IL31

Summary

IL31 (interleukin 31, HGNC:19372) is a protein-coding gene on chromosome 12q24.31, encoding Interleukin-31 (Q6EBC2). Activates STAT3 and possibly STAT1 and STAT5 through the IL31 heterodimeric receptor composed of IL31RA and OSMR.

IL31, which is made principally by activated Th2-type T cells, interacts with a heterodimeric receptor consisting of IL31RA (MIM 609510) and OSMR (MIM 601743) that is constitutively expressed on epithelial cells and keratinocytes. IL31 may be involved in the promotion of allergic skin disorders and in regulating other allergic diseases, such as asthma (Dillon et al., 2004 [PubMed 15184896]).

Source: NCBI Gene 386653 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 29 total
• MANE Select transcript: NM_001014336

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19372
Approved symbol	IL31
Name	interleukin 31
Location	12q24.31
Locus type	gene with protein product
Status	Approved
Aliases	IL-31
Ensembl gene	ENSG00000204671
Ensembl biotype	protein_coding
OMIM	609509
Entrez	386653

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000377035

RefSeq mRNA: 1 — MANE Select: NM_001014336 NM_001014336

CCDS: CCDS31919

Canonical transcript exons

ENST00000377035 — 3 exons

Exon	Start	End
ENSE00001472570	122172029	122172741
ENSE00001472572	122173844	122173992
ENSE00001472574	122174157	122174221

Expression profiles

Bgee: expression breadth tissue_specific, 4 present calls, max score 45.28.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.1426 / max 2086.0102, expressed in 2 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
133792	1.1426	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
bone marrow cell	CL:0002092	45.28	gold quality
granulocyte	CL:0000094	37.92	gold quality
sural nerve	UBERON:0015488	37.42	gold quality
colonic epithelium	UBERON:0000397	37.20	gold quality
mucosa of stomach	UBERON:0001199	36.92	silver quality
skeletal muscle tissue	UBERON:0001134	36.78	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
bone marrow	UBERON:0002371	36.40	gold quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
muscle tissue	UBERON:0002385	33.56	gold quality
gastrocnemius	UBERON:0001388	32.39	silver quality
muscle of leg	UBERON:0001383	32.16	silver quality
hindlimb stylopod muscle	UBERON:0004252	32.15	gold quality
tonsil	UBERON:0002372	31.93	gold quality
islet of Langerhans	UBERON:0000006	30.99	silver quality
urinary bladder	UBERON:0001255	30.11	gold quality
stromal cell of endometrium	CL:0002255	29.87	gold quality
prefrontal cortex	UBERON:0000451	29.21	gold quality
lymph node	UBERON:0000029	29.01	silver quality
duodenum	UBERON:0002114	28.14	gold quality
blood	UBERON:0000178	27.91	gold quality
right coronary artery	UBERON:0001625	27.82	gold quality
leukocyte	CL:0000738	27.59	gold quality
superior frontal gyrus	UBERON:0002661	27.19	gold quality
monocyte	CL:0000576	26.93	gold quality
vermiform appendix	UBERON:0001154	26.42	gold quality
gall bladder	UBERON:0002110	25.98	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	25.89	gold quality
placenta	UBERON:0001987	25.81	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.14

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOS, HAND2, JUN, JUNB, NFATC1, NFATC2, NFKB, RELA, SMAD3, STAT6

miRNA regulators (miRDB)

20 targeting IL31, 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-188-3P	100.00	68.76	1240
HSA-MIR-8087	99.90	69.55	1351
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-12129	99.72	67.45	1311
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-587	99.64	70.86	2611
HSA-MIR-298	99.63	67.56	1916
HSA-MIR-549A-3P	99.54	68.17	825
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-6727-3P	99.49	65.92	1333
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662
HSA-MIR-32-3P	99.36	68.20	2517
HSA-MIR-4722-3P	99.35	65.22	1099
HSA-MIR-664A-3P	99.22	71.08	2696
HSA-MIR-361-3P	99.19	66.45	1381
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-596	97.48	63.13	469

Literature-anchored findings (GeneRIF, showing 40)

• Findings suggest that IL-31 may participate in the cause of itch sensation and promote scratching behavior in NC/Nga mice with atopic dermatitis. (PMID:15925362)
• Significantly upregulated in pruritic atopic dermatitis. These findings provide a new link among staphylococcal colonization, subsequent T-cell recruitment/activation, and pruritus induction in patients with atopic dermatitis. (PMID:16461142)
• IL-31 expression is associated with CLA(+) T cells and might contribute to the development of atopic dermatitis-induced skin inflammation and pruritus (PMID:16461143)
• IL-31 is a potent inducer of proinflammatory mediators in human colonic SEMFs. IL-31 may function as a proinflammatory cytokine derived from Th2 cells. (PMID:17487427)
• This study presents the first genetic risk factor for the nonatopic type of eczema and indicates a primary role of IL-31-induced pruritus in the initiation of this disease. (PMID:17900679)
• The data suggest that increased IL-31Ralpha expression correlates with an enhanced response to IL-31. (PMID:18439099)
• serum IL-31 levels were significantly higher in patients with atopic dermatitis (AD) compared with control subjects; findings provide evidence that IL-31 has a role in AD pathophysiology with regard to pruritus and skin inflammation (PMID:18678344)
• overexpressed in patients with atopic dermatitis; staphylococcal superantigens induce expression in atopic individuals (PMID:18802341)
• unlike eczema, genetic variation at COL29A1 and IL31 loci is unlikely to implact inflammatory bowel disease risk (PMID:18839421)
• IL-31 acts on a broad range of immune- & non-immune cells & possesses potential pleiotropic physiological functions, including regulating hematopoiesis & immune response, causing inflammatory bowel disease, airway hypersensitivity & dermatitis[review] (PMID:18926762)
• Human CD4(+) T cells express a functional H(4)R. The receptor is upregulated under T(H)2 conditions, and its stimulation leads to induction of AP-1 and IL-31. (PMID:19281909)
• regulation of the IL-31 receptor and pro-inflammatory functions of IL-31 in human monocytes and monocyte-derived cells (PMID:19889120)
• IL-31 recognizes its receptor complex through two different binding sites (PMID:19920145)
• IL-31 serum levels may play a role in the pathophysiology of chronic spontaneous urticaria. (PMID:20163453)
• The ability of beta-defensins and cathelicidin LL-37 to stimulate the production and release of IL-31 by human mast cells provides a novel mechanism by which skin-derived antimicrobial peptides/proteins may contribute to inflammatory reactions (PMID:20190140)
• induces pro-inflammatory cytokines and atopic dermatitis-related chemokines in eosinophils (PMID:20410259)
• Letter: polymorphisms in the IL-31 gene do not appear to underlie epidermolysis bullosa pruriginosa. (PMID:21057749)
• Data not only illustrate various functions that cysteines perform during IL-31 biosynthesis and secretion, but also highlight their potential roles in cytokine effector functions. (PMID:21182835)
• IL-31 displays a unique and independent role in the pathophysiology of allergic rhinitis (PMID:21211659)
• Our findings show a functional role of IL-31 in human primary keratinocytes and provide a new link between TLR-2 ligands and IL-31 which might be dysregulated in atopic dermatitis. (PMID:21261663)
• IL-31 is important in atopic dermatitis pathophysiology. (PMID:21294778)
• IL-31-631 T>G polymorphism was significantly associated with IL-31 blood level but not with disease susceptibility. (PMID:21952721)
• Distinct SPINK5 and IL-31 gene variants (SNPs) were associated with the development of atopic eczema and non-atopic hand dermatitis in Taiwanese nurses. (PMID:22017185)
• This study suggests that IL-31 is an important regulator of keratinocyte differentiation and demonstrates a link between the presence of IL-31 in skin, as found in patients with atopic dermatitis, and filaggrin expression (PMID:22177328)
• IL-31 serum levels correlate with the SCORAD score, sleeplessness, and Th2 cytokines including IL-4 and IL-13, in sixty children with the extrinsic type of atopic dermatitis. (PMID:22509760)
• IL-31-specific activation of dendritic cells may be part of a positive feedback loop driving the progression of inflammatory skin diseases. (PMID:22539792)
• T cells in chronic atopic dermatitis (AD) skin produce IL-31 and AD lesions contain increased levels of these IL-31-producing T cells. (PMID:22621183)
• hypothesize that an altered regulation of IL-31 gene expression influence clinical course of AD. The available published data and our results lend support to an important role of IL-31 gene polymorphism in AD pathogenesis (PMID:22827739)
• IL-31 and IL-31RA are upregulated in patients with allergic rhinitis, and induce MUC5AC gene expression in human airway epithelial cells. (PMID:23392388)
• IL-31 induces pro-inflammatory effects in activated human macrophages via STAT-1 and 5 phosphorylation. Interleukin-31-induced ERK 1/2 activation contributes to the underlying mechanism of Th1 cytokine IL-12 suppression in macrophages. (PMID:23621408)
• Il-31 is not a TH2 cytokine in the classical sense but is likely to be expressed by a number of cells in an allergic situation in which IL-4 is present and possibly contribute to the allergic reaction. (PMID:23694808)
• CD4+CD26- malignant cells specifically produce IL-31 and clinical resolution of pruritus correlates with decreased IL-31 levels in the circulation (PMID:23698099)
• EGFR-TK inhibitors could cause keratinocytes injury, the release of IL-33 and the consequent interaction with its receptor on mast cells, that induces the secretion of several factors capable to cause skin manifestations, included IL-31 (PMID:23794184)
• IL-31 seems to be another sweat stimulator. (PMID:23874436)
• enhanced Th2 cytokine levels was correlated with IL-31 expression in NPs and provide a possible explanation for IL-31’s regulatory role in the pathogenesis of NPs. (PMID:24515918)
• Case Report: sporadic lichen amyloidosis with high expression of Il31. (PMID:24573820)
• IL-31-positive cells were observed as mononuclear infiltrating cells and as CD11b co-expressing cells in severe atopic dermatitis samples. (PMID:24667097)
• Data show that STAT6 and NF-kappaB are central players in mediating IL-31 expression induced by IL-4/IL-33. (PMID:24943220)
• TARC and interleukin-31 may be biomarkers for adult atopic dermatitis (PMID:24984931)
• IL-31 was increased after IVIG treatment in patients with KD and was significantly associated with CAL formation. (PMID:25122210)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Il31	ENSMUSG00000029437
rattus_norvegicus	Il31	ENSRNOG00000026192

Protein

Protein identifiers

Interleukin-31 — Q6EBC2 (reviewed: Q6EBC2)

All UniProt accessions (1): Q6EBC2

UniProt curated annotations — full annotation on UniProt →

Function. Activates STAT3 and possibly STAT1 and STAT5 through the IL31 heterodimeric receptor composed of IL31RA and OSMR. May function in skin immunity. Enhances myeloid progenitor cell survival in vitro. Induces RETNLA and serum amyloid A protein expression in macrophages.

Subcellular location. Secreted.

Tissue specificity. Detected at low levels in testis, bone marrow, skeletal muscle, kidney, colon, thymus, small intestine and trachea.

Induction. Up-regulated in skin homing T-cells of patients with atopic dermatitis (AD) and in activated circulating T-cells. Up-regulated in lesional biopsies of patients with allergic contact dermatitis (ACD).

RefSeq proteins (1): NP_001014358* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR027987	IL-31	Family

Pfam: PF15209

UniProt features (4 total): glycosylation site 2, signal peptide 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6EBC2-F1	80.04	0.49

Functional residue map

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

Glycosylation sites (2): 67, 100

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6788467	IL-6-type cytokine receptor ligand interactions

MSigDB gene sets: 32 (showing top): REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOMF_CYTOKINE_ACTIVITY, GOMF_SIGNALING_RECEPTOR_BINDING, WORSCHECH_TUMOR_REJECTION_UP, chr12q24, GOMF_SIGNALING_RECEPTOR_REGULATOR_ACTIVITY, REACTOME_INTERLEUKIN_6_FAMILY_SIGNALING, REACTOME_IL_6_TYPE_CYTOKINE_RECEPTOR_LIGAND_INTERACTIONS, GSE13522_WT_VS_IFNG_KO_SKING_T_CRUZI_Y_STRAIN_INF_UP, MIR95_5P, MIR4319, MIR125B_5P, MIR125A_5P, MIR298, GSE11924_TH2_VS_TH17_CD4_TCELL_UP

GO Biological Process (2): immune system process (GO:0002376), signal transduction (GO:0007165)

GO Molecular Function (3): cytokine activity (GO:0005125), 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-1 pathways:

Category	Pathways
Interleukin-6 family signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
biological_process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
receptor ligand activity	1
signaling receptor binding	1
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

710 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IL31	IL31RA	Q8NI17	999
IL31	OSMR	Q99650	995
IL31	OSM	P13725	843
IL31	IL13	P35225	836
IL31	IL17A	Q16552	781
IL31	TSLP	Q969D9	737
IL31	IFNG	P01579	734
IL31	IL4	P05112	730
IL31	IL11	P20809	726
IL31	IL33	O95760	720
IL31	IL22	Q9GZX6	720
IL31	IL5	P05113	712
IL31	TNF	P01375	709
IL31	TRPA1	O75762	696
IL31	TRPV1	Q8NER1	681

IntAct

5 interactions, top by confidence:

A	B	Type	Score
IL31	NTAQ1	psi-mi:“MI:0915”(physical association)	0.560
IL31	MAN1A1	psi-mi:“MI:0914”(association)	0.350
NTAQ1	IL31	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (17): IL31 (Two-hybrid), IL31 (Affinity Capture-RNA), MAN1A1 (Affinity Capture-MS), GOLM1 (Affinity Capture-MS), COL14A1 (Affinity Capture-MS), ROBO1 (Affinity Capture-MS), FSTL1 (Affinity Capture-MS), KIAA0319L (Affinity Capture-MS), PTPRS (Affinity Capture-MS), NIPBL (Affinity Capture-MS), DNAJC1 (Affinity Capture-MS), METAP2 (Affinity Capture-MS), EDEM2 (Affinity Capture-MS), XPNPEP3 (Affinity Capture-MS), ALG11 (Affinity Capture-MS)

ESM2 similar proteins: A0A140LIA7, B6CKP4, O02720, O02750, O08987, O42164, P04141, P04401, P05113, P08700, P20109, P35225, P41159, P41160, P42203, P46652, P46685, P47966, P48093, P50595, P50596, P51492, P51748, P61126, Q0MUT8, Q1XG29, Q257X2, Q28504, Q28603, Q28809, Q29406, Q4KM46, Q588G0, Q5I6E4, Q5J732, Q62575, Q6EBC2, Q706D0, Q706D1, Q864V6

Diamond homologs: Q6EAL8, Q6EBC2

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
IL31	up-regulates	IL31RA	binding
IL31	up-regulates	OSMR	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	23
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

195 predictions. Top by Δscore:

Variant	Effect	Δscore
12:122172737:TCCAC:T	acceptor_gain	1.0000
12:122172738:CCAC:C	acceptor_gain	1.0000
12:122172738:CCACC:C	acceptor_gain	1.0000
12:122172739:CAC:C	acceptor_gain	1.0000
12:122172739:CACC:C	acceptor_gain	1.0000
12:122172740:AC:A	acceptor_gain	1.0000
12:122172741:CC:C	acceptor_gain	1.0000
12:122172742:C:CA	acceptor_loss	1.0000
12:122172742:C:CC	acceptor_gain	1.0000
12:122172744:G:C	acceptor_gain	1.0000
12:122172744:G:GC	acceptor_gain	1.0000
12:122173840:TCAC:T	donor_loss	1.0000
12:122173841:CAC:C	donor_loss	1.0000
12:122173842:A:AC	donor_gain	1.0000
12:122173842:ACAT:A	donor_gain	1.0000
12:122173843:C:CA	donor_gain	1.0000
12:122173843:CA:C	donor_gain	1.0000
12:122173843:CAT:C	donor_gain	1.0000
12:122173843:CATC:C	donor_gain	1.0000
12:122173843:CATCT:C	donor_gain	1.0000
12:122174092:T:TA	donor_gain	1.0000
12:122174102:T:TA	donor_gain	1.0000
12:122172743:T:G	acceptor_loss	0.9900
12:122172749:A:AC	acceptor_gain	0.9900
12:122172749:A:C	acceptor_gain	0.9900
12:122173845:T:C	donor_gain	0.9900
12:122173845:T:TA	donor_gain	0.9900
12:122173878:T:TA	donor_gain	0.9900
12:122173993:C:CC	acceptor_gain	0.9800
12:122174076:C:A	donor_gain	0.9800

AlphaMissense

1063 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:122172499:G:C	F136L	0.971
12:122172499:G:T	F136L	0.971
12:122172501:A:G	F136L	0.971
12:122172500:A:G	F136S	0.958
12:122172476:A:G	F144S	0.957
12:122173875:A:G	L45S	0.952
12:122172575:A:G	L111P	0.951
12:122172475:A:C	F144L	0.927
12:122172475:A:T	F144L	0.927
12:122172477:A:G	F144L	0.927
12:122172476:A:C	F144C	0.924
12:122172500:A:C	F136C	0.922
12:122172632:A:G	L92P	0.918
12:122172468:A:G	C147R	0.903
12:122172505:T:A	K134N	0.894
12:122172505:T:G	K134N	0.894
12:122172506:T:A	K134I	0.889
12:122172466:G:C	C147W	0.874
12:122172652:G:C	S85R	0.874
12:122172652:G:T	S85R	0.874
12:122172654:T:G	S85R	0.874
12:122173854:A:G	L52P	0.868
12:122172494:A:G	L138P	0.857
12:122173864:A:G	S49P	0.857
12:122172566:A:G	L114P	0.856
12:122172575:A:T	L111H	0.855
12:122172587:A:C	I107S	0.843
12:122172467:C:G	C147S	0.842
12:122172468:A:T	C147S	0.842
12:122173963:A:G	C16R	0.841

dbSNP variants (sampled 300 via entrez): RS1001761841 (12:122173011 G>A,C), RS1002721308 (12:122171656 A>G), RS1002727071 (12:122174770 C>T), RS1003109443 (12:122174545 C>A,T), RS1003445604 (12:122175882 G>A), RS1003472731 (12:122176126 C>T), RS1003549918 (12:122174769 T>C), RS1004162345 (12:122173373 G>A), RS1004532171 (12:122173105 G>A,C), RS1006471400 (12:122171733 C>T), RS1006914835 (12:122171983 G>T), RS1008906606 (12:122172148 A>C,G), RS1009518115 (12:122172105 A>G), RS1009968824 (12:122172390 A>G), RS1010151945 (12:122175556 T>G)

Disease associations

OMIM: gene MIM:609509 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST004346_55	Psoriasis	2.000000e-08
GCST90020025_112	Waist-to-hip ratio adjusted for BMI	1.000000e-08
GCST90020027_1190	Waist-hip index	3.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

13 total (human), top 13 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
sodium arsenite	increases expression	1
enterotoxin B, staphylococcal	increases expression	1
CGP 52608	affects binding, increases reaction	1
diphenylarsinic acid	increases secretion	1
Resveratrol	affects cotreatment, decreases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	affects methylation	1
Latex	increases expression	1
Nickel	increases expression	1
Perfume	increases expression	1
Plant Extracts	decreases expression, affects cotreatment	1
Thiram	increases expression	1

Clinical trials (associated diseases)

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