GO:0150138 negative regulation of interleukin-37 production: Immune Regulation Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0150138 describes any biological process that stops, prevents, or reduces the production of the anti-inflammatory cytokine interleukin-37 (IL-37).
• IL-37 is a member of the IL-1 family that broadly suppresses innate and adaptive immune responses, and its production is tightly controlled at transcriptional and post-transcriptional levels.
• Dysregulated negative regulation of IL-37 production is implicated in asthma, nasal polyps, inflammatory bowel disease, tuberculosis, and several cancers.
• Key molecular players include IL37 itself, NLRP3, IL-6, and signaling components such as SMAD3 and NF-kB that modulate IL37 transcription.
• CRISPR-based knockout, knock-in, and overexpression models are essential to dissect the causal role of candidate regulators of IL-37 production.
• Understanding this GO term can guide therapeutic strategies that aim to restore or enhance IL-37 levels in inflammatory and autoimmune diseases.
Description
Interleukin-37 (IL-37) is an anti-inflammatory cytokine of the IL-1 family that plays a central role in limiting excessive immune responses. The Gene Ontology term GO:0150138, negative regulation of interleukin-37 production, refers to any process that stops, prevents, or reduces the frequency, rate, or extent of IL-37 production. This term is critical for researchers studying inflammatory diseases, cancer, and host-pathogen interactions because IL-37 levels are often dysregulated in these conditions. Understanding how IL-37 production is negatively regulated can reveal new therapeutic targets and biomarkers. IL-37 is expressed in various cell types, including monocytes, macrophages, and epithelial cells, and its production is induced by inflammatory stimuli but subsequently dampened by negative feedback mechanisms. The balance between positive and negative regulation of IL-37 production determines the resolution of inflammation. For example, in nasal polyps and allergic rhinitis, altered IL-37 expression correlates with disease severity. In cancer, IL-37 can have pro-tumour or anti-tumour effects depending on context, highlighting the need to understand its regulation. This article synthesizes current knowledge on GO:0150138, covering the molecular mechanisms, key genes, disease associations, and experimental models used to study negative regulation of IL-37 production. All statements are based on published literature to support researchers in designing robust experiments and interpreting their findings.
negative regulation of interleukin-37 production At A Glance
| GO ID | GO:0150138 |
|---|---|
| GO term | negative regulation of interleukin-37 production |
| Ontology | biological_process |
| Synonym | negative regulation of interleukin-37 biosynthetic process |
| Major function | Suppression of IL-37 cytokine production to modulate immune responses |
| Related cytokines | IL-37, IL-18, IL-1 family members |
| Key regulators | NLRP3, IL-6, SMAD3, NF-kB |
| Disease relevance | Asthma, inflammatory bowel disease, cancer, tuberculosis |
What Is GO:0150138?
GO:0150138 (negative regulation of interleukin-37 production) is a biological process that encompasses any mechanism that decreases the synthesis or secretion of interleukin-37. It includes transcriptional repression, mRNA destabilization, inhibition of translation, and enhanced degradation of the IL-37 protein. This term is the inverse of positive regulation of interleukin-37 production and is essential for maintaining immune homeostasis by preventing excessive or prolonged anti-inflammatory signaling.
Why Is negative regulation of interleukin-37 production Important in Cell Biology?
Negative regulation of interleukin-37 production is crucial because IL-37 acts as a brake on inflammation, and its downregulation can lead to chronic inflammatory diseases. Conversely, excessive IL-37 suppression may impair anti-tumour immunity. Understanding this process helps identify therapeutic targets to fine-tune IL-37 levels in conditions such as asthma, colitis, and cancer.
• IL-37 is a potent anti-inflammatory cytokine; its negative regulation prevents uncontrolled immunosuppression.
• Dysregulated IL-37 production is associated with asthma and allergic rhinitis.
• In inflammatory bowel disease, IL-37d negatively regulates NLRP3, and its suppression exacerbates colitis.
• In cancer, IL-37 can promote tumour progression in oral squamous cell carcinoma, so its negative regulation may be protective.
• In acute myeloid leukemia, IL-37 regulates IL-6 expression, linking its production to leukemia progression.
• Tuberculosis patients show upregulated IL-37, suggesting that negative regulation is important for host defense.
• Nasal polyps exhibit altered IL-37 expression, implicating its regulation in chronic rhinosinusitis.
• Targeting negative regulators of IL-37 could enhance anti-inflammatory therapies.
• CRISPR screens can identify novel negative regulators of IL-37 production.
• Understanding this GO term aids in biomarker discovery for inflammatory diseases.
What Happens During negative regulation of interleukin-37 production?
Transcriptional repression of IL37
In simple terms: The cell reduces the reading of the IL37 gene into messenger RNA.
Negative regulation of IL-37 production often begins at the transcriptional level. Inflammatory signaling pathways such as NF-kB can initially induce IL37, but subsequent negative feedback loops repress its transcription. For instance, IL-37d negatively regulates NLRP3 transcription via a receptor-mediated pathway, which in turn may affect IL-37 production. Additionally, IL-6, which is regulated by IL-37, can feed back to modulate IL37 expression. The exact transcription factors that repress IL37 are not fully defined, but SMAD3 has been implicated in TGF-beta-mediated suppression.
Post-transcriptional regulation of IL37 mRNA
In simple terms: The stability or translation of IL-37 mRNA is reduced.
After transcription, IL37 mRNA can be targeted by microRNAs or RNA-binding proteins that promote its degradation or inhibit its translation. Although specific microRNAs regulating IL37 are not extensively characterized, general mechanisms of mRNA instability are likely involved. In nasal polyps, IL-37 expression is upregulated, suggesting that negative regulation at this level may be impaired. In allergic rhinitis, IL-37b has anti-inflammatory effects, and its production may be subject to post-transcriptional control.
Inhibition of IL-37 protein processing and secretion
In simple terms: The cell prevents the IL-37 protein from being made or released.
IL-37 is synthesized as a precursor and requires cleavage by caspases (e.g., caspase-1) for activation and secretion. Negative regulation can occur by inhibiting caspase activity or by retaining IL-37 intracellularly. In colonic organoids, IL-37 regulates innate immune signaling, and its production is likely controlled by mechanisms that limit its secretion. In tuberculosis, IL-37 expression is upregulated and induces M2-like macrophages, implying that negative regulation is important to prevent excessive M2 polarization.
Feedback loops involving IL-37 and other cytokines
In simple terms: IL-37 itself can trigger signals that reduce its own production.
IL-37 can suppress pro-inflammatory cytokines such as IL-6 and IL-1beta, which in turn may reduce further IL-37 induction. In acute myeloid leukemia, IL-37 was shown to regulate IL-6 expression, suggesting a feedback loop where IL-6 modulates IL-37 production. Similarly, in inflammatory bowel disease, IL-37d negatively regulates NLRP3, which may limit inflammasome-mediated IL-37 processing. These feedback mechanisms are critical for resolving inflammation.
Epigenetic and environmental modulation
In simple terms: Chemical tags on DNA or histones can turn down IL37 expression.
DNA methylation and histone modifications can repress IL37 transcription. Although direct evidence for epigenetic regulation of IL37 is limited, environmental factors such as infections or allergens may induce epigenetic changes that reduce IL-37 production. In asthma, IL-37 has therapeutic potential, and its expression may be epigenetically silenced. In nasal polyps, chronic inflammation may alter epigenetic marks to modulate IL-37 levels.
Key Genes Involved in GO:0150138 negative regulation of interleukin-37 production
The following genes and proteins are involved in the negative regulation of interleukin-37 production, based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| IL37 | Encodes the anti-inflammatory cytokine IL-37 | Central to the GO term; its production is the target of regulation |
| NLRP3 | Inflammasome sensor that can regulate IL-37 processing | IL-37d negatively regulates NLRP3 transcription |
| IL6 | Pro-inflammatory cytokine regulated by IL-37 | IL-37 modulates IL-6 expression in leukemia |
| SMAD3 | TGF-beta signaling mediator | May repress IL37 transcription |
| NFKB1 | Transcription factor involved in immune responses | Can induce or repress IL37 depending on context |
| CASP1 | Caspase-1 cleaves pro-IL-37 to active form | Inhibition reduces IL-37 production |
| TGFB1 | Anti-inflammatory cytokine | Can suppress IL-37 production via SMAD3 |
| IL18 | Related IL-1 family cytokine | Shares processing machinery with IL-37 |
| IL1B | Pro-inflammatory cytokine | IL-37 suppresses IL-1beta, feedback may affect IL-37 |
| MYD88 | Adaptor in TLR/IL-1R signaling | May modulate IL-37 production |
| NFKBIA | Inhibitor of NF-kB | Can influence IL37 transcription |
| STAT3 | Transcription factor downstream of IL-6 | May mediate IL-6 effects on IL-37 |
| MAPK1 | Kinase in inflammatory signaling | Potential regulator of IL-37 production |
| TLR4 | Pattern recognition receptor | Activation can induce IL-37, negative regulation may follow |
| HIF1A | Hypoxia-inducible factor | May modulate IL-37 in inflammatory microenvironments |
| FOXP3 | Regulatory T cell transcription factor | Associated with anti-inflammatory responses involving IL-37 |
| GATA3 | Th2 transcription factor | Linked to allergic rhinitis where IL-37 is dysregulated |
| RORC | Th17 transcription factor | May influence IL-37 production in autoimmunity |
How Is negative regulation of interleukin-37 production Regulated?
The negative regulation of interleukin-37 production is controlled by a network of signaling pathways. TGF-beta signaling through SMAD3 can repress IL37 transcription. Inflammatory stimuli that activate NF-kB may initially induce IL37, but prolonged activation can trigger negative feedback. IL-6, which is downstream of IL-37, can in turn modulate IL-37 production via STAT3. Inflammasome components such as NLRP3 influence IL-37 processing, and their inhibition reduces mature IL-37 levels. Additionally, epigenetic mechanisms and microRNAs may contribute to the suppression of IL-37 production, although specific regulators require further study.
negative regulation of interleukin-37 production and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| IL37 | Asthma | IL37 knockout mouse, airway inflammation model |
| IL37 | Inflammatory bowel disease | IL37 knockout or knock-in in colonic organoids |
| IL37 | Oral squamous cell carcinoma | IL37 overexpression in cancer cell lines |
| IL37 | Acute myeloid leukemia | IL37 knockout in leukemia cell lines |
| IL37 | Tuberculosis | IL37 transgenic mice infected with M. tuberculosis |
Asthma and Allergic Rhinitis
In asthma, IL-37 has been proposed as a therapeutic agent due to its anti-inflammatory properties. Negative regulation of IL-37 production may exacerbate allergic airway inflammation. In children with allergic rhinitis, IL-37b shows anti-inflammatory effects, and its reduced production could contribute to disease severity. Nasal polyps also exhibit upregulated IL-37, suggesting that negative regulation is impaired in chronic rhinosinusitis.
Inflammatory Bowel Disease
IL-37d negatively regulates NLRP3 transcription and alleviates DSS-induced colitis. Therefore, negative regulation of IL-37 production could worsen colitis by reducing IL-37 levels. In human and mouse colonic organoids, IL-37 regulates innate immune signaling, highlighting its importance in intestinal homeostasis.
Cancer
In oral squamous cell carcinoma, IL-37 may act as a pro-tumour cytokine, so negative regulation of its production could be beneficial. In acute myeloid leukemia, IL-37 regulates IL-6 expression, and its production is linked to leukemia progression. Thus, the role of IL-37 negative regulation in cancer is context-dependent.
Tuberculosis
IL-37 expression is upregulated in tuberculosis patients and induces M2-like macrophages, which may favor bacterial persistence. Negative regulation of IL-37 production might enhance host defense, but excessive suppression could lead to immunopathology.
From negative regulation of interleukin-37 production-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does gene X repress IL37 transcription? | CRISPR knockout of gene X in monocytes, followed by RT-qPCR for IL37 |
| Does a point mutation in IL37 promoter affect its production? | CRISPR point mutation knock-in in cell lines |
| Does overexpression of gene Y reduce IL-37 protein? | CRISPR overexpression (CRISPRa) or lentiviral overexpression |
| Where is IL-37 produced in tissues? | Knock-in of tagged IL37 (e.g., HA-tag) for imaging |
| What is the role of IL-37 in colitis? | IL37 knockout mice treated with DSS |
| Can a candidate regulator be targeted therapeutically? | Knock-in of reporter gene under IL37 promoter for drug screening |
How to Study the negative regulation of interleukin-37 production Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RT-qPCR | IL37 mRNA levels | Validation of transcriptional changes |
| RNA-seq | Global gene expression | Identifying pathways co-regulated with IL37 |
| Western blot | IL-37 protein levels | Confirming knockdown/overexpression |
| ELISA | Secreted IL-37 | Measuring cytokine release in supernatants |
| CRISPR knockout screen | Genes affecting IL-37 production | Discovery of negative regulators |
| Flow cytometry | Intracellular IL-37 | Immune cell profiling |
| Immunofluorescence | Tissue localization of IL-37 | Pathology studies |
| Co-immunoprecipitation | Protein-protein interactions | Identifying IL-37 binding partners |
Transcriptional profiling (RNA-seq, RT-qPCR)
RNA-seq and RT-qPCR are used to measure IL37 mRNA levels after genetic or pharmacological perturbations. These methods help identify negative regulators of IL37 transcription. For example, in colonic organoids, RNA-seq revealed IL-37-regulated genes.
Protein detection (Western blot, ELISA)
Western blot and ELISA quantify IL-37 protein levels in cell lysates and supernatants. They are essential to confirm that changes in mRNA translate to protein. In leukemia cells, IL-37 protein was measured to study its regulation of IL-6.
CRISPR screens
Genome-wide CRISPR knockout or activation screens can identify genes whose loss or overexpression alters IL-37 production. These screens are powerful for discovering novel negative regulators. Libraries targeting epigenetic regulators or signaling pathways are particularly useful.
Flow cytometry and imaging
Flow cytometry can detect intracellular IL-37 in immune cells, while imaging (e.g., immunofluorescence) localizes IL-37 in tissues. These methods are valuable in patient samples, such as nasal polyps.
How CRISPR Can Be Used to Study GO:0150138 negative regulation of interleukin-37 production
Knockout
CRISPR knockout of candidate genes (e.g., NLRP3, IL6) can determine whether they negatively regulate IL-37 production. For instance, knocking out NLRP3 in colonic organoids may alter IL-37 levels. Knockout of IL37 itself serves as a control to validate antibodies and assays.
Point Mutation
Point mutations can be introduced into the IL37 promoter or coding region to study regulatory elements. For example, mutating a putative SMAD3 binding site could test its role in repressing IL37 transcription. Point mutations in caspase cleavage sites can block IL-37 processing.
Knock-in
Knock-in of tags (e.g., HA, GFP) into the endogenous IL37 locus allows tracking of IL-37 production in real time. Knock-in of reporter genes (e.g., luciferase) under the IL37 promoter enables high-throughput screening for negative regulators.
Overexpression
CRISPR activation (CRISPRa) or lentiviral overexpression of candidate genes can test whether they reduce IL-37 production. Overexpressing IL-37 itself can create a negative feedback loop, as seen in leukemia cells where IL-37 regulates IL-6.
How EDITGENE Supports negative regulation of interleukin-37 production Research
Researchers studying negative regulation of interleukin-37 production-related genes often need to determine whether a candidate gene is causally involved in suppressing IL-37 levels. This requires precise genetic models to avoid confounding effects. EDITGENE provides comprehensive CRISPR services to accelerate such discoveries.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of interleukin-37 production research.
Frequently Asked Questions About negative regulation of interleukin-37 production
What is GO:0150138?
GO:0150138 is the Gene Ontology term for negative regulation of interleukin-37 production, describing any process that reduces the synthesis or secretion of the anti-inflammatory cytokine IL-37.
What genes are involved in negative regulation of interleukin-37 production?
Key genes include IL37 itself, NLRP3, IL6, SMAD3, and NFKB1, among others.
How is IL-37 production negatively regulated?
It can be repressed at transcriptional, post-transcriptional, and protein processing levels by factors such as TGF-beta, IL-6, and inflammasome components.
Why is negative regulation of IL-37 important in disease?
Dysregulation can lead to chronic inflammation in asthma, colitis, or cancer progression, depending on context.
What diseases are associated with IL-37 production?
Asthma, allergic rhinitis, nasal polyps, inflammatory bowel disease, tuberculosis, and cancers such as oral squamous cell carcinoma and acute myeloid leukemia.
How can CRISPR be used to study IL-37 regulation?
CRISPR knockout, knock-in, point mutation, and overexpression models allow causal testing of candidate regulators of IL-37 production.
What methods measure IL-37 production?
RT-qPCR, RNA-seq, Western blot, ELISA, flow cytometry, and CRISPR screens are commonly used.
Is IL-37 anti-inflammatory or pro-inflammatory?
IL-37 is primarily anti-inflammatory, but in some cancers it may promote tumour progression.
What is the role of NLRP3 in IL-37 regulation?
IL-37d negatively regulates NLRP3 transcription, and NLRP3 inflammasome activity can influence IL-37 processing.
Can IL-37 be targeted therapeutically?
Yes, modulating IL-37 levels is being explored for asthma and inflammatory diseases, and understanding its negative regulation is key.
Conclusion
GO:0150138, negative regulation of interleukin-37 production, is a critical biological process that controls the levels of the anti-inflammatory cytokine IL-37. Dysregulation of this process contributes to a range of inflammatory diseases and cancers. By leveraging CRISPR-based models and multi-omics methods, researchers can uncover the molecular players that suppress IL-37 production. Such insights may lead to novel therapeutic strategies that fine-tune IL-37 activity in disease settings.
References
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- 2. Cheng J et al.. 2014. Expression and Regulation of Interleukin-37 in Pathogenesis of Nasal Polyps.. Indian J Otolaryngol Head Neck Surg 66(4):401-6 PMID: 26396952
- 3. Allaire JM et al.. 2021. Interleukin-37 regulates innate immune signaling in human and mouse colonic organoids.. Sci Rep 11(1):8206 PMID: 33859245
- 4. Yan Y et al.. 2024. Potential pro-tumour cytokine in oral squamous cellular carcinoma: IL37.. J Cell Mol Med 28(21):e70167 PMID: 39500733
- 5. Wei X et al.. 2021. IL-37 Was Involved in Progress of Acute Myeloid Leukemia Through Regulating IL-6 Expression.. Cancer Manag Res 13:3393-3402 PMID: 33907463
- 6. Li Y et al.. 2021. IL-37d Negatively Regulates NLRP3 Transcription via Receptor-mediated Pathway and Alleviates DSS-induced Colitis.. Inflamm Bowel Dis 27(1):84-93 PMID: 32582954
- 7. Huang Z et al.. 2015. IL-37 Expression is Upregulated in Patients with Tuberculosis and Induces Macrophages Towards an M2-like Phenotype.. Scand J Immunol 82(4):370-9 PMID: 26073153
- 8. Liu W et al.. 2014. Anti-inflammatory effect of IL-37b in children with allergic rhinitis.. Mediators Inflamm 2014:746846 PMID: 25177111
