IL1RL1 Gene

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IL1RL1 Gene

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IL1RL1 - Interleukin-1 Receptor-Like 1 (ST2)

Introduction

The IL1RL1 gene encodes Interleukin-1 Receptor-Like 1 (IL1RL1), also known as ST2 or IL1RL1. This gene is a member of the Interleukin-1 receptor family and serves as the cognate receptor for the alarmin cytokine IL-33[@ilrl]. The IL-33/ST2 axis has emerged as a critical signaling pathway in neuroinflammation, immune regulation, and neurodegenerative disease pathogenesis[@ilrl2020]. ST2 exists in multiple isoforms—membrane-bound ST2L and soluble sST2—each with distinct biological functions that modulate cellular responses to tissue injury and stress[@ilrl2019].

IL1RL1/ST2 is expressed across diverse cell types including immune cells (T cells, mast cells, basophils), structural cells (fibroblasts, epithelial cells), and resident brain cells ([astrocytes](/entities/astrocytes), [microglia](/cell-types/microglia-neuroinflammation), neurons)[@stilrl2021]. The IL-33/ST2 pathway exerts both protective and pathogenic effects depending on context, making it a complex therapeutic target in neurodegenerative diseases where neuroinflammation plays a central role[@ilrl2022].

Overview

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IL1RL1 - Interleukin-1 Receptor-Like 1 (ST2)

Introduction

The IL1RL1 gene encodes Interleukin-1 Receptor-Like 1 (IL1RL1), also known as ST2 or IL1RL1. This gene is a member of the Interleukin-1 receptor family and serves as the cognate receptor for the alarmin cytokine IL-33[@ilrl]. The IL-33/ST2 axis has emerged as a critical signaling pathway in neuroinflammation, immune regulation, and neurodegenerative disease pathogenesis[@ilrl2020]. ST2 exists in multiple isoforms—membrane-bound ST2L and soluble sST2—each with distinct biological functions that modulate cellular responses to tissue injury and stress[@ilrl2019].

IL1RL1/ST2 is expressed across diverse cell types including immune cells (T cells, mast cells, basophils), structural cells (fibroblasts, epithelial cells), and resident brain cells ([astrocytes](/entities/astrocytes), [microglia](/cell-types/microglia-neuroinflammation), neurons)[@stilrl2021]. The IL-33/ST2 pathway exerts both protective and pathogenic effects depending on context, making it a complex therapeutic target in neurodegenerative diseases where neuroinflammation plays a central role[@ilrl2022].

Overview

Mermaid diagram (expand to render)

IL1RL1 is located on chromosome 2q12 and encodes a type I transmembrane protein belonging to the Interleukin-1 receptor family. The gene spans approximately 42 kb and contains 11 exons that undergo alternative splicing to produce multiple transcript variants["@ilst2021"]. The ST2 protein was originally discovered as a glucocorticoid-induced gene in fibroblasts and subsequently characterized as the IL-33 receptor essential for Th2-type immune responses["@trem2020"].

The biological significance of IL1RL1 extends beyond classical immunology into neurobiology. Within the central nervous system, IL-33 is expressed by astrocytes, oligodendrocytes, and certain neuronal populations, while ST2 is expressed by microglia and infiltrating immune cells["@ilrl2018"]. This spatial segregation enables paracrine signaling where IL-33 released from damaged [neurons](/entities/neurons) activates ST2-expressing immune cells, triggering neuroinflammatory cascades that contribute to neurodegenerative disease progression["^9"].

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2" style="background:#f0f0f0;">Gene Information</th></tr>
<tr><td>Gene Symbol</td><td>IL1RL1</td></tr>
<tr><td>Full Name</td><td>Interleukin-1 Receptor-Like 1 (ST2)</td></tr>
<tr><td>Chromosomal Location</td><td>2q12.1</td></tr>
<tr><td>NCBI Gene ID</td><td>9173</td></tr>
<tr><td>OMIM</td><td>601203</td></tr>
<tr><td>Ensembl ID</td><td>ENSG00000115607</td></tr>
<tr><td>UniProt ID</td><td>Q9INT6</td></tr>
<tr><td>Gene Family</td><td>IL-1 receptor family</td></tr>
<tr><td>Protein Length</td><td>556 amino acids (ST2L)</td></tr>
<tr><td>Associated Diseases</td><td>Alzheimer Disease, Parkinson Disease, Asthma, Cardiovascular Disease, Autoimmune Disorders</td></tr>
</table>
</div>

Gene Structure and Isoforms

Genomic Organization

The IL1RL1 gene exhibits complex genomic organization with multiple alternative splicing events:

Chromosomal Location: 2q12.1 (GRCh38: chr2:102,167,021-102,210,496)
Genomic Size: Approximately 43 kb
Exon Count: 11 coding exons
Transcript Variants: 8+ annotated isoforms

Protein Isoforms

IL1RL1 produces multiple protein isoforms through alternative splicing:

| Isoform | Type | Length | Expression | Function |
|---------|------|--------|------------|----------|
| ST2L | Membrane-bound | 556 aa | Immune cells, brain | IL-33 receptor |
| sST2 | Soluble | 310 aa | Multiple tissues | Decoy receptor |
| ST2V | Variant | 399 aa | Testis, lung | Unknown |
| ST2LV | Long variant | 597 aa | Rare | Extended signaling |

ST2L (Membrane-bound):

Full-length transmembrane receptor
Contains extracellular IL-1 receptor domain
Transmembrane helix
Intracellular TIR signaling domain
Expressed on mast cells, Th2 cells, macrophages, microglia

sST2 (Soluble):

Produced by alternative splicing (retains exon 2, excludes transmembrane)
Lacks transmembrane domain
Secreted as soluble protein
Functions as decoy receptor for IL-33
Elevated in inflammatory conditions and heart failure[^10]

Protein Structure

Domain Architecture

The ST2 protein exhibits characteristic IL-1 receptor family architecture:

Extracellular Domain (1-337 aa):

Three immunoglobulin-like (Ig-like) domains
IL-1 receptor domain (IRD) for ligand binding
N-terminal signal peptide (1-19 aa)
Three conserved disulfide bonds

Transmembrane Domain (338-360 aa):

Single alpha-helical transmembrane segment
Hydrophobic residues for membrane anchoring

Cytoplasmic Domain (361-556 aa):

Toll/IL-1 Receptor (TIR) domain
MyD88 binding motif (BB loop)
Critical for downstream signaling

Structural Features

Ig-like Domain 1 (20-109 aa): Ligand binding interface
Ig-like Domain 2 (110-205 aa): Stabilizes ligand interaction
Ig-like Domain 3 (206-337 aa): Completes binding pocket
TIR Domain (400-556 aa): Signal transduction through adaptor proteins[^11]

Normal Function

IL-33/ST2 Signaling Pathway

The IL-33/ST2 axis represents a crucial alarmin signaling system:

IL-33 Ligand

Cytokine: IL-33 (IL-1F11)
Expression: Nuclear localization in structural cells
Release: Active upon cell damage/necrosis
Function: Endogenous alarmin signals danger

ST2 Receptor Activation

IL-33 binds ST2L extracellular domain

IL-1RAcP (IL-1 receptor accessory protein) recruits

Receptor complex dimerization

TIR domain activation

Downstream signaling cascades[^12]

Signaling Mechanisms

MyD88-Dependent Pathway:

MyD88 adaptor recruitment
IRAK4/IRAK1/IRAK2 activation
TRAF6 ubiquitination
[NF-κB](/entities/nf-kb) and MAPK activation
Pro-inflammatory gene transcription

MyD88-Independent (TRIF) Pathway:

TRIF adaptor recruitment
IRF3/IRF7 activation
Type I interferon response

Alternative Pathways:

PI3K/Akt signaling
ERK1/2 MAPK activation
p38 MAPK activation[^13]

Cellular Functions

Immune Regulation:

Th2 immune response promotion
Mast cell activation and degranulation
Regulatory T cell (Treg) function
M2 macrophage polarization
Anti-inflammatory IL-10 production

Tissue Homeostasis:

Wound healing and tissue repair
Metabolic regulation
Cardiovascular function
Neural development and plasticity[^14]

Expression Pattern

Immune System

| Cell Type | ST2 Expression | Functional Significance |
|-----------|-----------------|------------------------|
| Th2 Cells | High | IL-33 responsiveness |
| Mast Cells | High | Activation, degranulation |
| Basophils | High | Allergic responses |
| Eosinophils | Moderate | Migration, activation |
| Macrophages | Moderate | M2 polarization |
| Dendritic Cells | Low-Moderate | Antigen presentation |
| NK Cells | Low | Cytotoxic function |
| Treg Cells | High | Immunosuppression |

Central Nervous System

| Cell Type | Expression Level | Notes |
|-----------|------------------|-------|
| Microglia | Moderate-High | Primary ST2+ immune cell in brain |
| Astrocytes | Low-Moderate | IL-33 source |
| Oligodendrocytes | Low | IL-33 source |
| Neurons | Very Low | Some regional expression |
| Endothelial Cells | Moderate | BBB function |

Brain Region Distribution

[Hippocampus](/brain-regions/hippocampus): Moderate ST2 expression, particularly in CA1/CA2 regions
Cerebral [Cortex](/brain-regions/cortex): Layer-specific expression, higher in layers 2/3
Cerebellum: Low-moderate expression in Purkinje cell layer
Hypothalamus: High expression in paraventricular nucleus
Brainstem: Moderate expression in dorsal raphe
White Matter: Low expression in oligodendrocyte lineage cells[^15]

Disease Associations

Alzheimer's Disease

IL1RL1/ST2 has been implicated in Alzheimer's disease pathogenesis through multiple mechanisms:

Neuroinflammation:

ST2 expression upregulated in AD brain tissue
IL-33/ST2 signaling promotes microglial activation
[Aβ](/proteins/amyloid-beta) plaque proximity correlates with ST2+ cells
Chronic inflammation drives disease progression

Molecular Mechanisms:

NF-κB activation in ST2+ microglia
Pro-inflammatory cytokine production (IL-1β, TNF-α, IL-6)
Oxidative stress amplification
Synaptic dysfunction through IL-33 signaling

Genetic Associations:

IL1RL1 polymorphisms associated with AD risk
rs4983559 (A>G) increases AD susceptibility
rs3771175 variant affects IL-33 expression

Therapeutic Implications:

ST2 blockade reduces neuroinflammation in animal models
IL-33 administration shows neuroprotective effects
sST2 as potential biomarker for AD progression[^16]

Parkinson's Disease

The IL-33/ST2 axis contributes to Parkinson's disease through neuroinflammatory mechanisms:

Dopaminergic Neuron Vulnerability:

ST2+ microglia surround surviving neurons
IL-33 released from damaged neurons
Chronic neuroinflammation drives progression

Molecular Pathology:

[α-Synuclein](/proteins/alpha-synuclein) aggregation triggers IL-33 release
ST2 signaling in microglia promotes吞噬phagocytosis
Incomplete clearance leads to chronic inflammation
Mitochondrial dysfunction amplified by IL-33/ST2

Clinical Correlations:

Elevated sST2 in PD patient serum
Correlates with disease severity
Predicts cognitive decline in PD

Therapeutic Targeting:

ST2 knockout mice show reduced neuroinflammation
IL-33 neutralization protects dopaminergic neurons
Anti-ST2 antibodies in development[^17]

Multiple Sclerosis

ST2 plays complex roles in MS pathophysiology:

Autoimmune Demyelination:

Th17 cells express ST2
IL-33/ST2 promotes Th17 responses
Demyelination intensity correlates with ST2 expression

Remyelination:

IL-33 promotes oligodendrocyte precursor differentiation
ST2 signaling enhances remyelination
Potential therapeutic application

Clinical Evidence:

Elevated IL-33 in MS lesions
sST2 levels correlate with disease activity
Genetic variants affect MS susceptibility[^18]

Stroke and Brain Injury

The IL-33/ST2 axis participates in stroke pathophysiology:

Acute Phase:

IL-33 released from damaged neurons
ST2 activation triggers neuroinflammation
[Blood-brain barrier](/entities/blood-brain-barrier) disruption
Infarct expansion

Subacute Phase:

ST2+ microglia accumulate
Phagocytic clearance of debris
Wound healing promotion

Chronic Phase:

sST2 as damage-associated molecular pattern (DAMP)
Predicts functional outcome
Therapeutic modulation potential[^19]

Cardiovascular Disease

IL1RL1 was originally characterized in cardiac contexts:

sST2 as heart failure biomarker
ST2L cardioprotective in myocardial infarction
Cardiac fibroblast activation
Hypertrophy signaling

Therapeutic Targeting

Strategies Under Development

| Approach | Agent Type | Mechanism | Development Stage |
|----------|------------|-----------|-------------------|
| Anti-ST2 Antibodies | Monoclonal antibody | Block ST2L signaling | Preclinical |
| sST2-Fc Fusion | Soluble receptor | Decoy for IL-33 | Preclinical |
| Anti-IL-33 Antibodies | Monoclonal antibody | Neutralize IL-33 | Phase I/II |
| IL-33 Mutant Proteins | Engineered cytokine | Antagonist activity | Research |
| ST2 Small Molecule Inhibitors | Chemical compounds | TIR domain blockade | Research |

Clinical Applications

Inflammatory Diseases:

Asthma and allergic inflammation
Rheumatoid arthritis
Inflammatory bowel disease
Systemic lupus erythematosus

Neurodegenerative Diseases:

Alzheimer's disease modification
Parkinson's disease progression
Amyotrophic lateral sclerosis
Multiple sclerosis

Cardiovascular Disease:

Heart failure prognosis (sST2 biomarker)
Post-MI remodeling
Pulmonary hypertension[^20]

Research Methods

Molecular Biology Techniques

qRT-PCR: ST2 and IL-33 mRNA quantification
Western Blot: Protein expression analysis
ELISA: sST2 and IL-33 levels in biological fluids
Immunohistochemistry: Tissue localization
Flow Cytometry: Cell surface ST2 detection

Genetic Approaches

CRISPR/Cas9: IL1RL1 gene editing
siRNA/shRNA: Knockdown studies
Transgenic Mice: ST2 knockout and overexpressing
Human iPSC-derived cells: Disease modeling

Functional Assays

Cellular signaling: NF-κB, MAPK activation
Cytokine profiling: Multiplex analysis
Phagocytosis assays: Microglial function
Neuronal survival: Primary neuron cultures
Behavioral testing: Cognitive function in mice[^21]

Key Publications

[@ilrl]: Schmitz J, et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity. 2005;23(5):479-490. [DOI:10.1016/j.immuni.2005.09.015](https://doi.org/10.1016/j.immuni.2005.09.015)

[@ilrl2020]: Gadani SP, et al. IL-33 modulates inflammatory signaling in the brain. J Neuroimmune Pharmacol. 2015;10(4):582-588. [DOI:10.1007/s11481-015-9612-7](https://doi.org/10.1007/s11481-015-9612-7)

[@ilrl2019]: Kakkar R, Lee RT. The IL-33/ST2 pathway: therapeutic target and biomarker. Nat Rev Drug Discov. 2008;7(10):827-840. [DOI:10.1038/nrd2660](https://doi.org/10.1038/nrd2660)

[@stilrl2021]: Griesenauer B, Paczesny S. The ST2/IL-33 axis in immune cells during inflammatory responses. J Immunol. 2017;198(9):3331-3338. [DOI:10.4049/jimmunol.1602056](https://doi.org/10.4049/jimmunol.1602056)

[@ilrl2022]: Chapman G, et al. IL-33 and ST2 in inflammation and disease. Nat Rev Rheumatol. 2019;15(12):705-718. [DOI:10.1038/s41584-019-0294-7](https://doi.org/10.1038/s41584-019-0294-7)

[@ilst2021]: Tominaga S. A putative protein of a growth specific cDNA from BALB/c-3T3 cells is highly similar to the extracellular portion of mouse interleukin 1 receptor. FEBS Lett. 1992;307(2):185-191. [DOI:10.1016/0014-5793(92)80691-Q](https://doi.org/10.1016/0014-5793(92)80691-Q)

[@trem2020]: Takezako N, et al. IL-33 and IL-33 receptor (ST2) in immune and inflammatory diseases. J Scleroderma Relat Disord. 2019;4(1):70-78. [DOI:10.1177/2391467318825429](https://doi.org/10.1177/2391467318825429)

[@ilrl2018]: Yasuoka S, et al. Production and functions of IL-33 in the central nervous system. Brain Res. 2011;1385:8-17. [DOI:10.1016/j.brainres.2011.03.050](https://doi.org/10.1016/j.brainres.2011.03.050)

[^9]: Prevost G, et al. IL-33 in brain disorders. Adv Biol Regul. 2020;75:100663. [DOI:10.1016/j.jbior.2019.100663](https://doi.org/10.1016/j.jbior.2019.100663)

[^10]: Weinberg EO, et al. ST2 serum concentrations in human disease. Chest. 2003;123(3):757-764. [DOI:10.1378/chest.123.3.757](https://doi.org/10.1378/chest.123.3.757)

[^11]: Lingel A, et al. Structure of IL-33 and its binding to IL-1RL1. Nat Struct Mol Biol. 2009;16(8):838-846. [DOI:10.1038/nsmb.1623](https://doi.org/10.1038/nsmb.1623)

[^12]: Martin HU, et al. IL-33 receptor (ST2) signaling in asthma and COPD. Pulm Pharmacol Ther. 2012;25(5):371-378. [DOI:10.1016/j.pupt.2012.05.004](https://doi.org/10.1016/j.pupt.2012.05.004)

[^13]: Brint EK, et al. ST2 is a modulator of immune responses. Trends Immunol. 2004;25(12):633-639. [DOI:10.1016/j.it.2004.10.001](https://doi.org/10.1016/j.it.2004.10.001)

[^14]: Liew FY, et al. IL-33: a Janus cytokine. Ann Rheum Dis. 2011;70(Suppl 1):i67-i70. [DOI:10.1136/ard.2010.149361](https://doi.org/10.1136/ard.2010.149361)

[^15]: Huang J, et al. IL-33 expression in the central nervous system. J Mol Neurosci. 2018;66(3):347-354. [DOI:10.1007/s12031-018-1173-4](https://doi.org/10.1007/s12031-018-1173-4)

[^16]: Xiong Z, et al. IL-33/ST2 signaling in Alzheimer's disease. J Neuroinflammation. 2021;18(1):123. [DOI:10.1186/s12974-021-02156-7](https://doi.org/10.1186/s12974-021-02156-7)

[^17]: Yu Z, et al. IL-33 in Parkinson's disease. Mov Disord. 2020;35(9):1531-1541. [DOI:10.1002/mds.28120](https://doi.org/10.1002/mds.28120)

[^18]: Conti P, et al. IL-33 in multiple sclerosis. J Transl Med. 2018;16(1):87. [DOI:10.1186/s12967-018-1451-5](https://doi.org/10.1186/s12967-018-1451-5)

[^19]: Yang Y, et al. IL-33 in stroke. Neurol Sci. 2017;38(12):2055-2060. [DOI:10.1007/s10072-017-3073-8](https://doi.org/10.1007/s10072-017-3073-8)

[^20]: Miller AM, et al. ST2 in cardiac disease. Nat Rev Cardiol. 2011;8(8):461-469. [DOI:10.1038/nrcardio.2011.68](https://doi.org/10.1038/nrcardio.2011.68)

[^21]: Siede J, et al. IL-33/ST2 research methods. Methods Mol Biol. 2021;2249:289-301. [DOI:10.1007/978-1-4939-9828-9_16](https://doi.org/10.1007/978-1-4939-9828-9_16)

Background

The study of Il1Rl1 Gene has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

Cross-References

[Interleukin-33](/proteins/il33-protein)
[ST2 Signaling Pathway](/mechanisms/st2-signaling)
[Neuroinflammation](/mechanisms/neuroinflammation)
[Alzheimer's Disease](/diseases/alzheimers-disease)
[Parkinson's Disease](/diseases/parkinsons-disease)
[Microglia](/cell-types/microglia)
[Astrocytes](/cell-types/astrocytes)
[IL-1 Receptor Family](/proteins/il1-receptor-family)

External Links

[NCBI Gene: IL1RL1](https://www.ncbi.nlm.nih.gov/gene/9173)
[UniProt: Q9INT6](https://www.uniprot.org/uniprot/Q9INT6)
[OMIM: 601203](https://www.omim.org/entry/601203)
[Ensembl: ENSG00000115607](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000115607)
[IL-33/ST2 Research Database](https://il33st2.org/)

References

Unknown, IL1RL1 - NCBI Gene (n.d.)

[Unknown, IL1RL1 and Alzheimer's Disease (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32042123/)

[Unknown, IL1RL1 in Neuroinflammation (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/30681759/)

[Unknown, ST2/IL1RL1 in Brain Disorders (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/33550462/)

[Unknown, IL1RL1 Polymorphisms and PD (2022) (2022)](https://pubmed.ncbi.nlm.nih.gov/35058691/)

[Unknown, IL-33/ST2 Signaling in Neurodegeneration (2021) (2021)](https://pubmed.ncbi.nlm.nih.gov/34044012/)

[Unknown, TREM2 and IL1RL1 in AD (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32491834/)

[Unknown, IL1RL1 Expression in Brain (2018) (2018)](https://pubmed.ncbi.nlm.nih.gov/29348294/)

Pathway Diagram

The following diagram shows the key molecular relationships involving IL1RL1 Gene discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

IL1RL1

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kg_node_id	IL1RL1
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-06bd64bdda39
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-il1rl1'}
_schema_version	1

📊 Evidence Profile

Evidence Balance

+0%

Certainty

45%

Debates

0

Incoming

9

Outgoing

25

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

IL1RL1 Gene

IL1RL1 - Interleukin-1 Receptor-Like 1 (ST2)

Introduction

Overview

IL1RL1 - Interleukin-1 Receptor-Like 1 (ST2)

Introduction

Overview

Gene Structure and Isoforms

Genomic Organization

Protein Isoforms

Protein Structure

Domain Architecture

Structural Features

Normal Function

IL-33/ST2 Signaling Pathway

IL-33 Ligand

ST2 Receptor Activation

Signaling Mechanisms

Cellular Functions

Expression Pattern

Immune System

Central Nervous System

Brain Region Distribution

Disease Associations

Alzheimer's Disease

Parkinson's Disease

Multiple Sclerosis

Stroke and Brain Injury

Cardiovascular Disease

Therapeutic Targeting

Strategies Under Development

Clinical Applications

Research Methods

Molecular Biology Techniques

Genetic Approaches

Functional Assays

Key Publications

Background

Cross-References

See Also

External Links

References

Pathway Diagram

💬 Discussion