IL31 (Interleukin 31)
<div class="infobox infobox-gene">
| 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 modificationThe 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 administrationThe 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 dysfunctionMechanisms 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 enhancementChronic 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-αThis 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 |
See Also
- [IL-6 Cytokine Family](/cytokines/il-6-family) — Cytokine family overview
- [Pruritus Mechanisms](/mechanisms/pruritus) — Itch signaling
- [Neuroinflammation](/mechanisms/neuroinflammation) — Inflammatory mechanisms
- [Alzheimer's Disease](/diseases/alzheimers-disease) — AD context
- [Parkinson's Disease](/diseases/parkinsons-disease) — PD context
- [JAK-STAT Signaling](/mechanisms/jak-stat-signaling) — Signaling pathway details
- [Sensory Neurons](/cell-types/sensory-neurons) — Pain and itch receptors
- [Cytokine Networks in Neurodegeneration](/mechanisms/cytokine-networks)
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 nucleusDownstream 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 mechanismItch 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 behaviorComparison 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 unknownPotential 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 modelsBiomarker 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)