IL1RL1 Human
Description
IL1RL1 Human: Gene and Protein Overview
IL1RL1 (Interleukin 1 Receptor-Like 1), also known as ST2 or IL33R, is a protein-coding gene located on chromosome 2q12.1 in humans. It encodes a transmembrane receptor in the interleukin-1 receptor family and serves as the primary receptor for the cytokine IL-33 .
Gene Structure and Isoforms
The IL1RL1 gene spans ~40 kb and includes 13 exons . Alternative splicing generates distinct transcript isoforms:
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Membrane-bound ST2L: Contains transmembrane and intracellular TIR domains, enabling IL-33 signaling .
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Soluble sST2: Lacks transmembrane domains, acts as a decoy receptor to neutralize IL-33 .
Transcript Variants
Protein Structure and Function
The membrane-bound IL1RL1 protein (ST2L) consists of:
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Extracellular Domain: Immunoglobulin-like domains for IL-33 binding .
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Intracellular TIR Domain: Triggers signaling via MYD88, IRAK, and TRAF6, activating MAPK and NF-κB pathways .
Signaling Pathway
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IL-33 Binding: Activates ST2L, recruiting MYD88 and IL1RAcP .
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Downstream Targets: Phosphorylates ERK1/2, p38 MAPK, and JNK, regulating immune responses .
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Soluble sST2: Competes with ST2L for IL-33, dampening inflammation .
Expression and Cellular Localization
IL1RL1 is expressed in:
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Immune Cells: Mast cells, activated Th2 cells, macrophages .
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Non-Immune Cells: Cardiac myocytes, epithelial cells, endothelial cells .
Tissue-Specific Expression
Key Polymorphisms Linked to Disease
Lung Cancer Risk Stratification
| Factor | rs12479210/T | rs1420101/T | OR (95% CI) | FDR-Adjusted p |
|---|---|---|---|---|
| Males | 1.49 (1.20–1.86) | 1.42 (1.10–1.82) | Dominant model | 0.032 |
| Age >60 | 1.60 (1.21–2.12) | – | Additive model | 0.020 |
Therapeutic Targets
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sST2 Inhibition: Blocks IL-33 signaling in inflammatory diseases (e.g., asthma, cardiovascular conditions) .
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ST2L Agonism: Enhances cardioprotection in heart failure via IL-33-mediated pathways .
Biomarker Potential
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sST2 Levels: Elevated in asthma, sepsis, and myocardial infarction; inversely correlated with Alzheimer’s disease risk in APOE-ε4 carriers .
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IL1RL1 Expression: Downregulated in lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) .
Research Frontiers
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T-Cell Specific Promoters: A type 1 immunity-restricted promoter upstream of IL1RL1 drives ST2L expression in CTLs and Th1 cells .
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Ethnic-Specific Effects: rs1921622’s AD-protective role is stronger in Chinese vs. European populations .
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Microglial Regulation: sST2 modulates amyloid-β clearance and microglial activation in Alzheimer’s disease .
Product Specs
Q&A
What is IL1RL1 and what are its major variants?
IL1RL1, also known as ST2, IL33R, DER4, T1, ST2V, FIT-1, or MGC32623, is a member of the IL-1 receptor family that encodes a transmembrane protein with a structure similar to IL-1R1 . The gene encodes two major splice variants: ST2L, which contains the transmembrane domain, and sST2, a soluble form that is secreted and acts as a decoy receptor for IL-33 . The soluble form (sST2) plays an important role as a negative regulator of TH2 cytokine production . The full-length protein contains 318 amino acids with a molecular mass of approximately 36.0kDa, though it shows multiple bands between 40-57kDa on SDS-PAGE under reducing conditions due to glycosylation .
What is the biological significance of IL1RL1 in immune regulation?
IL1RL1 functions as a receptor for interleukin-33 (IL-33), and upon stimulation, it recruits several downstream signaling molecules including MYD88, IRAK1, IRAK4, and TRAF6 . This activation leads to the phosphorylation of various mitogen-activated protein kinases (MAPKs) including MAPK3/ERK1, MAPK1/ERK2, MAPK14, and MAPK8 . IL1RL1 is believed to be involved in helper T-cell function, particularly in TH2-like inflammatory pathways . The receptor can be induced by proinflammatory stimuli, further supporting its role in immune regulation and inflammatory responses . The balance between the membrane-bound receptor (ST2L) and the soluble decoy receptor (sST2) appears to be critical for regulating IL-33-mediated inflammation .
How is IL1RL1 associated with asthma pathogenesis?
IL1RL1 has been genetically associated with asthma in multiple genome-wide association studies, particularly with childhood-onset asthma . Research has demonstrated that ST2L expression (the transmembrane variant) is increased in severe asthma, especially in patients with features of TH2-like inflammation . Studies have found that epithelial ST2L expression correlates with markers of TH2 inflammation, including CLCA1 expression, eotaxin-3 expression, and fractional exhaled nitric oxide (Feno) levels . This suggests that IL1RL1 plays a significant role in the TH2 inflammatory pathway that is characteristic of a subset of asthma patients. The relationship between IL1RL1 expression and asthma severity indicates that targeting this pathway may have therapeutic potential, particularly for patients with TH2-high asthma .
What role does IL1RL1 play in leukemia development?
Recent research has identified IL1RL1 as a gene dynamically expressed on Cbfb-MYH11+ leukemia stem cells . In acute myeloid leukemia (AML) characterized by the presence of the inversion of chromosome 16 [inv(16)] and the resulting fusion oncogene CBFB-MYH11, IL1RL1 is upregulated prior to other markers like CSF2RB . Studies using a mouse knock-in model have shown that Cbfb-MYH11 induces changes in gene expression, including upregulation of IL1RL1, and results in the accumulation of abnormal myeloid cells . A subset of these cells are enriched for leukemia stem cell (LSC) activity, and IL1RL1 expression appears to be associated with populations that have high LSC activity . This suggests IL1RL1 may play a role in leukemogenesis or leukemia stem cell maintenance, though the exact mechanisms require further investigation.
Which single nucleotide polymorphisms (SNPs) in IL1RL1 are associated with disease phenotypes?
Multiple SNPs in IL1RL1 have been associated with both ST2L mRNA expression and sST2 protein levels, potentially explaining the genetic relationship between IL1RL1 and asthma susceptibility . Three SNPs have been significantly associated with ST2L mRNA expression:
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rs12712135 - Located in the first intron of ST2L mRNA
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rs1041973 - A missense amino acid change at position 78 in both ST2L and sST2
Additionally, ten SNPs were significantly associated with sST2 levels in bronchoalveolar lavage (BAL) fluid, with some located only in ST2L mRNA . The data is summarized in the following tables:
Table: SNPs Associated with ST2L mRNA Expression
| rsID | Location | MAF | P value (Recessive model) | Odds Ratio |
|---|---|---|---|---|
| 12712135 | Intron of ST2L mRNA | 0.44 | 0.048 | 5.2 |
| 1041973 | Missense A to E position 78 | 0.288 | 0.02 (Dominant) | 0.15 |
| 10185897 | Intron in ST2L mRNA | 0.142 | 0.01 | n/a |
Two additional SNPs in IL1RL1 were associated with markers of TH2 inflammation: rs7571371 (associated with Feno) and rs12999517 (associated with TH2 score) . These genetic associations provide further evidence for the role of IL1RL1 in asthma pathogenesis and TH2-mediated inflammation.
What are the optimal methods for studying IL1RL1 expression in human samples?
Based on the research methodologies described in the literature, several approaches have proven effective for studying IL1RL1 expression:
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mRNA expression analysis: Endobronchial brushings and biopsies can be collected to evaluate ST2L mRNA expression using quantitative PCR techniques . This allows comparison of expression levels across different severity levels of disease and correlation with other biomarkers.
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Protein detection: Soluble ST2 (sST2) can be measured in biological fluids such as bronchoalveolar lavage (BAL) fluid using enzyme-linked immunosorbent assays (ELISA) .
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Genotyping: Subjects can be genotyped to determine the relationship between SNPs in IL1RL1 and expression levels of both ST2L and sST2 . This approach helps identify genetic factors that may influence expression patterns.
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In vitro cell culture: Epithelial cells can be grown in air-liquid interface culture to evaluate ST2L and sST2 responses to various stimuli, such as IFN-γ and IL-13 . This model allows for controlled studies of the regulation of IL1RL1 expression.
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Recombinant protein studies: For functional studies, recombinant IL1RL1 protein can be produced in expression systems such as Sf9 Baculovirus cells, resulting in a glycosylated polypeptide that can be purified using chromatographic techniques .
What in vitro systems are most appropriate for functional studies of IL1RL1?
For functional studies of IL1RL1, several in vitro systems have been utilized effectively:
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Air-liquid interface cultures: Primary bronchial epithelial cells grown at air-liquid interface provide a physiologically relevant model for studying the regulation of ST2L and sST2 in response to cytokines and other stimuli . This model maintains the cellular architecture and functionality similar to the in vivo airway epithelium.
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Sf9 Baculovirus expression system: This system has been successfully used to produce recombinant IL1RL1 protein for functional studies . The resulting protein is glycosylated, which is important for maintaining proper structure and function.
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Mouse knock-in models: These models, particularly those with the Cbfb-MYH11 fusion gene, have been valuable for studying the role of IL1RL1 in leukemogenesis and identifying cell populations with leukemia stem cell activity that express IL1RL1 .
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Cell signaling assays: Since IL1RL1 stimulation recruits MYD88, IRAK1, IRAK4, and TRAF6, followed by phosphorylation of various MAPKs, in vitro systems that allow for the detection of these signaling events (such as phospho-specific western blotting or kinase activity assays) are appropriate for functional studies .
How does the balance between ST2L and sST2 influence inflammatory responses?
The balance between the membrane-bound receptor ST2L and the soluble decoy receptor sST2 appears to be critical for regulating IL-33-mediated inflammation . ST2L mediates the cellular effects of IL-33, while sST2 acts as a negative regulator by sequestering IL-33 and preventing it from binding to ST2L . In asthma, particularly severe and TH2-high asthma, there is evidence of increased ST2L expression, suggesting a shift in this balance toward enhanced IL-33 signaling .
Research has shown that IFN-γ appears to be a key regulator of sST2 expression, potentially providing a mechanism for modulating the ST2L/sST2 balance . Additionally, genetic factors influence this balance, as different SNPs in IL1RL1 are associated with either ST2L mRNA expression or sST2 protein levels . This complex regulatory system likely plays an important role in determining the intensity and duration of IL-33-mediated inflammatory responses.
Further studies examining the functional significance of SNPs in IL1RL1 and the counter-regulatory role of sST2 may provide more insight into whether this pathway is critical to the initiation, maintenance, and/or augmentation of TH2-inflammation in asthma . Understanding this balance may lead to more targeted therapeutic approaches that address the underlying dysregulation in inflammatory diseases.
What is the relationship between IL1RL1 expression and leukemia stem cell (LSC) activity?
Recent research has identified IL1RL1 as being dynamically expressed on Cbfb-MYH11+ leukemia stem cells, suggesting a potential role in leukemogenesis or leukemia stem cell maintenance . Studies using a mouse knock-in model have shown that expression of the leukemogenic fusion gene Cbfb-MYH11 induces expression of IL1RL1 prior to other markers like CSF2RB . This temporal relationship implies that IL1RL1 upregulation may be an early event in the development of leukemia.
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Promoting survival or self-renewal of LSCs through IL-33-mediated signaling
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Modulating the bone marrow microenvironment to create a niche favorable for LSC maintenance
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Influencing the differentiation potential of leukemic progenitors
Understanding the functional significance of IL1RL1 expression on LSCs could potentially reveal new therapeutic targets for acute myeloid leukemia, particularly those characterized by the Cbfb-MYH11 fusion oncogene.
In which human tissues is IL1RL1 predominantly expressed?
IL1RL1 shows a distinctive tissue expression pattern in humans. It is highly expressed in several organs and tissues including:
At the cellular level, IL1RL1 has been reported to be expressed on various cell types including:
This broad expression pattern suggests that IL1RL1 may have diverse physiological functions beyond its well-characterized role in immune regulation. The tissue-specific expression may also contribute to the diverse pathological roles of IL1RL1 in different diseases, from respiratory conditions like asthma to potential involvement in malignancies such as leukemia.
What factors regulate IL1RL1 expression and alternative splicing?
IL1RL1 expression and alternative splicing appear to be regulated by multiple factors:
Understanding the complex regulation of IL1RL1 expression and alternative splicing could provide insights into how this pathway could be therapeutically targeted in various disease contexts.
What are the most promising therapeutic applications targeting IL1RL1?
Based on current research, targeting the IL1RL1/IL-33 axis appears most promising for treating TH2-high asthma. ST2L is increased in severe asthma, particularly in patients with features of TH2-like inflammation, suggesting that targeting this pathway may provide therapeutic benefits . Potential therapeutic approaches could include:
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Neutralizing antibodies against IL-33 or IL1RL1
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Recombinant sST2 as a decoy receptor to sequester IL-33
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Small molecule inhibitors of the downstream signaling pathways activated by IL1RL1
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Modulation of IL1RL1 alternative splicing to favor sST2 production
What are the critical knowledge gaps in IL1RL1 research that require further investigation?
Despite significant advances in understanding IL1RL1 biology, several critical knowledge gaps remain:
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Mechanistic understanding of genetic associations: While multiple SNPs in IL1RL1 have been associated with asthma and expression levels of ST2L and sST2, the functional consequences of these genetic variations are not fully understood .
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Role in leukemia progression: The functional significance of IL1RL1 expression on leukemia stem cells needs further investigation to determine whether it plays a causal role in leukemogenesis or is merely a marker of certain cell populations .
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Regulation of alternative splicing: The precise mechanisms controlling the balance between ST2L and sST2 production require further elucidation .
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Tissue-specific functions: While IL1RL1 is expressed in multiple tissues, its function in many of these contexts remains poorly characterized .
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Integration with other inflammatory pathways: How IL1RL1 signaling interacts with other inflammatory and immune pathways in different disease contexts needs further exploration.
Product Science Overview
Interleukin-1 receptor-like 1 (IL1RL1), also known as ST2, is a member of the interleukin-1 receptor family. This receptor is encoded by the IL1RL1 gene and plays a crucial role in the immune system by mediating responses to interleukin-33 (IL-33), a cytokine involved in inflammatory and immune responses .
IL1RL1 is a transmembrane protein that consists of three extracellular immunoglobulin-like domains, a single transmembrane domain, and an intracellular Toll/IL-1 receptor (TIR) domain. The extracellular domains are responsible for binding IL-33, while the TIR domain is involved in signal transduction .
Upon binding to IL-33, IL1RL1 forms a complex with the IL-1 receptor accessory protein (IL-1RAcP), which initiates a signaling cascade that activates nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinases (MAPKs). These pathways lead to the production of pro-inflammatory cytokines and chemokines, which are essential for immune responses .
IL1RL1 is expressed in various cell types, including mast cells, eosinophils, basophils, and Th2 cells. It is particularly important in the context of allergic inflammation and asthma, where it contributes to the activation and recruitment of immune cells to sites of inflammation .
In addition to its role in allergic diseases, IL1RL1 has been implicated in other conditions such as cardiovascular diseases, autoimmune disorders, and cancer. For example, elevated levels of IL1RL1 have been observed in patients with heart failure, suggesting a potential role in the pathogenesis of this condition .
Recombinant human IL1RL1 is produced using recombinant DNA technology, which involves inserting the IL1RL1 gene into an expression vector and introducing it into a host cell, such as Escherichia coli or Chinese hamster ovary (CHO) cells. The host cells then produce the IL1RL1 protein, which can be purified and used for research or therapeutic purposes .
Recombinant IL1RL1 is valuable for studying the receptor’s structure and function, as well as for developing potential therapeutic interventions targeting IL1RL1-mediated pathways. For instance, recombinant IL1RL1 can be used to screen for small molecules or antibodies that inhibit IL-33 binding, which may have therapeutic potential in treating allergic and inflammatory diseases .
