus	UBERON:0002771	42.76	gold quality
secondary oocyte	CL:0000655	42.57	gold quality
gingiva	UBERON:0001828	42.29	gold quality
esophagus squamous epithelium	UBERON:0006920	41.97	gold quality
skin of hip	UBERON:0001554	41.76	silver quality
cartilage tissue	UBERON:0002418	41.52	gold quality
vastus lateralis	UBERON:0001379	41.41	gold quality
quadriceps femoris	UBERON:0001377	41.37	gold quality
superficial temporal artery	UBERON:0001614	41.33	gold quality
oviduct epithelium	UBERON:0004804	41.11	gold quality
palpebral conjunctiva	UBERON:0001812	41.10	gold quality
oral cavity	UBERON:0000167	41.06	gold quality
mucosa of paranasal sinus	UBERON:0005030	40.98	gold quality
mammary duct	UBERON:0001765	40.77	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.95

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

37 targeting IL36B, 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-5692A	100.00	74.40	6850
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-2681-5P	99.75	67.64	1655
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-891B	99.59	69.81	1083
HSA-MIR-6832-5P	99.58	64.82	1132
HSA-MIR-199A-5P	99.51	69.71	1107
HSA-MIR-199B-5P	99.51	69.74	1098
HSA-MIR-4311	99.31	70.47	3041
HSA-MIR-5589-3P	99.29	68.30	1443
HSA-MIR-6071	99.16	67.77	1780
HSA-MIR-7151-3P	99.04	69.72	2370
HSA-MIR-6830-3P	98.62	68.07	1760
HSA-MIR-1301-5P	98.09	66.62	495
HSA-MIR-6502-5P	98.09	66.73	495
HSA-MIR-4772-3P	98.04	65.60	1203
HSA-MIR-4275	97.96	68.42	1549

Literature-anchored findings (GeneRIF, showing 15)

• IL-1F6 and IL-1F8, in addition to IL-1F9, activate the pathway leading to NF-kappaB in an IL-1Rrp2-dependent manner in Jurkat cells (PMID:14734551)
• Joint and serum IL-1F8 protein levels did not correlate with inflammation, but they were high in samples from patients with rheumatoid arthritis (PMID:16646978)
• IL-1F8 functions as an inducer of antimicrobial peptide and matrix metalloproteinase expression by keratinocytes; IL-1F8 is overexpressed in transgenic psoriatic model mouse skin. (PMID:21242515)
• Interleukin-36 (IL-36) ligands require processing for full agonist (IL-36alpha, IL-36beta, and IL-36gamma) or antagonist (IL-36Ra) activity (PMID:21965679)
• IL36B expression is induced in keratinocytes by Toll-like receptor ligands suggesting a function in barrier immune defense. (PMID:22318382)
• IL-36 promotes myeloid cell infiltration, activation, and inflammatory activity in skin (PMID:24829417)
• With a focus on the skin as a target for microbial and viral invasion, the current knowledge of IL-36: IL-36alpha, IL-36beta and IL-36gamma, functions is reviewed. One physiological function of the IL-36smay be to counteract microbial immune evasion. [Review] (PMID:28811383)
• IL-36-mediated IL-6 and CXCL8 production in human lung fibroblasts and bronchial epithelial cells may be involved in pulmonary inflammation especially caused by bacterial or viral infections. (PMID:28869889)
• these findings suggest that IL-36beta could induce cell cycle arrest at S phase, inhibit keratin 10 and involucrin expressions and promote inflammatory activity in HaCaT cell lines. (PMID:31601303)
• Biology of IL-36 Signaling and Its Role in Systemic Inflammatory Diseases. (PMID:31736959)
• IL-36 s in the colorectal cancer: is interleukin 36 good or bad for the development of colorectal cancer? (PMID:32013927)
• IL-36 is Closely Related to Neutrophilic Inflammation in Chronic Obstructive Pulmonary Disease. (PMID:35698471)
• IL-36 Cytokines: Their Roles in Asthma and Potential as a Therapeutic. (PMID:35903102)
• Increased Interleukin-36beta Expression Promotes Angiogenesis in Japanese Atopic Dermatitis. (PMID:37446281)
• Emerging Role of the IL-36/IL-36R Axis in Multiple Inflammatory Skin Diseases. (PMID:38189700)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	il1fma	ENSDARG00000089383
danio_rerio	il1b	ENSDARG00000098700
mus_musculus	Il36b	ENSMUSG00000026985
rattus_norvegicus	Il36b	ENSRNOG00000043323

Paralogs (7): IL1B (ENSG00000125538), IL37 (ENSG00000125571), IL36G (ENSG00000136688), IL1RN (ENSG00000136689), IL36A (ENSG00000136694), IL36RN (ENSG00000136695), IL1F10 (ENSG00000136697)

Protein

Protein identifiers

Interleukin-36 beta — Q9NZH7 (reviewed: Q9NZH7)

Alternative names: FIL1 eta, Interleukin-1 eta, Interleukin-1 family member 8, Interleukin-1 homolog 2

All UniProt accessions (1): Q9NZH7

UniProt curated annotations — full annotation on UniProt →

Function. Cytokine that binds to and signals through the IL1RL2/IL-36R receptor which in turn activates NF-kappa-B and MAPK signaling pathways in target cells linked to a pro-inflammatory response. Part of the IL-36 signaling system that is thought to be present in epithelial barriers and to take part in local inflammatory response; similar to the IL-1 system with which it shares the coreceptor IL1RAP. Stimulates production of interleukin-6 and interleukin-8 in synovial fibrobasts, articular chondrocytes and mature adipocytes. Induces expression of a number of antimicrobial peptides including beta-defensins 4 and 103 as well as a number of matrix metalloproteases. Seems to be involved in skin inflammatory response by acting on keratinocytes, dendritic cells and indirectly on T-cells to drive tissue infiltration, cell maturation and cell proliferation. In cultured keratinocytes induces the expression of macrophage, T-cell, and neutrophil chemokines, such as CCL3, CCL4, CCL5, CCL2, CCL17, CCL22, CL20, CCL5, CCL2, CCL17, CCL22, CXCL8, CCL20 and CXCL1, and the production of pro-inflammatory cytokines such as TNF, IL-8 and IL-6.

Subunit / interactions. 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. Secreted.

Tissue specificity. Expression at low levels in tonsil, bone marrow, heart, placenta, lung, testis and colon but not in any hematopoietic cell lines. Not detected in adipose tissue. Expressed at higher levels in psoriatic plaques than in symptomless psoriatic skin or healthy control skin. Increased levels are not detected in inflamed joint tissue.

Post-translational modifications. N-terminal truncation leads to a dramatic enhancement of its activity (>1000-fold).

Induction. By pro-inflammatory cytokines IL1A, IL1B and TNF in synovial fibroblasts. By IL1A and TNF in keratinocytes. Constitutive in articular chondrocytes.

Similarity. Belongs to the IL-1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NZH7-1	1	yes
Q9NZH7-2	2

RefSeq proteins (2): NP_055253, NP_775270* (*=MANE)

Domains & families (InterPro)

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

UniProt features (4 total): propeptide 1, chain 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NZH7-F1	54.74	0.02

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9014826	Interleukin-36 pathway

MSigDB gene sets: 102 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_POSITIVE_REGULATION_OF_CELL_ADHESION, GOBP_CELL_CELL_ADHESION, GOBP_REGULATION_OF_LEUKOCYTE_DIFFERENTIATION, GOBP_REGULATION_OF_HEMOPOIESIS, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_POSITIVE_REGULATION_OF_CELL_DIFFERENTIATION

GO Biological Process (7): inflammatory response (GO:0006954), immune response (GO:0006955), cytokine-mediated signaling pathway (GO:0019221), innate immune response (GO:0045087), positive regulation of T cell differentiation (GO:0045582), cellular response to lipopolysaccharide (GO:0071222), immune system process (GO:0002376)

GO Molecular Function (2): cytokine activity (GO:0005125), interleukin-1 receptor binding (GO:0005149)

GO Cellular Component (3): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Interleukin-1 family signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
defense response	1
immune system process	1
response to stimulus	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
immune response	1
defense response to symbiont	1
T cell differentiation	1
regulation of T cell differentiation	1
positive regulation of lymphocyte differentiation	1
positive regulation of T cell activation	1
response to lipopolysaccharide	1
cellular response to molecule of bacterial origin	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
biological_process	1
receptor ligand activity	1
cytokine receptor binding	1
growth factor receptor binding	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

662 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IL36B	IL36RN	Q9UBH0	965
IL36B	IL1RL2	Q9HB29	912
IL36B	IL1A	P01583	811
IL36B	IL1B	P01584	728
IL36B	IL1F10	Q8WWZ1	720
IL36B	IL1RAP	Q9NPH3	718
IL36B	IL1RN	P18510	665
IL36B	IL1R1	P14778	593
IL36B	IL6	P05231	540
IL36B	IL33	O95760	528
IL36B	IL18R1	Q13478	521
IL36B	IL36A	Q9UHA7	506
IL36B	NFKB1	P19838	496
IL36B	IFNG	P01579	495
IL36B	CCR1	P32246	461

IntAct

3 interactions, top by confidence:

A	B	Type	Score
LSM6	PRMT5	psi-mi:“MI:0914”(association)	0.530
LSM1	RAB14	psi-mi:“MI:0914”(association)	0.350

BioGRID (3): IL36B (Affinity Capture-MS), IL36B (Affinity Capture-MS), IL36B (Affinity Capture-Luminescence)

ESM2 similar proteins: A0A1U8QGE6, A0A1W2PPD8, A0A6A6H2E0, A4H5X5, B1NWF3, B1VKF6, I1R9B4, O30075, O83202, P07885, P09003, P09004, P0C7P4, P14975, P15397, P15718, P16130, P22281, P24620, P24621, P27269, P27336, P39308, P44047, P61511, P61512, P83944, P86937, P86938, Q02330, Q03286, Q05106, Q1KXV6, Q1R1Y6, Q2GPK5, Q2YD11, Q41407, Q4DBW3, Q53932, Q5AR53

Diamond homologs: P25085, Q8R460, Q9D6Z6, Q9JLA2, Q9NZH6, Q9NZH7, Q9NZH8, Q9QYY1, Q9UBH0, Q9UHA7, A4UYK8, P01584, P09428, P10749, P14628, P18510, P21621, P26889, P26890, P41687, P46648, P48090, P51493, P51745, P79162, P79182, Q28292, Q28386, Q29056, Q2HZH0, Q2MH07, Q63264, Q6PUD2, Q6R2X3, Q865X8, Q866R8, Q8WNR2, Q9GMZ4, Q9WVG1, Q9XS77

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	14
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1072 predictions. Top by Δscore:

Variant	Effect	Δscore
2:113031782:CA:C	acceptor_gain	1.0000
2:113031783:A:AC	acceptor_gain	1.0000
2:113031783:A:C	acceptor_gain	1.0000
2:113027952:T:A	donor_gain	0.9900
2:113028022:A:AC	donor_gain	0.9900
2:113028023:C:CC	donor_gain	0.9900
2:113031781:CCA:C	acceptor_gain	0.9900
2:113031785:G:C	acceptor_gain	0.9900
2:113029076:TGA:T	acceptor_gain	0.9800
2:113028021:G:T	donor_gain	0.9700
2:113027943:ATG:A	donor_gain	0.9600
2:113029079:C:CC	acceptor_gain	0.9500
2:113031629:T:TA	donor_gain	0.9500
2:113031611:G:C	donor_gain	0.9400
2:113031782:C:T	acceptor_gain	0.9300
2:113031785:G:GC	acceptor_gain	0.9300
2:113025985:TAG:T	donor_gain	0.9200
2:113025986:AGA:A	donor_gain	0.9200
2:113027975:T:TA	donor_gain	0.9200
2:113029075:GTGA:G	acceptor_gain	0.9100
2:113028045:T:TA	donor_gain	0.9000
2:113022776:ACCTG:A	acceptor_loss	0.8900
2:113022777:CCT:C	acceptor_loss	0.8900
2:113022778:CTG:C	acceptor_loss	0.8900
2:113022779:T:TC	acceptor_loss	0.8900
2:113022780:G:C	acceptor_loss	0.8900
2:113027945:G:A	donor_gain	0.8800
2:113031723:CCTTT:C	acceptor_gain	0.8800
2:113049873:TGA:T	donor_gain	0.8800
2:113031606:G:C	donor_gain	0.8700

AlphaMissense

1031 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:113031105:A:G	W22R	0.922
2:113031105:A:T	W22R	0.922
2:113031121:A:C	D16E	0.890
2:113031121:A:T	D16E	0.890
2:113031083:A:G	L29S	0.885
2:113031103:C:A	W22C	0.868
2:113031103:C:G	W22C	0.868
2:113028949:A:G	L84S	0.840
2:113029041:G:C	F53L	0.837
2:113029041:G:T	F53L	0.837
2:113029043:A:G	F53L	0.837
2:113028978:G:C	F74L	0.819
2:113028978:G:T	F74L	0.819
2:113028980:A:G	F74L	0.819
2:113031123:C:G	D16H	0.812
2:113029003:A:G	I66T	0.802
2:113031128:A:G	I14T	0.792
2:113031122:T:G	D16A	0.787
2:113031122:T:A	D16V	0.767
2:113031128:A:T	I14N	0.749
2:113029003:A:C	I66S	0.740
2:113031128:A:C	I14S	0.734
2:113031087:A:G	S28P	0.728
2:113028943:A:T	L86H	0.727
2:113031104:C:G	W22S	0.727
2:113031109:C:A	M20I	0.725
2:113031109:C:G	M20I	0.725
2:113031109:C:T	M20I	0.725
2:113028943:A:G	L86P	0.710
2:113029072:A:T	L43H	0.703

dbSNP variants (sampled 300 via entrez): RS1000119218 (2:113039350 C>A), RS1000170594 (2:113044092 C>T), RS1000195479 (2:113036234 C>A,G,T), RS1000247614 (2:113042593 A>C), RS1000264006 (2:113044370 G>A), RS1000287850 (2:113026038 C>A,G,T), RS1000398883 (2:113038085 T>G), RS1000455672 (2:113048248 C>T), RS1000489940 (2:113050273 T>C), RS1000506830 (2:113042762 G>A), RS1000542893 (2:113036625 G>A), RS1000652045 (2:113040711 C>T), RS1000933548 (2:113035195 G>A), RS1000957334 (2:113054423 C>T), RS1001210589 (2:113046960 G>A)

Disease associations

OMIM: gene MIM:605508 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST005173_18	Coronary artery calcified atherosclerotic plaque (130 HU threshold) in type 2 diabetes	5.000000e-06
GCST006104_7	Interleukin-1-receptor antagonist levels	1.000000e-06
GCST006636_1	Menstruation quality of life impact (dysmenorrhea)	3.000000e-12
GCST006637_3	Pain medicine use during menstruation	2.000000e-09

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004723	coronary artery calcification
EFO:0004754	interleukin 1 receptor antagonist measurement
EFO:0007889	dysmenorrheic pain measurement
EFO:0007010	drug use measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Lipopolysaccharides	affects cotreatment, increases expression, decreases reaction	2
bisphenol A	affects methylation	1
sodium arsenite	increases expression	1
nickel chloride	increases expression, increases reaction	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, increases expression	1
CGP 52608	affects binding, increases reaction	1
lipopolysaccharide, E. coli O26-B6	increases expression, increases reaction	1
abrine	increases expression	1
archazolid B	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Benzo(a)pyrene	increases methylation	1
Ozone	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Triclosan	decreases reaction, increases expression	1
Okadaic Acid	increases expression	1
Lactic Acid	decreases expression	1

Clinical trials (associated diseases)

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