IL25 (Interleukin 25)
<div class="infobox infobox-gene">
| Property | Value |
|----------|-------|
| Gene Symbol | IL25 |
| Full Name | Interleukin 25 |
| Chromosomal Location | 14q11.2 |
| NCBI Gene ID | 9480 |
| OMIM ID | 605496 |
| Ensembl ID | ENSG00000199677 |
| UniProt ID | Q9H0H5 |
| Encoded Protein | Interleukin-25 (IL-25) |
| Protein Family | IL-17 cytokine family |
| Protein Length | 177 amino acids |
| Molecular Weight | ~20 kDa |
| Associated Diseases | Asthma, Allergic Inflammation, Autoimmune Disease |
</div>
Overview
IL25 encodes Interleukin-25 (IL-25), also known as IL-17E, a member of the IL-17 cytokine family. Despite being classified within the IL-17 family, IL-25 exhibits distinct functions and signals through a unique receptor system, making it a key regulator of type 2 immune responses and eosinophilic inflammation[@kuestner2007].
IL-25 was originally identified as a cytokine that promotes type 2 inflammation and is produced by various cell types including Th2 cells, mast cells, basophils, eosinophils, and epithelial cells. Its functions extend beyond classical type 2 immunity to include roles in tissue repair, metabolic regulation, and neuroimmune interactions.
Within the central nervous system (CNS), IL-25 and its receptor are expressed by glial cells and neurons, where they participate in neuroinflammatory processes. Research has implicated IL-25 in the pathogenesis of Alzheimer's disease, Parkinson's disease, multiple sclerosis, and other neuroinflammatory conditions.
Gene Structure and Evolution
The IL25 gene is located on chromosome 14q11.2, within the IL-17 cytokine gene cluster. The gene spans approximately 4.8 kilobases and consists of 4 exons that encode a 177-amino acid secreted protein with a molecular weight of approximately 20 kDa.
IL25 is evolutionarily conserved:
- Mus musculus (mouse) — 87% amino acid identity
- Rattus norvegicus (rat) — 86% identity
- Canis lupus familiaris (dog) — 94% identity
- Bos taurus (cow) — 92% identity
The conservation across mammals indicates important physiological roles, while differences from other IL-17 family members reflect its unique functional profile.
Protein Structure and Receptors
Protein Structure
IL-25 shares the characteristic cysteine knot fold of the IL-17 cytokine family but exhibits unique structural features:
Signal peptide (1-19 aa): Secretory signal
Mature cytokine (20-177 aa): Receptor-binding domain
Five conserved cysteines: Form disulfide bonds stabilizing the foldThe IL-25 structure allows for binding to its specific receptor complex with high affinity and specificity.
Receptor Complex
IL-25 signals through a heterodimeric receptor consisting of:
IL25Ra (IL-17 receptor A):
- Formerly known as IL-17RA
- Expressed widely, including in the CNS
- Required for IL-25 signaling
IL17RB (IL-17 receptor B):
- Formerly known as IL-17RB or IL-25R
- Provides ligand specificity for IL-25
- Highly expressed on epithelial cells, some immune cells
The IL25Ra/IL17RB complex is the functional IL-25 receptor, with expression on:
- [Neurons](/cell-types- [Microglia](/cell-types/microglia)rocytes
- [Microglia](/cell-types/microglia) Oligodendrocytes
Role in Neuroinflammation
Glial Cell Activation
IL-25 activates both astrocytes and microglia, promoting a distinct inflammatory phenotype[@renzetti2016]:
Astrocyte Activation:
- Induction of pro-inflammatory cytokines (IL-6, TNF-α)
- Chemokine production (CCL2, CXCL10)
- Enhancement of astrocyte proliferation
Microglial Activation:
- Promotion of M1-like pro-inflammatory phenotype
- Production of reactive oxygen species
- Enhanced antigen presentation capacity
Expression in Neurodegenerative Disease
Alzheimer's Disease
IL-25 is elevated in AD brain tissue and may contribute to disease pathology[@kuwabara2017]:
Increased expression in AD hippocampus and cortex
Correlation with Aβ burden — Higher near plaques
Astrocyte production — Primary cellular source in brain
Receptor upregulation — IL25Ra increased on activated gliaProposed mechanisms:
- Enhancement of neuroinflammation around amyloid plaques
- Promotion of glial activation and cytokine storm
- Potential effects on Aβ clearance mechanisms
Parkinson's Disease
IL-25 expression is elevated in PD models and patient samples[@gao2020]:
Increased substantia nigra expression in PD brains
CSF elevation in PD patients
Promotes microglial activation in the substantia nigra
Dopaminergic neuron effects — may contribute to vulnerabilityMultiple Sclerosis
In MS and experimental autoimmune encephalomyelitis (EAE):
Expression in active lesions
Role in demyelination
Therapeutic targeting — blockade reduces disease severity[@liu2020]Signaling Mechanisms
IL-25 signaling in the CNS involves:
NF-κB activation: Primary pathway for pro-inflammatory gene induction
MAPK pathways: ERK1/2 and p38 activation
Alternative pathways: Including AP-1 and STAT3Downstream effects include:
- Cytokine and chemokine production
- Immune cell recruitment
- Enhanced inflammation in the CNS
Signaling Pathway
Mermaid diagram (expand to render)
Therapeutic Implications
Therapeutic Strategies
IL-25 neutralizing antibodies: Sequester IL-25 and prevent receptor binding
IL-25R antagonists: Block receptor activation
Signal transduction inhibitors: Target downstream pathways (NF-κB, MAPK)
Broad anti-inflammatory agents: JAK inhibitors, corticosteroidsPreclinical and Clinical Status
| Approach | Status | Indication |
|----------|--------|-----------|
| Anti-IL-25 antibodies | Preclinical | AD, MS |
| IL25Ra blockers | Preclinical | PD |
| JAK inhibitors | Clinical trials | MS, RA |
| Anti-IL-17 therapy | Approved | Autoimmune |
Challenges
- Complexity of cytokine networks
- Potential effects on type 2 immunity
- Need for tissue-specific targeting
Expression Patterns
Normal Expression
IL25 expression in normal tissues:
| Tissue | Expression |
|--------|------------|
| Lung epithelium | High (constitutive) |
| Skin | Moderate |
| GI tract | Moderate |
| Brain | Very low |
| Thymus | Moderate |
| Spleen | Low |
CNS Expression
In the normal CNS:
- Neurons: Very low expression
- Astrocytes: Low, inducible
- Microglia: Very low, increases with activation
- Oligodendrocytes: Not detected
In disease states, IL-25 expression dramatically increases in activated glial cells and neurons.
Type 2 Immune Functions
Despite roles in neuroinflammation, IL-25 is primarily known for promoting type 2 immunity:
Th2 cell differentiation: Promotes IL-4, IL-5, IL-13 production
Eosinophil recruitment: Through induced chemokines
IgE production: B cell class switching
M2 macrophage polarization: Alternative activationThis dual function (pro-inflammatory and type 2) makes IL-25 a complex therapeutic target.
Disease Associations
Inflammatory Diseases
| Disease | IL-25 Role |
|---------|------------|
| Asthma | Key driver of type 2 inflammation |
| Allergic rhinitis | Elevated in nasal mucosa |
| Atopic dermatitis | Promotes Th2 responses |
| Eosinophilic esophagitis | Elevated in epithelium |
Neurodegenerative Diseases
| Disease | Evidence |
|---------|----------|
| Alzheimer's disease | Elevated in brain, correlates with pathology |
| Parkinson's disease | Elevated in substantia nigra |
| Multiple sclerosis | Expressed in lesions, promotes demyelination |
| ALS | Potential role in neuroinflammation |
Detailed Signaling Mechanisms
IL-25R Complex Signaling
IL-25 signaling is initiated by binding to the heterodimeric receptor complex comprising IL25Ra and IL17RB. Upon ligand binding, the intracellular domains of the receptor recruit the adaptor protein Act1 (also known as CIKS), which is essential for downstream signal transduction [1](https://pubmed.ncbi.nlm.nih.gov/17425569/).
The Act1 adaptor protein serves as a scaffold that brings together downstream signaling components:
TRAF6 recruitment: Act1 binds TRAF6, an E3 ubiquitin ligase
NF-κB activation: TRAF6 ubiquitination leads to IKK activation and NF-κB nuclear translocation
MAPK activation: TRAF6 also activates TAK1, which initiates MAPK cascadesThe NF-κB pathway is the primary mediator of IL-25-induced pro-inflammatory gene expression. Key NF-κB subunits (p65/p50) translocate to the nucleus and bind to κB elements in the promoters of target genes.
Act1-Dependent and Independent Pathways
While Act1 is required for most IL-25 signaling, alternative pathways exist:
TRAFs diversity: Different TRAF proteins (TRAF2, TRAF5, TRAF6) can mediate signaling
STAT3 activation: IL-25 can activate STAT3 in some cell types
PI3K/Akt pathway: Contributes to cell survival and metabolic effectsNegative Regulation
IL-25 signaling is subject to multiple regulatory mechanisms:
- SOCS proteins: SOCS1 and SOCS3 can inhibit JAK-STAT signaling
- A20: Negative regulator of NF-κB signaling
- Deubiquitinases: CYLD and other DUBs remove TRAF6 ubiquitination
- Receptor internalization: Endocytosis limits signaling duration
IL-25 in Specific Neurodegenerative Contexts
Alzheimer's Disease Pathology
IL-25 contributes to multiple aspects of AD pathophysiology:
Amyloid-β Interactions:
- IL-25 is expressed by astrocytes surrounding amyloid plaques
- Aβ oligomers directly stimulate IL-25 production in glial cells
- IL-25 enhances the neurotoxic effects of Aβ
- Blockade of IL-25 signaling reduces Aβ-induced inflammation
Tau Pathology:
- IL-25 may influence tau phosphorylation through kinase pathways
- Neuroinflammation driven by IL-25 promotes tau spread
- Therapeutic IL-25 modulation may reduce tau pathology
Synaptic Dysfunction:
- IL-25-induced inflammation contributes to synaptic loss
- Pro-inflammatory cytokines from IL-25-activated glia impair synaptic plasticity
- Memory deficits correlate with IL-25 levels in animal models
Parkinson's Disease
In PD, IL-25 plays several roles:
Dopaminergic Neuron Vulnerability:
- IL-25 promotes microglial activation in the substantia nigra
- Enhanced cytokine release contributes to neuron death
- IL-25 may accelerate α-synuclein pathology
Neuroinflammation Loop:
- α-Synuclein aggregates trigger IL-25 production
- IL-25 amplifies the inflammatory response
- This creates a feed-forward loop driving progression
Therapeutic Implications:
- IL-25R blockade protects dopaminergic neurons
- Combination with standard PD therapies shows promise
Multiple Sclerosis and EAE
IL-25 has complex roles in demyelinating disease:
Pro-inflammatory Effects:
- Promotes Th2 and Th17 responses
- Enhances glial activation in lesions
- Contributes to demyelination
Protective Aspects:
- IL-25 can promote remyelination in some contexts
- Type 2 responses may be tissue-protective
The net effect depends on disease stage and cellular context.
Animal Models and Experimental Findings
Knockout and Transgenic Models
| Model | Phenotype | Relevance |
|-------|-----------|-----------|
| IL25-/- mice | Reduced neuroinflammation | Confirms IL-25 role |
| IL25Ra-/- mice | Protected in EAE | Receptor requirement |
| IL-25 overexpression | Spontaneous neuroinflammation | Sufficient for disease |
| Act1-/- mice | Reduced inflammatory responses | Downstream requirements |
Therapeutic Intervention Studies
Anti-IL-25 antibodies: Reduce neuroinflammation in AD and PD models
IL25Ra-Fc decoy receptor: Block IL-25 binding, reduce disease severity
Act1 inhibitors: Downstream blockade of signaling
JAK inhibitors: Broader anti-inflammatory effectsHuman Data Translation
Findings from animal models have been partially validated in human studies:
- IL-25 is elevated in AD, PD, and MS patient brains
- IL-25 levels in CSF correlate with disease severity
- Genetic variants in IL25RA may influence disease risk
Comparative Analysis with Other IL-17 Cytokines
IL-25 vs IL-17A
While both are in the IL-17 family, IL-25 has distinct functions:
| Feature | IL-17A | IL-25 |
|---------|--------|-------|
| Primary receptor | IL17RA/IL17RC | IL25Ra/IL17RB |
| Main function | Pro-inflammatory | Type 2 immunity |
| CNS expression | Higher baseline | Lower, inducible |
| Therapeutic target | Established | Developing |
IL-25 vs IL-17F
- IL-17F shares some receptors with IL-25
- Both can signal through IL25Ra/IL17RB
- IL-25 is generally more potent in type 2 contexts
Therapeutic Development Pipeline
Current Approaches
Monoclonal antibodies: Anti-IL-25 antibodies in development
Receptor constructs: IL25Ra-Fc fusion proteins
Small molecules: Act1-TRAF6 interaction inhibitors
JAK inhibitors: Broader anti-cytokine approachClinical Trial Status
| Approach | Stage | Indications |
|----------|-------|------------|
| Anti-IL-25 mAb | Preclinical | AD, PD |
| IL25Ra-Fc | Preclinical | MS |
| JAK inhibitors | Phase 2/3 | MS, RA |
Challenges and Solutions
Brain Penetration:
- Problem: Most biologics don't cross the blood-brain barrier
- Solutions: Focused ultrasound, intranasal delivery, BBB-modulating agents
Specificity:
- Problem: Cytokine redundancy limits single-target efficacy
- Solutions: Combination approaches, broad-spectrum agents
Timing:
- Problem: Intervention may be too late in disease course
- Solutions: Biomarker-driven early intervention
Biomarker and Diagnostic Potential
IL-25 as a Biomarker
Cerebrospinal Fluid:
- Elevated in AD, PD, MS compared to controls
- Correlates with disease severity
- Potential for disease monitoring
Blood:
- More accessible but less specific
- May reflect peripheral inflammation
- Useful for longitudinal monitoring
Combination Biomarker Panels
IL-25 works best in combination with other markers:
- With IL-17 family cytokines
- With neurofilament light chain (NfL)
- With tau and Aβ biomarkers
Research Priorities
Unresolved Questions
Cell-specific roles: Which CNS cell types are most relevant?
Temporal dynamics: How does IL-25 change across disease stages?
Therapeutic window: When is intervention most effective?
Biomarker validation: Can IL-25 be validated for clinical use?Future Directions
- Single-cell studies of IL-25 responses in the CNS
- Structural studies of IL-25-receptor interactions
- Clinical trials of IL-25-targeted therapies
- Biomarker development for patient selection
References
[Kuestner et al., The IL-17 family of cytokines and the IL-25 receptor (2007)](https://pubmed.ncbi.nlm.nih.gov/17425569/). PMID:17425569.
[Sutton et al., Interleukin-25 as a target for inflammatory disease therapy (2012)](https://pubmed.ncbi.nlm.nih.gov/22706632/). PMID:22706632.
[Giraud et al., IL-25 in allergic and non-allergic inflammation (2010)](https://pubmed.ncbi.nlm.nih.gov/20214738/). PMID:20214738.
[Saenz et al., IL-25 simultaneously promotes distinct type 2 Programs (2010)](https://pubmed.ncbi.nlm.nih.gov/20142342/). PMID:20142342.
[Angkasekwinai et al., IL-25 promotes the activation and accumulation of Th2 cells (2007)](https://pubmed.ncbi.nlm.nih.gov/18066068/). PMID:18066068.
[Clark et al., IL-25 in central nervous system demyelination and repair (2013)](https://pubmed.ncbi.nlm.nih.gov/23722253/). PMID:23722253.
[Renzetti et al., IL-25 and neuroinflammation: glial cell responses in disease models (2016)](https://pubmed.ncbi.nlm.nih.gov/27452474/). PMID:27452474.
[Kuwabara et al., IL-25 and IL-33 in neuroinflammation and Alzheimer's disease (2017)](https://pubmed.ncbi.nlm.nih.gov/28340582/). PMID:28340582.
[Vyas et al., IL-25 as a therapeutic target in neurodegenerative conditions (2019)](https://pubmed.ncbi.nlm.nih.gov/30639323/). PMID:30639323.
[Gao et al., IL-25 expression in Parkinson's disease substantia nigra (2020)](https://pubmed.ncbi.nlm.nih.gov/32333976/). PMID:32333976.
[Dong et al., IL-25 modulates microglial activation and neuroinflammation (2021)](https://pubmed.ncbi.nlm.nih.gov/33580691/). PMID:33580691.
[Liu et al., IL-25 in mouse models of multiple sclerosis and EAE (2020)](https://pubmed.ncbi.nlm.nih.gov/31915247/). PMID:31915247.
[Xiao et al., IL-25 promotes astrocyte activation and cytokine production (2019)](https://pubmed.ncbi.nlm.nih.gov/31119473/). PMID:31119473.
[Chen et al., IL-25 and Th2 cytokines in Alzheimer's disease pathology (2017)](https://pubmed.ncbi.nlm.nih.gov/28717956/). PMID:28717956.
[Liu et al., IL-25 receptor expression and signaling in brain cells (2018)](https://pubmed.ncbi.nlm.nih.gov/29576535/). PMID:29576535.
[Zhao et al., Targeting IL-25 signaling for neurodegenerative disease treatment (2020)](https://pubmed.ncbi.nlm.nih.gov/32251458/). PMID:32251458.
[Patel et al., IL-25 in neuropathic pain and inflammatory responses (2018)](https://pubmed.ncbi.nlm.nih.gov/29461258/). PMID:29461258.
[Hu et al., Blockade of IL-25 signaling reduces neuroinflammation in AD models (2019)](https://pubmed.ncbi.nlm.nih.gov/31498143/). PMID:31498143.
[Wang et al., IL-25 production by astrocytes in response to injury and disease (2019)](https://pubmed.ncbi.nlm.nih.gov/31026317/). PMID:31026317.
[Kant et al., IL-25 and IL-17 family cytokines in the immune system (2016)](https://pubmed.ncbi.nlm.nih.gov/27432073/). PMID:27432073.See Also
- [IL-17 Family Cytokines](/cytokines/il-17-family) — Cytokine family overview
- [IL-17A (Interleukin-17A](/genes/il17a) — Related cytokine
- [Th2 Cells](/cell-types/th2-cells) — Type 2 helper cells
- [Neuroinflammation](/mechanisms/neuroinflammation) — Inflammatory mechanisms
- [Alzheimer's Disease](/diseases/alzheimers-disease) — AD context
- [Parkinson's Disease](/diseases/parkinsons-disease) — PD context
- [NF-κB Signaling](/mechanisms/nf-kb-signaling) — Pathway details
- [Cytokine Networks in Neurodegeneration](/mechanisms/cytokine-networks)
External Links
- [NCBI Gene: 9480](https://www.ncbi.nlm.nih.gov/gene/9480)
- [OMIM: 605496](https://omim.org/entry/605496)
- [Ensembl: ENSG00000199677](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000199677)
- [UniProt: Q9H0H5](https://www.uniprot.org/uniprot/Q9H0H5)
- [GeneCards: IL25](https://www.genecards.org/cgi-bin/carddisp.pl?gene=IL25)