IL25 (Interleukin 25)

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IL25 (Interleukin 25)

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IL25 (Interleukin 25)

| 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.

...

IL25 (Interleukin 25)

| 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 fold

The 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 glia

Proposed 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 vulnerability

Multiple 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 STAT3

Downstream 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, corticosteroids

Preclinical 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 activation

This 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 cascades

The 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 effects

Negative 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 effects

Human 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 approach

Clinical 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.

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)

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IL25

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-il25
kg_node_id	IL25
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-610088ceb6d2
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-il25'}
_schema_version	1

📊 Evidence Profile

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📗 Cite This Artifact

IL25 (Interleukin 25)

IL25 (Interleukin 25)

Overview

IL25 (Interleukin 25)

Overview

Gene Structure and Evolution

Protein Structure and Receptors

Protein Structure

Receptor Complex

Role in Neuroinflammation

Glial Cell Activation

Expression in Neurodegenerative Disease

Alzheimer's Disease

Parkinson's Disease

Multiple Sclerosis

Signaling Mechanisms

Signaling Pathway

Therapeutic Implications

Therapeutic Strategies

Preclinical and Clinical Status

Challenges

Expression Patterns

Normal Expression

CNS Expression

Type 2 Immune Functions

Disease Associations

Inflammatory Diseases

Neurodegenerative Diseases

Detailed Signaling Mechanisms

IL-25R Complex Signaling

Act1-Dependent and Independent Pathways

Negative Regulation

IL-25 in Specific Neurodegenerative Contexts

Alzheimer's Disease Pathology

Parkinson's Disease

Multiple Sclerosis and EAE

Animal Models and Experimental Findings

Knockout and Transgenic Models

Therapeutic Intervention Studies

Human Data Translation

Comparative Analysis with Other IL-17 Cytokines

IL-25 vs IL-17A

IL-25 vs IL-17F

Therapeutic Development Pipeline

Current Approaches

Clinical Trial Status

Challenges and Solutions

Biomarker and Diagnostic Potential

IL-25 as a Biomarker

Combination Biomarker Panels

Research Priorities

Unresolved Questions

Future Directions

References

See Also

External Links

💬 Discussion