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
...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><strong>Gene Symbol</strong></td><td>IL1RL1</td></tr>
<tr><td><strong>Full Name</strong></td><td>Interleukin-1 Receptor-Like 1 (ST2)</td></tr>
<tr><td><strong>Chromosomal Location</strong></td><td>2q12.1</td></tr>
<tr><td><strong>NCBI Gene ID</strong></td><td>9173</td></tr>
<tr><td><strong>OMIM</strong></td><td>601203</td></tr>
<tr><td><strong>Ensembl ID</strong></td><td>ENSG00000115607</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>Q9INT6</td></tr>
<tr><td><strong>Gene Family</strong></td><td>IL-1 receptor family</td></tr>
<tr><td><strong>Protein Length</strong></td><td>556 amino acids (ST2L)</td></tr>
<tr><td><strong>Associated Diseases</strong></td><td>Alzheimer Disease, Parkinson Disease, Asthma, Cardiovascular Disease, Autoimmune Disorders</td></tr>
</table>
</div>
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
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)
See Also
- [IL1RL1 Protein (ST2)](/proteins/il1rl1-protein)
- [Interleukin-1 Family Cytokines](/topics/il-1-family)
- [Neuroinflammation Mechanisms](/mechanisms/neuroinflammation)
- [Microglia in Neurodegeneration](/cell-types/microglia)
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)