GO:0002114 interleukin-33 receptor activity: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0002114 (interleukin-33 receptor activity) is a molecular function defined as combining with interleukin-33 and transmitting the signal across the membrane to initiate a change in cell activity.
• The canonical IL-33 receptor is the ST2/IL1RL1 receptor, which forms a signaling complex with IL-1RAcP to activate NF-kB and MAP kinase pathways.
• IL-33 is a nuclear cytokine of the IL-1 family that is released upon cell damage or stress and acts as an alarmin.
• The IL-33/ST2 axis is implicated in type 2 inflammation, atopic dermatitis, asthma, COPD, and diverse diseases, making it a therapeutic target.
• Oxidized IL-33 can signal through a ST2-independent RAGE/EGFR complex, revealing context-dependent receptor activity.
• CRISPR knockout, knock-in, point mutation, and overexpression models are essential to dissect IL-33 receptor signaling in disease.
Description
Interleukin-33 receptor activity (GO:0002114) is a molecular function that enables a cell to bind the cytokine interleukin-33 (IL-33) and transmit a signal across the membrane, thereby initiating changes in cell behavior. This activity is central to alarmin-driven immune responses and tissue homeostasis. IL-33 is a nuclear cytokine of the IL-1 family that is released upon cell damage or stress and acts on neighboring cells expressing its receptor. The canonical receptor for IL-33 is ST2 (also known as IL1RL1), which associates with the IL-1 receptor accessory protein (IL-1RAcP) to form a functional signaling complex. Since its discovery, the IL-33/ST2 axis has been recognized as a key regulator of type 2 immunity, inflammation, and tissue repair. Understanding the molecular details of interleukin-33 receptor activity is therefore critical for researchers studying allergy, autoimmunity, cancer, and chronic inflammatory diseases.
interleukin-33 receptor activity At A Glance
| GO ID | GO:0002114 |
|---|---|
| GO term | interleukin-33 receptor activity |
| Ontology | molecular_function |
| Synonym | IL-33R, IL-33 receptor activity |
| Definition | Combining with interleukin-33 and transmitting the signal from one side of the membrane to the other to initiate a change in cell activity. |
| Major function | Binds IL-33 and initiates intracellular signaling, typically via ST2/IL1RL1 and IL-1RAcP. |
| Cellular location | Plasma membrane of responsive cells, including mast cells, Th2 cells, ILC2s, and epithelial cells. |
| Key ligand | Interleukin-33 (IL-33), an IL-1 family cytokine released as an alarmin. |
| Associated diseases | Atopic dermatitis, asthma, COPD, inflammatory and fibrotic diseases. |
What Is GO:0002114?
According to the Gene Ontology, interleukin-33 receptor activity (GO:0002114) is defined as combining with interleukin-33 and transmitting the signal from one side of the membrane to the other to initiate a change in cell activity. In other words, it is the function of a receptor that specifically binds IL-33 and converts that binding event into an intracellular signal, often through conformational changes and recruitment of signaling adaptors.
Why Is interleukin-33 receptor activity Important in Cell Biology?
Interleukin-33 receptor activity is a pivotal node in innate and adaptive immunity, linking tissue damage to type 2 inflammatory responses. Because IL-33 is released as an alarmin upon cell stress or injury, its receptor activity serves as a sensor for tissue integrity and a driver of cytokine production, mucus secretion, and tissue remodeling. Dysregulation of this activity contributes to allergic and inflammatory diseases such as atopic dermatitis, asthma, and COPD, and it also influences tumor immunity and fibrosis. Therefore, understanding the molecular mechanisms of IL-33 receptor activity is essential for developing targeted therapies and for interpreting disease-associated genetic variants.
• Central to type 2 immune responses and allergic inflammation.
• Acts as an alarmin sensor for tissue damage and stress.
• Implicated in atopic dermatitis pathogenesis.
• Contributes to asthma and COPD through ST2-dependent and independent pathways.
• Modulates tumor microenvironment and cancer immunity.
• Plays a role in fibrosis and tissue remodeling.
• Target for therapeutic antibodies and small molecules.
• Genetic variants in IL1RL1 affect receptor activity and disease risk.
• Involved in host defense against parasites and viruses.
• Key to understanding neuroimmune interactions.
What Happens During interleukin-33 receptor activity?
Ligand binding and receptor activation
In simple terms: IL-33 binds to its receptor ST2 on the cell surface, like a key fitting a lock.
Interleukin-33 receptor activity begins when the cytokine IL-33 binds to the extracellular domain of ST2 (IL1RL1) on the plasma membrane. This binding induces conformational changes that allow ST2 to recruit the IL-1 receptor accessory protein (IL-1RAcP), forming a heterodimeric signaling complex. The formation of this complex is the first step in transmitting the signal across the membrane.
Intracellular signaling cascades
In simple terms: Once the receptor is activated, it triggers a chain of signals inside the cell that turn on inflammation genes.
The activated IL-33 receptor complex recruits the adaptor protein MyD88, which then interacts with IRAK kinases and TRAF6, leading to activation of NF-kB and MAP kinase pathways. These signaling events culminate in the production of type 2 cytokines such as IL-4, IL-5, and IL-13, as well as other inflammatory mediators. This cascade is a hallmark of interleukin-33 receptor activity in immune cells.
Regulation by oxidation and ST2-independent pathways
In simple terms: Sometimes IL-33 can be modified by oxidation, and it can signal through a different receptor complex, showing the flexibility of the system.
Oxidized IL-33 can drive epithelial pathogenesis via a ST2-independent RAGE/EGFR signaling complex, as shown in COPD models. This indicates that interleukin-33 receptor activity is not limited to ST2 and can be context-dependent. Such alternative signaling may contribute to disease pathology in chronic inflammatory conditions.
Cellular responses and outcomes
In simple terms: The signals lead to changes in cell behavior, such as cytokine release, cell survival, and tissue remodeling.
Activation of interleukin-33 receptor activity leads to diverse cellular outcomes, including cytokine secretion, cell proliferation, survival, and mucus production. In mast cells, it triggers degranulation and release of mediators. In Th2 cells and ILC2s, it promotes type 2 cytokine production and tissue repair functions. These responses are critical for host defense but can become pathogenic in chronic inflammation.
Key Genes Involved in GO:0002114 interleukin-33 receptor activity
The following genes and proteins are central to interleukin-33 receptor activity and its downstream signaling.
| Gene | Major Role | Research Relevance |
|---|---|---|
| IL33 | Encodes the cytokine interleukin-33, the ligand for the receptor. | Target for knockout and overexpression to study alarmin release and signaling. |
| IL1RL1 | Encodes ST2, the canonical receptor for IL-33. | Key gene for knockout, knock-in, and point mutation studies of receptor activity. |
| IL1RAP | Encodes IL-1RAcP, the accessory protein that partners with ST2. | Essential for signaling; knockout models reveal its role in complex formation. |
| MYD88 | Adaptor protein recruited to the activated receptor complex. | Knockout studies show its requirement for IL-33-induced NF-kB activation. |
| IRAK1 | Kinase involved in downstream signaling from the receptor. | Point mutations can dissect kinase-dependent vs independent functions. |
| IRAK4 | Kinase that interacts with MyD88 and IRAK1. | Target for knockout to block IL-33 signaling. |
| TRAF6 | E3 ubiquitin ligase that mediates NF-kB activation. | Knockout models demonstrate its role in IL-33-driven inflammation. |
| NFKB1 | Transcription factor activated downstream of the receptor. | Reporter assays and knockout models study transcriptional responses. |
| MAPK1 | Kinase in the MAPK pathway activated by IL-33. | Phosphorylation studies and inhibitors reveal pathway dynamics. |
| MAPK3 | Another MAPK family member activated by IL-33. | Similar to MAPK1, used in signaling studies. |
| IL4 | Type 2 cytokine produced upon IL-33 receptor activation. | Readout for functional IL-33 responses in knockout models. |
| IL5 | Type 2 cytokine induced by IL-33 signaling. | Biomarker in allergic inflammation models. |
| IL13 | Type 2 cytokine downstream of IL-33 receptor activity. | Key effector in asthma and atopic dermatitis models. |
| RAGE | Receptor for oxidized IL-33 in ST2-independent signaling. | Knockout and knockdown studies explore alternative pathways. |
| EGFR | Receptor tyrosine kinase involved in oxidized IL-33 signaling. | Inhibitors and CRISPR models dissect its contribution. |
| GATA3 | Transcription factor in Th2 cells activated by IL-33. | Knockout models show its role in type 2 immunity. |
| RORα | Transcription factor in ILC2s responsive to IL-33. | Reporter models study ILC2 activation. |
| STAT6 | Transcription factor downstream of IL-4/IL-13 signaling. | Knockout models link IL-33 to STAT6-dependent responses. |
How Is interleukin-33 receptor activity Regulated?
Interleukin-33 receptor activity is regulated at multiple levels. The availability of IL-33 is controlled by its release from damaged or stressed cells, as it lacks a signal peptide and is released passively or via active mechanisms. Extracellular IL-33 can be oxidized, which alters its activity and can switch signaling to ST2-independent pathways. Receptor expression on target cells is modulated by cytokines and transcription factors, affecting responsiveness. Negative regulators such as soluble ST2 can act as decoy receptors to dampen signaling. Additionally, post-translational modifications of signaling components, such as ubiquitination and phosphorylation, fine-tune the strength and duration of the signal.
interleukin-33 receptor activity and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| IL33 | Atopic dermatitis, asthma | Knockout mice and human skin organoids. |
| IL1RL1 | Allergic inflammation, COPD | ST2 knockout and knock-in cell lines. |
| RAGE | COPD epithelial pathogenesis | RAGE knockout epithelial cells. |
| EGFR | COPD, fibrosis | EGFR inhibitor-treated and CRISPR knockout models. |
| IL4 | Type 2 inflammation | Reporter cell lines and knockout mice. |
Atopic dermatitis
Interleukin-33 receptor activity is strongly implicated in atopic dermatitis, where IL-33 released from skin cells activates ST2-expressing immune cells to drive type 2 inflammation and itch. Elevated IL-33 levels correlate with disease severity, and targeting the IL-33/ST2 axis is a therapeutic strategy.
Asthma and COPD
In asthma, IL-33 receptor activity promotes airway inflammation, mucus production, and bronchial hyperresponsiveness. In COPD, oxidized IL-33 can signal through a ST2-independent RAGE/EGFR complex, contributing to epithelial pathogenesis. These findings highlight the receptor's role in chronic airway diseases.
Cancer and tumor immunity
The IL-33/ST2 axis can either promote or suppress tumors depending on context. IL-33 receptor activity enhances type 2 immune responses that may favor tumor progression, but it can also boost anti-tumor immunity by activating eosinophils and NK cells. Understanding these dual roles is critical for cancer immunotherapy.
Fibrosis and tissue remodeling
IL-33 receptor activity contributes to fibrosis in multiple organs by stimulating fibroblasts and promoting extracellular matrix deposition. This has been studied in models of lung, liver, and skin fibrosis, where blockade of IL-33 signaling reduces pathology.
From interleukin-33 receptor activity-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does ST2 mediate IL-33-induced signaling? | IL1RL1 knockout cell lines and mice. |
| What is the role of oxidized IL-33 in COPD? | RAGE/EGFR knockout epithelial cells. |
| How does IL-33 affect Th2 differentiation? | CRISPR knock-in of reporters in T cells. |
| Can soluble ST2 block IL-33 activity? | Overexpression of soluble ST2 in vitro. |
| What are the downstream targets of IL-33 signaling? | RNA-seq and proteomics in knockout models. |
| Does a point mutation in IL1RL1 affect receptor function? | Point-mutation knock-in cell lines. |
How to Study the interleukin-33 receptor activity Process
| Method | What It Measures | Typical Application |
|---|---|---|
| CRISPR knockout | Loss of gene function | Determine necessity of ST2 in IL-33 signaling. |
| CRISPR knock-in | Tagged or mutant protein expression | Track receptor localization and function. |
| RNA-seq | Global gene expression changes | Identify IL-33-induced transcriptional programs. |
| Proteomics | Protein abundance and modifications | Map signaling complexes and post-translational changes. |
| Flow cytometry | Cell surface receptor levels | Quantify ST2 expression on immune cells. |
| ELISA | Cytokine concentrations | Measure IL-4, IL-5, IL-13 release. |
| Immunofluorescence | Protein localization | Visualize receptor internalization. |
| Western blot | Phosphorylation of signaling proteins | Assess NF-kB and MAPK activation. |
CRISPR knockout and knock-in models
CRISPR/Cas9-mediated knockout of IL1RL1, IL33, or signaling components is widely used to dissect interleukin-33 receptor activity. Knock-in of tagged or mutant receptors allows precise tracking and functional analysis.
Transcriptomic and proteomic profiling
RNA-seq and proteomics in cells stimulated with IL-33 or in knockout models reveal downstream gene expression and protein networks. These methods identify biomarkers and pathways regulated by the receptor.
Imaging and flow cytometry
Flow cytometry and immunofluorescence can measure receptor expression, internalization, and signaling activation at single-cell resolution. These techniques are essential for studying cell-type-specific responses.
Functional assays and cytokine measurement
ELISA and multiplex assays quantify cytokines such as IL-4, IL-5, and IL-13 produced upon IL-33 receptor activation. These functional readouts are standard in evaluating receptor activity.
How CRISPR Can Be Used to Study GO:0002114 interleukin-33 receptor activity
Knockout
CRISPR knockout of IL1RL1 (ST2) or IL33 abolishes interleukin-33 receptor activity, providing a clean background to study its role in inflammation and disease. Knockout models are used to validate drug targets and identify compensatory pathways.
Point Mutation
Introducing point mutations in the IL-33 binding domain of ST2 or in signaling motifs can dissect residues critical for ligand binding versus signal transduction. Such models help understand disease-associated variants.
Knock-in
Knock-in of fluorescent tags or epitope tags into the endogenous IL1RL1 locus allows real-time tracking of receptor expression and trafficking without overexpression artifacts. This is valuable for studying receptor dynamics.
Overexpression
Overexpression of IL-33 or ST2 in cell lines can amplify signaling for biochemical studies, but may not reflect physiological levels. It is useful for screening inhibitors and studying downstream pathways.
How EDITGENE Supports interleukin-33 receptor activity Research
Researchers studying interleukin-33 receptor activity-related genes often need to determine whether a candidate gene is causally involved in receptor signaling, inflammation, or disease progression. EDITGENE provides a comprehensive suite of CRISPR-based services to enable such investigations with precision and reproducibility.
Contact EDITGENE today to design your custom CRISPR model for interleukin-33 receptor activity research.
Frequently Asked Questions About interleukin-33 receptor activity
What is interleukin-33 receptor activity?
Interleukin-33 receptor activity (GO:0002114) is the molecular function of binding IL-33 and transmitting a signal across the membrane to change cell behavior.
What genes are involved in interleukin-33 receptor activity?
Key genes include IL33, IL1RL1 (ST2), IL1RAP, MYD88, IRAK1/4, TRAF6, and downstream transcription factors like NFKB1.
What is the role of ST2 in IL-33 signaling?
ST2 (IL1RL1) is the canonical receptor that binds IL-33 and recruits IL-1RAcP to initiate signaling.
How is interleukin-33 receptor activity regulated?
It is regulated by IL-33 release, oxidation, soluble decoy receptors, and post-translational modifications of signaling components.
What diseases are associated with IL-33 receptor activity?
Atopic dermatitis, asthma, COPD, fibrosis, and cancer are linked to dysregulated IL-33/ST2 signaling.
Can CRISPR be used to study IL-33 receptor activity?
Yes, CRISPR knockout, knock-in, and point mutation models are powerful tools to dissect the receptor's function.
What is the difference between ST2 and soluble ST2?
Soluble ST2 acts as a decoy receptor that binds IL-33 and inhibits signaling, while membrane-bound ST2 transmits signals.
What are downstream targets of IL-33 receptor activation?
NF-kB and MAP kinase pathways are activated, leading to production of IL-4, IL-5, IL-13, and other inflammatory mediators.
Is IL-33 receptor activity involved in cancer?
Yes, it can have dual roles in tumor immunity, either promoting or suppressing tumors depending on context.
How can I model IL-33 receptor activity in the lab?
Use CRISPR knockout of IL1RL1 or IL33, knock-in reporters, and functional assays like ELISA and RNA-seq.
Conclusion
Interleukin-33 receptor activity (GO:0002114) is a fundamental molecular function that bridges tissue damage to immune responses. Its canonical signaling through ST2 and IL-1RAcP, as well as alternative pathways involving oxidized IL-33, underscores its complexity and therapeutic potential. Understanding this activity is crucial for developing treatments for allergic and inflammatory diseases. CRISPR-based models and advanced profiling methods continue to unravel the precise mechanisms and disease contributions of this receptor.
References
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- 3. Strickson S et al.. 2023. Oxidised IL-33 drives COPD epithelial pathogenesis via ST2-independent RAGE/EGFR signalling complex.. Eur Respir J 62(3) PMID: 37442582
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- 5. Schmitz J et al.. 2005. 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 23(5):479-90 PMID: 16286016
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