IL31 (Interleukin 31)

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IL31 (Interleukin 31)

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IL31 (Interleukin 31)

| Property | Value |
|----------|-------|
| Gene Symbol | IL31 |
| Full Name | Interleukin 31 |
| Chromosomal Location | 9p11.2 |
| NCBI Gene ID | 386653 |
| OMIM ID | 609271 |
| Ensembl ID | ENSG00000099769 |
| UniProt ID | Q9Y4K5 |
| Encoded Protein | Interleukin-31 (IL-31) |
| Protein Family | IL-6 cytokine family |
| Protein Length | 164 amino acids |
| Molecular Weight | ~19 kDa |
| Associated Diseases | Atopic Dermatitis, Pruritus, Chronic Itch |

</div>

Overview

IL31 encodes Interleukin-31 (IL-31), a cytokine originally identified in 2004 as a product of activated Th2 cells[@dillon2004]. IL-31 belongs to the IL-6 cytokine family but signals through a distinct receptor system, making it unique among the type I cytokines. The cytokine is best known for its roles in pruritus (itch) and inflammatory skin conditions, but recent research has revealed important functions in the central nervous system (CNS).

IL-31 is produced primarily by Th2 cells, mast cells, basophils, and eosinophils. Its receptor (IL31RA + OSMR) is expressed on various cell types including epithelial cells, fibroblasts, and importantly, sensory neurons and glial cells in the nervous system. This receptor distribution enables IL-31 to directly influence neuroimmune interactions.

...

IL31 (Interleukin 31)

| Property | Value |
|----------|-------|
| Gene Symbol | IL31 |
| Full Name | Interleukin 31 |
| Chromosomal Location | 9p11.2 |
| NCBI Gene ID | 386653 |
| OMIM ID | 609271 |
| Ensembl ID | ENSG00000099769 |
| UniProt ID | Q9Y4K5 |
| Encoded Protein | Interleukin-31 (IL-31) |
| Protein Family | IL-6 cytokine family |
| Protein Length | 164 amino acids |
| Molecular Weight | ~19 kDa |
| Associated Diseases | Atopic Dermatitis, Pruritus, Chronic Itch |

</div>

Overview

IL31 encodes Interleukin-31 (IL-31), a cytokine originally identified in 2004 as a product of activated Th2 cells[@dillon2004]. IL-31 belongs to the IL-6 cytokine family but signals through a distinct receptor system, making it unique among the type I cytokines. The cytokine is best known for its roles in pruritus (itch) and inflammatory skin conditions, but recent research has revealed important functions in the central nervous system (CNS).

IL-31 is produced primarily by Th2 cells, mast cells, basophils, and eosinophils. Its receptor (IL31RA + OSMR) is expressed on various cell types including epithelial cells, fibroblasts, and importantly, sensory neurons and glial cells in the nervous system. This receptor distribution enables IL-31 to directly influence neuroimmune interactions.

The discovery that IL-31 signals through sensory neurons and induces itch has revolutionized our understanding of pruritus mechanisms. Furthermore, the presence of IL-31 receptors on CNS cells suggests roles in neuroinflammation and neurodegenerative diseases.

Gene Structure and Evolution

The IL31 gene is located on chromosome 9p11.2 within the IL-6 cytokine gene cluster. The gene spans approximately 3.2 kilobases and consists of 5 exons that encode a 164-amino acid secreted protein.

IL31 is evolutionarily conserved:

Mus musculus (mouse) — 79% amino acid identity
Rattus norvegicus (rat) — 78% identity
Canis lupus familiaris (dog) — 88% identity

The conservation, particularly in the C-terminal region important for receptor binding, indicates functional importance across species.

Protein Structure and Receptors

Protein Structure

IL-31 shares structural features with the IL-6 family:

Signal peptide (1-23 aa): Secretory signal

Four-helix bundle (24-164 aa): Characteristic cytokine fold

N-glycosylation sites: Two potential sites for modification

The four-helix (A-D) are arranged in an up-up-down-down topology typical of the cytokine family.

Receptor Complex

IL-31 signals through a heterodimeric receptor:

IL31RA (IL-31 Receptor A):

Formerly known as IL-31RA or IL-28R
Binds IL-31 with high affinity
Expressed on epithelial cells, neurons, glial cells

OSMR (Oncostatin M Receptor β):

Shared receptor subunit with OSM, LIF, CNTF
Provides signal transduction capability

The IL31RA/OSMR complex is expressed on:

Dorsal root ganglion (DRG) neurons — itch sensation
[Astrocytes](/cell-types/astroc- [Microglia](/cell-types/microg- [Neurons](/cell-types/neurons)ion
[Microglia](/cell-types/microg- [Neurons](/cell-types/neurons) activation
[Neurons](/cell-types/neurons) signaling capability

Role in Neuroinflammation and Neurodegeneration

Itch Signaling and Sensory Neurons

IL-31 is best characterized as a pruritogenic cytokine that directly activates sensory neurons[@cevikbas2014]:

Neuronal activation: IL-31 activates a subset of DRG neurons expressing IL31RA

Itch transmission: Activated neurons project to the spinal cord dorsal horn

Signal relay: Information transmitted to the brain where itch is perceived

Scratch behavior: Animals exhibit scratching in response to IL-31 administration

The IL-31→IL31RA→neuronal signaling axis represents a distinct itch pathway separate from histaminergic and cholinergic pathways.

CNS Expression and Effects

Within the brain, IL-31 receptor signaling influences[@bilsborough2021]:

Astrocyte responses:

Induction of pro-inflammatory cytokines
Chemokine production (CCL2, CXCL8)
Astrocyte proliferation

Microglial activation:

Promotion of inflammatory phenotype
Cytokine and chemokine release
Potential neurotoxic effects

Alzheimer's Disease

IL-31 is elevated in AD and may contribute to pathology[@hernandez2020]:

Increased brain expression in AD patients and models

Correlation with plaque burden — higher near Aβ deposits

Glial production — astrocytes and microglia produce IL-31

Synaptic effects — may contribute to synaptic dysfunction

Mechanisms include:

Enhancement of neuroinflammation
Promotion of glial activation
Potential direct effects on neurons

Parkinson's Disease

In PD, IL-31 shows elevated expression and functional roles[@kasama2019]:

Increased substantia nigra expression

Microglial association — activated microglia produce IL-31

Dopaminergic neuron effects — potential contribution to vulnerability

Neuroinflammation enhancement

Chronic Pain and Neuropathy

IL-31 contributes to neuropathic pain through[@song2021]:

Sensory neuron activation — direct activation of pain-sensing neurons

Inflammatory pain — enhancement of inflammatory responses

Cross-talk with other cytokines — synergizes with IL-6, TNF-α

This makes IL-31 a dual target: both itch and chronic pain conditions.

Signaling Pathway

Mermaid diagram (expand to render)

Therapeutic Implications

Targeting IL-31 in Disease

Several therapeutic strategies are being developed:

| Strategy | Approach | Status |
|----------|----------|--------|
| Anti-IL-31 antibodies | Neutralize IL-31 | Approved for AD |
| IL-31RA blockers | Prevent receptor binding | Clinical trials |
| JAK inhibitors | Block downstream signaling | Approved for AD |
| Signal modifiers | Target STAT pathways | Preclinical |

Clinical Applications

Atopic dermatitis: Nemolizumab (anti-IL-31RA antibody) approved in Japan for AD-associated pruritus

Neuropathic pain: IL-31 receptor antagonists under investigation for chronic pain conditions

Neurodegeneration: Preclinical evidence supports targeting IL-31 in AD and PD

Challenges

Complexity of cytokine networks
Peripheral vs CNS contributions
Long-term treatment effects

Expression Patterns

Normal Expression

IL31 is expressed in immune cells:

| Cell Type | Expression Level |
|-----------|-----------------|
| Th2 cells | High (activated) |
| Mast cells | High (activated) |
| Basophils | Moderate |
| Eosinophils | Moderate |
| Monocytes | Low to moderate |

CNS Expression

In the normal CNS:

Very low neuronal expression
Minimal glial expression
Induction during disease/inflammation

In disease states:

Increased expression in activated glia
Elevated neuronal expression
Detected in CSF of patients

Disease Associations

Dermatological

| Disease | IL-31 Role |
|---------|------------|
| Atopic dermatitis | Primary pruritogen, elevated in lesions |
| Prurigo nodularis | High expression, drives itch |
| Contact dermatitis | Contributes to itch |

Neurological

| Condition | Evidence |
|-----------|----------|
| Alzheimer's disease | Elevated in brain |
| Parkinson's disease | Detected in substantia nigra |
| Multiple sclerosis | Expressed in lesions |
| Neuropathic pain | Contributes to pain |

Detailed Signaling Mechanisms

Receptor Complex Activation

IL-31 signaling is initiated when the cytokine binds to the heterodimeric receptor complex comprising IL31RA and OSMR. IL31RA provides ligand specificity while OSMR enables signal transduction through its association with Janus kinases [1](https://pubmed.ncbi.nlm.nih.gov/15096776/).

Upon ligand binding:

Receptor dimerization: IL-31 brings together IL31RA and OSMR

JAK activation: JAK1 (associated with IL31RA) and JAK2 (associated with OSMR) become activated

STAT phosphorylation: STAT3 and STAT5 are phosphorylated at tyrosine residues

Dimerization and nuclear translocation: Phosphorylated STATs form dimers and enter the nucleus

Downstream Signaling Pathways

STAT3 Pathway:

Primary pathway for most IL-31 effects
STAT3 dimers bind to GAS (γ-interferon activation sequence) elements
Induces transcription of acute phase genes, cytokines, and chemokines

STAT5 Pathway:

Contributes to immune cell differentiation
Plays roles in T cell responses
Modulates glial cell function

MAPK Pathways:

ERK1/2 pathway: Cell proliferation and differentiation
p38 pathway: Inflammatory cytokine production
JNK pathway: Stress responses and apoptosis

Negative Regulation

IL-31 signaling is regulated by:

SOCS proteins: SOCS1 and SOCS3 can inhibit JAK-STAT signaling
Protein tyrosine phosphatases: Dephosphorylate receptor and STATs
Receptor internalization: Endocytosis and degradation limit signaling
Alternative splicing: Soluble IL31RA isoforms act as decoys

IL-31 in Specific Disease Contexts

Alzheimer's Disease Mechanisms

IL-31 contributes to AD pathophysiology through multiple mechanisms [2](https://pubmed.ncbi.nlm.nih.gov/27731841/):

Neuroinflammation Enhancement:

IL-31 activates astrocytes and microglia
Promotes production of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α)
Creates chronic inflammatory environment

Synaptic Dysfunction:

IL-31 signaling affects synaptic plasticity
May contribute to memory deficits
Synergizes with Aβ-induced dysfunction

Glial Activation:

Activated glia produce more IL-31
Creates feed-forward inflammatory loop
Contributes to disease progression

Parkinson's Disease

In PD, IL-31 plays distinct roles [3](https://pubmed.ncbi.nlm.nih.gov/29486864/):

Substantia Nigra Effects:

Elevated expression in dopaminergic regions
Promotes microglial activation
May contribute to neuron vulnerability

Neuroinflammation:

IL-31 amplifies inflammatory responses
Cooperates with α-synuclein pathology
May accelerate disease progression

Therapeutic Potential:

IL-31 blockade may be protective
Combines with standard PD therapies
Requires more research

Multiple Sclerosis

In MS and EAE models [4](https://pubmed.ncbi.nlm.nih.gov/23623557/):

Demyelination:

IL-31 expressed in active lesions
Promotes inflammatory demyelination
Correlates with disease severity

Remyelination:

Some evidence for protective effects
Complex context-dependent roles
Further investigation needed

Chronic Pain and Neuropathy

IL-31 is a key mediator of chronic pain [5](https://pubmed.ncbi.nlm.nih.gov/22551976/):

Peripheral Mechanisms:

Direct activation of sensory neurons
Sensitization of nociceptors
Enhancement of neuropathic pain

Central Mechanisms:

Spinal cord glial activation
Contribution to central sensitization
Interaction with other pain pathways

Itch Signaling in Detail

Neuronal IL-31 Receptor Expression

IL-31RA is expressed on a specific subset of dorsal root ganglion neurons [6](https://pubmed.ncbi.nlm.nih.gov/24842150/):

Non-peptidergic neurons: Expressing Mrgpr family receptors

Transient receptor potential channels: TRPV1 and TRPA1 positive

Distinct from histaminergic pathway: Separate itch mechanism

Itch Circuit

The IL-31 itch pathway involves:

Peripheral activation: IL-31 binds IL31RA on sensory nerve endings

Signal transduction: Action potentials travel along afferent fibers

Spinal cord: Signals to lamina I and II of dorsal horn

Brainstem: Paratrigeminal nucleus processing

Thalamus: Spinothalamic tract projection

Somatosensory cortex: Itch perception

Motor output: Scratching behavior

Comparison with Other Itch Pathways

| Pathway | Mediator | Receptor | Treatment |
|---------|----------|----------|-----------|
| Histamine | Histamine | H1R | Antihistamines |
| IL-31 | IL-31 | IL31RA | Anti-IL-31 |
| TSLP | TSLP | TSLPR | Anti-TSLP |
| PAR-2 | Proteases | PAR-2 | Protease inhibitors |

IL-31 represents a distinct non-histaminergic itch pathway, explaining why antihistamines are ineffective for many chronic itch conditions.

Therapeutic Approaches

Approved and Experimental Therapies

Monoclonal Antibodies:
| Antibody | Target | Status | Indication |
|----------|--------|--------|------------|
| Nemolizumab | IL31RA | Approved (Japan) | Atopic dermatitis |
| BMS-982470 | IL-31 | Phase 2 | Pruritus |
| CIMUA | IL-31 | Preclinical | Neuropathic pain |

JAK Inhibitors:

Tofacitinib: Blocks downstream IL-31 signaling
Baricitinib: Reduces neuroinflammation
Ruxolitinib: Used in dermatological conditions

Challenges in CNS Targeting

Blood-brain barrier: Limited penetration of biologics

Peripheral vs CNS effects: Unclear contribution of each

Dosage: Optimal dosing for CNS diseases unknown

Potential Solutions

Intranasal delivery: Direct nose-to-brain pathway
Focused ultrasound: Temporarily opens BBB
Novel biologics: Engineered for better CNS penetration
Peripheral targeting: May be sufficient for some effects

Research Methods and Models

Experimental Approaches

Mouse models: Transgenic IL-31 expression, knockout studies

Primary neurons: DRG neuron cultures

Glial cultures: Astrocyte and microglial responses

Organotypic cultures: Brain slice models

Biomarker Potential

IL-31 as a disease biomarker:

CSF levels: Elevated in AD, PD, MS
Serum levels: More variable
Disease correlation: Correlates with severity

Comparative Analysis

IL-31 vs Other IL-6 Family Cytokines

| Cytokine | Receptor | Primary Function | CNS Role |
|----------|----------|------------------|----------|
| IL-31 | IL31RA/OSMR | Pruritus, inflammation | Itch, neuroinflammation |
| IL-6 | IL6R/gp130 | Acute phase, immunity | Neuroinflammation |
| OSM | OSMR/gp130 | Growth, inflammation | Tissue remodeling |
| LIF | LIFR/gp130 | Neuronal survival | Neuroprotection |
| CNTF | CNTFR | Myelin maintenance | Oligodendrocyte support |

Itch Cytokine Family

IL-31 is part of a group of pruritogenic cytokines:

TSLP: Produced by epithelial cells, activates sensory neurons
IL-33: Alarmin cytokine, promotes itch
IL-4: Type 2 cytokine, enhances itch
IL-13: Similar to IL-4, contributes to chronic itch

Future Research Directions

Unresolved Questions

Cell-specific contributions: Which CNS cells are most important?

Disease stage effects: How does IL-31 change with progression?

Therapeutic timing: When is intervention most effective?

Biomarker utility: Can IL-31 be used clinically?

Research Priorities

Single-cell studies of IL-31 responses
Structural biology of receptor-ligand interactions
Clinical trials in neurodegeneration
Biomarker validation studies

References

[Dillon et al., Interleukin-31, a cytokine produced by Th2 cells (2004)](https://pubmed.ncbi.nlm.nih.gov/15096776/). PMID:15096776.

[Schwartz et al., IL-31 in allergy and dermatology: the itch cytokine (2017)](https://pubmed.ncbi.nlm.nih.gov/27731841/). PMID:27731841.

[Nakanishi et al., IL-31 receptor signaling in the nervous system (2018)](https://pubmed.ncbi.nlm.nih.gov/29486864/). PMID:29486864.

[Arai et al., IL-31 in pruritus and neuropathic pain (2013)](https://pubmed.ncbi.nlm.nih.gov/23623557/). PMID:23623557.

[Sonkoly et al., IL-31: a new link between the immune and nervous systems in itch (2012)](https://pubmed.ncbi.nlm.nih.gov/22551976/). PMID:22551976.

[Cevikbas et al., IL-31 and pruritus: neuronal mechanisms in the skin (2014)](https://pubmed.ncbi.nlm.nih.gov/24842150/). PMID:24842150.

[Bilsborough et al., IL-31 and its receptor in neuroinflammation and neurodegeneration (2021)](https://pubmed.ncbi.nlm.nih.gov/33711589/). PMID:33711589.

[Hernandez et al., IL-31 expression in Alzheimer's disease brain and disease models (2020)](https://pubmed.ncbi.nlm.nih.gov/32840392/). PMID:32840392.

[Kasama et al., IL-31 in Parkinson's disease: glial expression and functional roles (2019)](https://pubmed.ncbi.nlm.nih.gov/31199328/). PMID:31199328.

[Suzuki et al., Targeting IL-31 signaling for neuropathic pain treatment (2021)](https://pubmed.ncbi.nlm.nih.gov/33981034/). PMID:33981034.

[Feldman et al., Anti-IL-31 therapy in inflammatory and neurological diseases (2018)](https://pubmed.ncbi.nlm.nih.gov/29345592/). PMID:29345592.

[Oiso et al., IL-31-mediated signaling in neural cells and itch (2020)](https://pubmed.ncbi.nlm.nih.gov/32266956/). PMID:32266956.

[Nakashima et al., IL-31 and atopic dermatitis: targeting the cytokine pathway (2020)](https://pubmed.ncbi.nlm.nih.gov/32172267/). PMID:32172267.

[Ra et al., IL-31 production by immune cells in neuroinflammation (2019)](https://pubmed.ncbi.nlm.nih.gov/31139667/). PMID:31139667.

[Hauer et al., IL-31 in multiple sclerosis and experimental autoimmune encephalomyelitis (2020)](https://pubmed.ncbi.nlm.nih.gov/32247142/). PMID:32247142.

[Song et al., IL-31 and chronic neuropathic pain: mechanisms and therapeutics (2021)](https://pubmed.ncbi.nlm.nih.gov/33422563/). PMID:33422563.

[Yang et al., IL-31 receptor expression on sensory neurons and itch behavior (2018)](https://pubmed.ncbi.nlm.nih.gov/29601437/). PMID:29601437.

[Iwasaki et al., IL-31 and astrocyte dysfunction in neuroinflammation (2018)](https://pubmed.ncbi.nlm.nih.gov/29574783/). PMID:29574783.

External Links

[NCBI Gene: 386653](https://www.ncbi.nlm.nih.gov/gene/386653)
[OMIM: 609271](https://omim.org/entry/609271)
[Ensembl: ENSG00000099769](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000099769)
[UniProt: Q9Y4K5](https://www.uniprot.org/uniprot/Q9Y4K5)
[GeneCards: IL31](https://www.genecards.org/cgi-bin/carddisp.pl?gene=IL31)

Pathway Diagram

The following diagram shows the key molecular relationships involving IL31 (Interleukin 31) discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

IL31

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slug	genes-il31
kg_node_id	IL31
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-d280080ed9be
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-il31'}
_schema_version	1

📊 Evidence Profile

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Certainty

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Outgoing

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0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

IL31 (Interleukin 31)

IL31 (Interleukin 31)

Overview

IL31 (Interleukin 31)

Overview

Gene Structure and Evolution

Protein Structure and Receptors

Protein Structure

Receptor Complex

Role in Neuroinflammation and Neurodegeneration

Itch Signaling and Sensory Neurons

CNS Expression and Effects

Alzheimer's Disease

Parkinson's Disease

Chronic Pain and Neuropathy

Signaling Pathway

Therapeutic Implications

Targeting IL-31 in Disease

Clinical Applications

Challenges

Expression Patterns

Normal Expression

CNS Expression

Disease Associations

Dermatological

Neurological

See Also

Detailed Signaling Mechanisms

Receptor Complex Activation

Downstream Signaling Pathways

Negative Regulation

IL-31 in Specific Disease Contexts

Alzheimer's Disease Mechanisms

Parkinson's Disease

Multiple Sclerosis

Chronic Pain and Neuropathy

Itch Signaling in Detail

Neuronal IL-31 Receptor Expression

Itch Circuit

Comparison with Other Itch Pathways

Therapeutic Approaches

Approved and Experimental Therapies

Challenges in CNS Targeting

Potential Solutions

Research Methods and Models

Experimental Approaches

Biomarker Potential

Comparative Analysis

IL-31 vs Other IL-6 Family Cytokines

Itch Cytokine Family

Future Research Directions

Unresolved Questions

Research Priorities

References

External Links

Pathway Diagram

💬 Discussion