GO:0032741 positive regulation of interleukin-18 production: Inflammasome Signaling Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0032741 describes any process that activates or increases the frequency, rate, or extent of interleukin-18 (IL-18) production, including its biosynthesis and secretion.
• IL-18 is a pro-inflammatory cytokine processed by the NLRP3 inflammasome and released via unconventional secretion, often involving autophagy-related machinery.
• Positive regulation of IL-18 production is critical in psoriasis, colorectal cancer, arthritis, malaria, and intestinal tolerance.
• Key molecular players include NLRP3, caspase-1, HMGB1, GBP5, P2X7 receptor, and NCF4, which modulate inflammasome activation and IL-18 release.
• Experimental models such as knockout mice, point-mutation knock-in, and overexpression cell lines are essential to dissect the causal roles of these regulators.
• CRISPR-based screening and bioinformatics can identify novel regulators of IL-18 production, accelerating therapeutic target discovery.
Description
Interleukin-18 (IL-18) is a pleiotropic pro-inflammatory cytokine that plays a central role in innate and adaptive immunity. The Gene Ontology term GO:0032741, positive regulation of interleukin-18 production, encompasses all molecular events that enhance the synthesis, processing, or secretion of bioactive IL-18. Dysregulated IL-18 production is implicated in a wide range of pathologies, from autoimmune skin inflammation to cancer progression and metabolic disorders. Understanding how IL-18 production is positively regulated is therefore essential for developing targeted therapies. Recent studies have identified diverse mechanisms, including inflammasome activation, autophagy-based unconventional secretion, and microbial metabolite sensing, that converge on IL-18 release. This article synthesizes current knowledge on the regulators, mechanisms, and research models relevant to GO:0032741, providing a resource for researchers aiming to manipulate this pathway.
positive regulation of interleukin-18 production At A Glance
| GO ID | GO:0032741 |
|---|---|
| GO term | positive regulation of interleukin-18 production |
| Ontology | biological_process |
| Synonym | activation of interleukin-18 production; positive regulation of IL-18 production; positive regulation of interleukin-18 biosynthetic process; positive regulation of interleukin-18 secretion; stimulation of interleukin-18 production; up regulation of interleukin-18 production; up-regulation of interleukin-18 production; upregulation of interleukin-18 production |
| Major function | Enhances the synthesis, processing, and release of bioactive IL-18, a key pro-inflammatory cytokine. |
| Related processes | Inflammasome activation, autophagy-based unconventional secretion, cytokine processing. |
| Key regulators | NLRP3, caspase-1, HMGB1, GBP5, P2X7 receptor, NCF4. |
| Disease relevance | Psoriasis, colorectal cancer, arthritis, malaria, intestinal inflammation. |
What Is GO:0032741?
GO:0032741 is defined as any process that activates or increases the frequency, rate, or extent of interleukin-18 production. This includes transcriptional upregulation of the IL18 gene, post-translational processing of pro-IL-18 into its active form, and secretion of the mature cytokine. The term covers both biosynthetic and secretory aspects, as well as positive regulation of IL-18 secretion.
Why Is positive regulation of interleukin-18 production Important in Cell Biology?
Positive regulation of IL-18 production is a central node in inflammatory signaling, and its dysregulation contributes to the pathogenesis of numerous human diseases. IL-18 amplifies Th1 and Th17 responses, promotes IFN-γ production, and can drive tissue damage in autoimmunity. In cancer, IL-18 can either enhance anti-tumor immunity or promote tumor progression depending on context. Understanding the positive regulators of IL-18 production offers opportunities for therapeutic intervention in inflammatory diseases, cancer, and infectious diseases.
• IL-18 is a master pro-inflammatory cytokine involved in psoriasis, arthritis, and inflammatory bowel diseases.
• Positive regulation of IL-18 production is essential for host defense against intracellular pathogens such as malaria parasites.
• In colorectal cancer, modulation of IL-18 production affects immune surveillance and tumor progression.
• IL-18 and cGAMP orchestrate a metabolic switch that programs intestinal tolerance, highlighting its role in tissue homeostasis.
• Gut microbial metabolites can modulate IL-18 production and intraepithelial T cell function.
• Marginal zone B cells produce atheroprotective IgM antibodies in a T cell-dependent manner that may involve IL-18.
• Dietary interventions, such as barley kernel products with probiotics, can affect inflammatory markers including IL-18.
• Therapies targeting IL-18 production are being explored for autoinflammatory diseases and cancer.
• CRISPR screening can identify novel positive regulators of IL-18, accelerating drug target discovery.
• Understanding IL-18 regulation is key to designing vaccines and immunotherapies that harness its adjuvant properties.
What Happens During positive regulation of interleukin-18 production?
Inflammasome Activation and Caspase-1 Processing
In simple terms: The inflammasome is a molecular platform that activates an enzyme called caspase-1, which cuts pro-IL-18 into its active form.
Positive regulation of IL-18 production often begins with the assembly of the NLRP3 inflammasome, which recruits and activates caspase-1. Activated caspase-1 cleaves pro-IL-18 into mature IL-18, which is then secreted. This process is triggered by danger signals such as ATP, microbial components, or crystalline substances. Studies have shown that modulation of the P2X7 receptor and NLRP3-related signaling pathways can suppress IL-18 production in arthritis models. Additionally, NCF4 attenuates colorectal cancer progression by modulating inflammasome activation and immune surveillance, affecting IL-18 levels.
Autophagy-Based Unconventional Secretion
In simple terms: Cells can release IL-18 without the usual secretory pathway by using autophagy, a recycling system.
HMGB1, a nuclear protein, can be secreted by keratinocytes through an autophagy-based unconventional pathway that plays a pivotal role in psoriatic skin inflammation. This pathway also promotes IL-18 secretion, linking autophagy to positive regulation of IL-18 production. The mechanism involves the translocation of HMGB1 and IL-18 into autophagosomes, which then fuse with the plasma membrane to release their contents. This non-classical secretion route is important in inflammatory skin diseases and may be targeted therapeutically.
Transcriptional and Post-Transcriptional Control
In simple terms: The amount of IL-18 produced can be increased by turning up the IL18 gene or stabilizing its mRNA.
Positive regulation of IL-18 production can occur at the transcriptional level, where NF-κB and other transcription factors enhance IL18 gene expression. Post-transcriptional mechanisms, such as mRNA stabilization, also contribute. In intestinal tolerance, a metabolic switch orchestrated by IL-18 and the cyclic dinucleotide cGAMP programs gene expression changes that affect IL-18 production. Gut microbial fatty acid isomerization modulates intraepithelial T cells, potentially through effects on IL-18 transcription.
Microbial and Dietary Modulation
In simple terms: Gut bacteria and diet can influence how much IL-18 is made.
The gut microbiota can modulate IL-18 production through metabolites such as short-chain fatty acids and fatty acid isomers. A randomized controlled study showed that barley kernel products with probiotics affected inflammatory markers, including IL-18, in healthy subjects. Additionally, gut microbial fatty acid isomerization modulates intraepithelial T cells, which may involve IL-18 regulation. These findings highlight the role of environmental factors in positive regulation of IL-18 production.
Cytokine Networks and Amplification Loops
In simple terms: IL-18 can stimulate other immune cells to produce more IL-18, creating a feedback loop.
IL-18 itself can induce IFN-γ, which in turn activates macrophages and other cells to produce more IL-18, establishing a positive feedback loop. In malaria, modulation of IL-18 release produced positive outcomes on parasitaemia development and cytokines production, indicating a role in amplifying immune responses. Marginal zone B cells produce atheroprotective IgM antibodies in a T cell-dependent manner, which may involve IL-18 as a mediator.
Key Genes Involved in GO:0032741 positive regulation of interleukin-18 production
The following genes and proteins are key players in the positive regulation of interleukin-18 production, based on published literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| IL18 | Encodes the pro-inflammatory cytokine IL-18 | Central to the term; target for knockout and overexpression studies |
| NLRP3 | Inflammasome sensor that activates caspase-1 | Key regulator; knockout mice used to study IL-18 production |
| CASP1 | Cysteine protease that cleaves pro-IL-18 | Essential for maturation; point mutations affect activity |
| HMGB1 | Mediates autophagy-based unconventional secretion | Knockout reduces IL-18 release in psoriasis models |
| GBP5 | Guanylate-binding protein that regulates inflammasome | Target of sinomenine in arthritis; modulates IL-18 |
| P2RX7 | P2X7 receptor for ATP, activates NLRP3 | Knockout or antagonist reduces IL-18 production |
| NCF4 | Regulates inflammasome activation and immune surveillance | Knockout increases IL-18 in colorectal cancer |
| cGAMP | Cyclic dinucleotide that programs intestinal tolerance | Synthetic analog used to modulate IL-18 |
| IFNG | Interferon-gamma, induced by IL-18 | Feedback loop; knockout affects IL-18 production |
| NFKB1 | Transcription factor for IL18 gene | Overexpression increases IL-18 transcription |
| MAPK1 | Kinase involved in inflammasome priming | Inhibitors reduce IL-18 production |
| TLR4 | Pattern recognition receptor for LPS | Stimulation increases pro-IL-18 expression |
| MYD88 | Adaptor for TLR signaling | Knockout impairs IL-18 production |
| CARD8 | Inflammasome sensor | Polymorphisms affect IL-18 levels |
| AIM2 | Inflammasome sensor for DNA | Activates caspase-1 and IL-18 |
| NLRC4 | Inflammasome sensor for flagellin | Activates caspase-1 and IL-18 |
| GSDMD | Gasdermin D, mediates pyroptosis and IL-18 release | Knockout reduces IL-18 secretion |
How Is positive regulation of interleukin-18 production Regulated?
Positive regulation of IL-18 production is tightly controlled at multiple levels. Inflammasome assembly is regulated by danger-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) that activate NLRP3, NLRC4, AIM2, or CARD8. Autophagy-based unconventional secretion of HMGB1 and IL-18 is regulated by autophagy-related genes and can be modulated by pharmacological agents. The metabolic switch orchestrated by IL-18 and cGAMP involves mTOR signaling and affects intestinal tolerance. Gut microbial metabolites, such as fatty acid isomers, can also regulate IL-18 production. Additionally, dietary components like barley kernel products with probiotics have been shown to influence IL-18 levels in healthy subjects.
positive regulation of interleukin-18 production and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| HMGB1 | Psoriasis | Keratinocyte-specific knockout mice |
| NCF4 | Colorectal cancer | Ncf4 knockout mice or cell lines |
| GBP5 | Rheumatoid arthritis | Collagen-induced arthritis in mice with Gbp5 knockout |
| IL18 | Malaria | Il18 knockout mice infected with Plasmodium |
| NLRP3 | Autoinflammatory diseases | Nlrp3 knock-in mice with point mutations |
Psoriasis and Skin Inflammation
In psoriatic skin inflammation, autophagy-based unconventional secretion of HMGB1 by keratinocytes promotes IL-18 release, contributing to the inflammatory milieu. Targeting this pathway may reduce IL-18 production and alleviate psoriasis symptoms. Knockout of HMGB1 or autophagy genes in keratinocytes reduces IL-18 secretion and skin inflammation in mouse models.
Colorectal Cancer
NCF4 attenuates colorectal cancer progression by modulating inflammasome activation and immune surveillance. Loss of NCF4 leads to increased IL-18 production, which can enhance anti-tumor immunity but also promote chronic inflammation. The dual role of IL-18 in cancer makes it a complex therapeutic target.
Arthritis
Sinomenine ameliorates collagen-induced arthritis in mice by targeting GBP5 and regulating the P2X7 receptor to suppress NLRP3-related signaling pathways, thereby reducing IL-18 production. This highlights the potential of small molecules to inhibit positive regulation of IL-18 production in autoimmune arthritis.
Malaria and Infectious Diseases
Modulation of interleukin-18 release produced positive outcomes on parasitaemia development and cytokines production during malaria in mice. IL-18 is critical for host defense against Plasmodium, and its positive regulation can influence disease outcome. Understanding these mechanisms may aid vaccine development.
From positive regulation of interleukin-18 production-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does gene X regulate IL-18 production? | CRISPR knockout of gene X in macrophages, followed by IL-18 ELISA |
| Does a point mutation in gene Y affect IL-18 processing? | Knock-in mice or cell lines with the specific point mutation |
| Can overexpression of gene Z enhance IL-18 secretion? | Lentiviral overexpression in epithelial cells or fibroblasts |
| What is the role of gene W in psoriasis? | Keratinocyte-specific knockout or overexpression in mouse skin |
| How does gene V affect intestinal tolerance? | Intestinal organoids with CRISPR knockout and IL-18 measurement |
| Does a SNP in gene U alter IL-18 levels? | CRISPR knock-in of the SNP in human cell lines |
How to Study the positive regulation of interleukin-18 production Process
| Method | What It Measures | Typical Application |
|---|---|---|
| ELISA | IL-18 protein concentration | Quantify IL-18 secretion in supernatants |
| Western blot | Pro-IL-18 and cleaved IL-18 | Assess inflammasome processing |
| qPCR | IL18 mRNA levels | Measure transcriptional upregulation |
| RNA-seq | Global gene expression | Identify pathways co-regulated with IL-18 |
| CRISPR screen | Genes affecting IL-18 production | Discover novel regulators |
| Immunoprecipitation | Protein-protein interactions | Map inflammasome complexes |
| Flow cytometry | Intracellular IL-18 | Analyze IL-18 in specific cell types |
| Multiplex cytokine assay | Multiple cytokines including IL-18 | Profile inflammatory responses |
ELISA and Cytokine Profiling
Enzyme-linked immunosorbent assay (ELISA) is the standard method to quantify IL-18 protein levels in cell culture supernatants and serum. It measures both pro-IL-18 and mature IL-18, depending on the antibody used. This method is widely used to assess positive regulation of IL-18 production in response to genetic or pharmacological perturbations.
Western Blot and Immunoprecipitation
Western blotting can detect pro-IL-18 and cleaved IL-18 in cell lysates, providing information on processing. Immunoprecipitation can identify interacting partners such as NLRP3, caspase-1, and HMGB1. These techniques are essential for mechanistic studies of IL-18 regulation.
RNA Sequencing and qPCR
RNA sequencing and quantitative PCR measure IL18 mRNA levels and expression of related genes. They can reveal transcriptional changes in response to stimuli or genetic modifications. This is useful for identifying positive regulators at the transcriptional level.
CRISPR Screening and Functional Genomics
Genome-wide CRISPR knockout or activation screens can identify novel positive regulators of IL-18 production. Cells are engineered to express a reporter under the IL18 promoter or to secrete IL-18, and then subjected to library screening. Hits are validated by targeted knockout and cytokine assays.
How CRISPR Can Be Used to Study GO:0032741 positive regulation of interleukin-18 production
Knockout
CRISPR knockout is used to delete candidate genes and assess their impact on IL-18 production. For example, knockout of NCF4 in colorectal cancer cells increased inflammasome activation and IL-18 release. Knockout of HMGB1 in keratinocytes reduced autophagy-based IL-18 secretion. These models help establish causality.
Point Mutation
Point mutations can be introduced to mimic disease-associated SNPs or to abrogate specific phosphorylation sites. For instance, point mutations in NLRP3 that cause constitutive activation lead to increased IL-18 production. Such models are valuable for studying gain-of-function or loss-of-function mechanisms.
Knock-in
Knock-in of reporter genes (e.g., GFP) or epitope tags into the IL18 locus allows real-time tracking of IL-18 expression and secretion. Knock-in of human IL18 into mouse models can facilitate preclinical testing of human-specific therapeutics. These models are essential for precise regulation studies.
Overexpression
Overexpression of candidate genes using lentiviral or transgenic approaches can test whether a gene is sufficient to enhance IL-18 production. For example, overexpression of GBP5 or P2X7 receptor increased IL-18 release in arthritis models. Overexpression models are useful for gain-of-function studies.
How EDITGENE Supports positive regulation of interleukin-18 production Research
Researchers studying positive regulation of interleukin-18 production-related genes often need to determine whether a candidate gene is causally involved in IL-18 synthesis, processing, or secretion. EDITGENE provides comprehensive CRISPR-based services to generate knockout, point-mutation, knock-in, and overexpression cell models, as well as library screening and bioinformatics support, enabling precise functional dissection of this pathway.
Contact EDITGENE today to design your custom CRISPR model for positive regulation of interleukin-18 production research.
Frequently Asked Questions About positive regulation of interleukin-18 production
What is GO:0032741?
GO:0032741 is the Gene Ontology term for positive regulation of interleukin-18 production, describing any process that activates or increases the frequency, rate, or extent of IL-18 production.
What genes are involved in positive regulation of interleukin-18 production?
Key genes include IL18, NLRP3, CASP1, HMGB1, GBP5, P2RX7, and NCF4, among others.
How is IL-18 production regulated?
IL-18 production is regulated by inflammasome activation, caspase-1 cleavage, autophagy-based secretion, and transcriptional mechanisms.
What diseases are associated with IL-18 overproduction?
Psoriasis, colorectal cancer, rheumatoid arthritis, and malaria are associated with dysregulated IL-18 production.
What is the role of HMGB1 in IL-18 production?
HMGB1 mediates autophagy-based unconventional secretion of IL-18 in keratinocytes, contributing to psoriatic inflammation.
How can I study positive regulation of IL-18 production?
Use CRISPR knockout, point mutation, knock-in, or overexpression models combined with ELISA, Western blot, and RNA-seq.
What is the connection between NCF4 and IL-18?
NCF4 attenuates colorectal cancer progression by modulating inflammasome activation and IL-18 production.
Can diet affect IL-18 production?
Yes, gut microbial metabolites and dietary components like barley kernel products with probiotics can influence IL-18 levels.
What is the role of cGAMP in IL-18 regulation?
cGAMP, a cyclic dinucleotide, orchestrates a metabolic switch with IL-18 to program intestinal tolerance.
How does sinomenine affect IL-18?
Sinomenine ameliorates arthritis by targeting GBP5 and regulating the P2X7 receptor to suppress NLRP3-related signaling and IL-18 production.
Conclusion
Positive regulation of interleukin-18 production (GO:0032741) is a critical biological process with far-reaching implications for inflammation, immunity, and disease. The integration of inflammasome signaling, autophagy-based secretion, and transcriptional control ensures tight regulation of this potent cytokine. Dysregulation contributes to psoriasis, cancer, arthritis, and infectious diseases, making it an attractive therapeutic target. Advances in CRISPR modeling and functional genomics are accelerating the discovery of novel regulators, offering hope for new treatments.
References
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- 3. Li L et al.. 2024. NCF4 attenuates colorectal cancer progression by modulating inflammasome activation and immune surveillance.. Nat Commun 15(1):5170 PMID: 38886341
- 4. Li JM et al.. 2023. Sinomenine ameliorates collagen-induced arthritis in mice by targeting GBP5 and regulating the P2X7 receptor to suppress NLRP3-related signaling pathways.. Acta Pharmacol Sin 44(12):2504-2524 PMID: 37482570
- 5. Song X et al.. 2023. Gut microbial fatty acid isomerization modulates intraepithelial T cells.. Nature 619(7971):837-843 PMID: 37380774
- 6. Harrison J et al.. 2024. Marginal zone B cells produce 'natural' atheroprotective IgM antibodies in a T cell-dependent manner.. Cardiovasc Res 120(3):318-328 PMID: 38381113
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