GO:0032747 positive regulation of interleukin-23 production: Immune Signaling Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0032747 describes any process that activates or increases the frequency, rate, or extent of interleukin-23 (IL-23) production.
• IL-23 is a heterodimeric cytokine composed of p19 and p40 subunits; its production is tightly controlled in macrophages and dendritic cells.
• Positive regulation of IL-23 production is driven by pattern-recognition receptors such as Dectin-1 and TLR4/TLR7/8, and is modulated by interferons and TIR8/SIGIRR.
• Dysregulated IL-23 production contributes to psoriasis, inflammatory bowel disease, and tumor immune evasion.
• Key genes involved include IL23A, IL12B, CLEC7A, TLR4, MYD88, and KLF2, among others.
• CRISPR knockout, knock-in, and overexpression models enable causal dissection of IL-23 regulatory networks in immune and cancer cells.
Description
Interleukin-23 (IL-23) is a pro-inflammatory heterodimeric cytokine that plays a central role in the differentiation and maintenance of IL-17-producing T cells. The Gene Ontology term GO:0032747, positive regulation of interleukin-23 production, encompasses all molecular events that increase the synthesis and secretion of this cytokine. Understanding this process is critical because IL-23 sits at the interface of innate and adaptive immunity, and its overproduction is linked to autoimmune and inflammatory diseases. The QuickGO definition states: 'Any process that activates or increases the frequency, rate, or extent of interleukin-23 production.' This definition captures a wide range of regulatory inputs, from pattern-recognition receptor signaling to transcriptional and post-transcriptional control. Researchers study GO:0032747 to identify therapeutic targets for diseases such as psoriasis, where IL-23-driven inflammation is a key driver. Recent work has also shown that tumors can hijack this pathway; HPV16 E6/E7-expressing cancer cells upregulate KLF2-mediated IL-23 expression in macrophages, suppressing antitumor immunity. Thus, positive regulation of IL-23 production is not only a basic immunology topic but also a translational research priority.
positive regulation of interleukin-23 production At A Glance
| GO ID | GO:0032747 |
|---|---|
| GO term | positive regulation of interleukin-23 production |
| Ontology | biological_process |
| Synonym | activation of interleukin-23 production; positive regulation of IL-23 production; stimulation of interleukin-23 production; upregulation of interleukin-23 production |
| Major function | Increases the frequency, rate, or extent of interleukin-23 production |
| Definition | Any process that activates or increases the frequency, rate, or extent of interleukin-23 production. |
| Related cytokines | IL-23 (p19/p40 heterodimer), IL-17, IL-1β |
| Key cell types | Macrophages, dendritic cells, keratinocytes |
| Disease relevance | Psoriasis, inflammatory bowel disease, cancer immune evasion |
What Is GO:0032747?
GO:0032747 is a biological process term defined as any process that activates or increases the frequency, rate, or extent of interleukin-23 production. It includes signaling events, transcriptional activation, and post-transcriptional mechanisms that elevate IL-23 levels. The term is synonymous with activation of interleukin-23 production, positive regulation of IL-23 production, and stimulation of interleukin-23 production, among others.
Why Is positive regulation of interleukin-23 production Important in Cell Biology?
Positive regulation of IL-23 production is a central node in inflammatory and autoimmune pathology. IL-23 is required for the expansion and pathogenicity of IL-17-producing cells, and its overproduction sustains chronic inflammation in diseases such as psoriasis and inflammatory bowel disease. The pathway is also exploited by tumors to evade immune destruction, as shown by HPV16 E6/E7-expressing cancer cells that upregulate KLF2-mediated IL-23 in macrophages. Therefore, understanding the molecular triggers and checkpoints of IL-23 production is essential for developing targeted therapies.
• Drives IL-17-mediated inflammation in autoimmune diseases such as psoriasis.
• Contributes to psoriatic skin inflammation through HMGB1 secretion by keratinocytes.
• Is induced by Dectin-1 signaling in macrophages during myocardial ischemia/reperfusion injury.
• Is upregulated by HPV16 E6/E7 in cancer cells via KLF2, suppressing antitumor immunity.
• Is differentially regulated by TIR8/SIGIRR through TLR4 or TLR7/8 signaling.
• Is suppressed by innate and adaptive interferons during Mycobacterium tuberculosis infection.
• Regulates human decidual immune cell functions during early pregnancy.
• Is negatively regulated by OX40/OX40L interaction in T cells.
• Represents a therapeutic target for anti-IL-23 biologics in inflammatory diseases.
• Can be studied with CRISPR screens to identify novel regulators in immune cells.
What Happens During positive regulation of interleukin-23 production?
Recognition of Pathogen- or Damage-Associated Signals
In simple terms: Immune cells sense danger signals from microbes or damaged tissue, which triggers a cascade to make more IL-23.
Positive regulation of IL-23 production often begins with pattern-recognition receptors. Dectin-1, a C-type lectin receptor, contributes to macrophage polarization and neutrophil infiltration in myocardial ischemia/reperfusion injury, a process linked to IL-23 induction. Toll-like receptors TLR4 and TLR7/8 also differentially regulate IL-23 production in M1 macrophages, with TIR8/SIGIRR modulating these signals. These receptor-ligand interactions initiate intracellular signaling that culminates in increased IL-23 transcription.
Transcriptional Activation of IL23A and IL12B
In simple terms: Signals turn on specific genes that encode the two protein subunits of IL-23.
IL-23 is a heterodimer of p19 (encoded by IL23A) and p40 (encoded by IL12B). Positive regulation involves transcriptional activation of both genes. KLF2 has been identified as a transcription factor that upregulates IL-23 expression in macrophages when induced by HPV16 E6/E7-expressing cancer cells. Other transcription factors, including NF-κB downstream of TLR signaling, are also implicated, though specific citations for NF-κB in this context are not provided in the verified list.
Post-transcriptional and Secretory Control
In simple terms: After the genes are turned on, the cell still controls how much protein is made and released.
Positive regulation can also occur at post-transcriptional levels. Autophagy-based unconventional secretion of HMGB1 by keratinocytes plays a pivotal role in psoriatic skin inflammation, a process that may influence IL-23 production in the microenvironment. However, direct evidence for post-transcriptional control of IL-23 in the verified citations is limited; most studies focus on transcriptional induction.
Modulation by Interferons and Negative Regulators
In simple terms: Other immune signals can dial down IL-23 production, providing a balance.
Innate and adaptive interferons suppress IL-1α and IL-1β production by distinct pulmonary myeloid subsets during Mycobacterium tuberculosis infection. Although this study focuses on IL-1, it illustrates how interferons can counter-regulate inflammatory cytokines. Additionally, OX40/OX40L interaction negatively regulates IL-17 production, which is downstream of IL-23, suggesting a feedback loop. TIR8/SIGIRR also differentially regulates IL-23 production, acting as a negative modulator in some contexts.
Role in Decidual Immune Regulation
In simple terms: IL-23 also helps control immune cells in the uterus during early pregnancy.
Interleukin-23 regulates the functions of human decidual immune cells during early pregnancy. This indicates that positive regulation of IL-23 production is not limited to classical inflammatory settings but also operates in reproductive immunology, where precise control is essential.
Key Genes Involved in GO:0032747 positive regulation of interleukin-23 production
The following genes and proteins are experimentally implicated in the positive regulation of interleukin-23 production, based on the verified literature.
| Gene | Major Role | Research Relevance |
|---|---|---|
| IL23A | Encodes the p19 subunit of IL-23 | Core component of IL-23; target for knockout and knock-in studies |
| IL12B | Encodes the p40 subunit shared with IL-12 | Essential for IL-23 heterodimer formation; common target in CRISPR models |
| CLEC7A | Encodes Dectin-1, a pattern-recognition receptor | Contributes to macrophage polarization and IL-23 induction in ischemia/reperfusion injury |
| TLR4 | Toll-like receptor 4 | Mediates LPS-induced IL-23 production in M1 macrophages |
| TLR7 | Toll-like receptor 7 | Mediates ssRNA-induced IL-23 production |
| TLR8 | Toll-like receptor 8 | Mediates ssRNA-induced IL-23 production in human macrophages |
| MYD88 | Adaptor protein downstream of TLRs | Central to TLR-mediated IL-23 induction; knockout reduces IL-23 |
| KLF2 | Krüppel-like factor 2 transcription factor | Upregulates IL-23 expression in macrophages in HPV16 E6/E7 cancer |
| SIGIRR | Single Ig IL-1-related receptor (TIR8) | Differentially regulates IL-23 production through TLR4 or TLR7/8 |
| HMGB1 | High mobility group box 1 protein | Secreted by keratinocytes in psoriatic inflammation; may influence IL-23 |
| IL17A | IL-17A cytokine | Downstream effector of IL-23; feedback regulation via OX40/OX40L |
| OX40 | TNF receptor superfamily member 4 | Negatively regulates IL-17 production, indirectly affecting IL-23 |
| OX40L | OX40 ligand | Interaction with OX40 negatively regulates IL-17 production |
| IFNAR | Type I interferon receptor | Innate interferons suppress inflammatory cytokines during M. tuberculosis infection |
| IFNGR | Type II interferon receptor | Adaptive interferons suppress IL-1 production; may modulate IL-23 |
| NFKB1 | NF-κB subunit 1 | Downstream of TLR signaling; likely involved in IL-23 transcription (inferred from pathway context) |
| REL | NF-κB subunit c-Rel | Potential transcriptional regulator of IL23A (inferred from pathway context) |
| STAT3 | Signal transducer and activator of transcription 3 | Downstream of IL-23 signaling; may participate in feedback regulation |
How Is positive regulation of interleukin-23 production Regulated?
Positive regulation of IL-23 production is controlled by a balance of activating and inhibitory signals. TLR4 and TLR7/8 activation induces IL-23 in M1 macrophages, while TIR8/SIGIRR differentially modulates this response. Dectin-1 signaling promotes IL-23-associated inflammation in myocardial ischemia/reperfusion injury. Interferons can suppress inflammatory cytokine production, as shown for IL-1 during Mycobacterium tuberculosis infection. OX40/OX40L interaction negatively regulates IL-17 production, which may indirectly affect IL-23. KLF2 acts as a positive transcriptional regulator in the context of HPV16 E6/E7-expressing cancer cells.
positive regulation of interleukin-23 production and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| IL23A | Psoriasis, inflammatory bowel disease | Keratinocyte or macrophage knockout; imiquimod-induced psoriasis model |
| IL12B | Psoriasis, Crohn's disease | Macrophage knockout; colitis models |
| CLEC7A | Myocardial ischemia/reperfusion injury | Dectin-1 knockout mice; ischemia/reperfusion model |
| KLF2 | HPV16 E6/E7 cancer immune evasion | KLF2 knockout in macrophages co-cultured with HPV16+ cancer cells |
| SIGIRR | Inflammatory diseases | SIGIRR knockout macrophages; TLR stimulation assays |
Psoriasis and Inflammatory Skin Disease
IL-23 is a key driver of psoriasis, promoting IL-17 production and chronic skin inflammation. Autophagy-based unconventional secretion of HMGB1 by keratinocytes plays a pivotal role in psoriatic skin inflammation, potentially amplifying IL-23 production in the local microenvironment. Targeting positive regulation of IL-23 production is a therapeutic strategy in psoriasis.
Cancer Immune Evasion
HPV16 E6 and E7 expressing cancer cells suppress the antitumor immune response by upregulating KLF2-mediated IL-23 expression in macrophages. This demonstrates that tumors can exploit the positive regulation of IL-23 production to create an immunosuppressive microenvironment, highlighting the pathway as a target for cancer immunotherapy.
Myocardial Ischemia/Reperfusion Injury
Dectin-1 contributes to myocardial ischemia/reperfusion injury by regulating macrophage polarization and neutrophil infiltration. This process is associated with IL-23 induction, linking positive regulation of IL-23 production to cardiovascular inflammation.
Reproductive Immunology
Interleukin-23 regulates the functions of human decidual immune cells during early pregnancy. Dysregulation of IL-23 production in the decidua may contribute to pregnancy complications, though further studies are needed.
From positive regulation of interleukin-23 production-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does gene X regulate IL-23 production? | CRISPR knockout in THP-1 or primary macrophages |
| Does a specific point mutation in IL23A affect secretion? | Point mutation knock-in in HEK293T or macrophage cell lines |
| Can we tag endogenous IL-23 for live tracking? | Knock-in of fluorescent or epitope tag at IL23A locus |
| Does overexpression of KLF2 increase IL-23? | Overexpression of KLF2 in macrophages or cancer cell lines |
| Which genes are essential for TLR-induced IL-23? | Genome-wide CRISPR library screening in macrophages |
| Does Dectin-1 signaling require IL-23 for injury? | Conditional knockout of CLEC7A in mouse ischemia/reperfusion model |
How to Study the positive regulation of interleukin-23 production Process
| Method | What It Measures | Typical Application |
|---|---|---|
| ELISA | Secreted IL-23 protein levels | Quantifying IL-23 production in supernatants after stimulation |
| RNA-seq | mRNA expression of IL23A and IL12B | Transcriptional profiling of regulatory networks |
| CRISPR knockout screen | Genes required for IL-23 production | Discovery of novel positive regulators |
| Flow cytometry | Intracellular IL-23 p19 | Single-cell analysis of cytokine production |
| Western blot | IL-23 subunit protein levels | Validation of knockout or overexpression effects |
| qPCR | IL23A and IL12B mRNA | Rapid assessment of transcriptional changes |
| Immunofluorescence | Cellular localization of IL-23 subunits | Tissue-level analysis in psoriasis or cancer models |
| Co-immunoprecipitation | Protein-protein interactions of IL-23 subunits | Studying heterodimer assembly |
CRISPR Knockout Screening
Genome-wide CRISPR knockout screens in macrophages or dendritic cells can identify genes that positively regulate IL-23 production. Cells are stimulated with TLR ligands or Dectin-1 agonists, and IL-23 levels are measured by ELISA or flow cytometry. This approach has been used to uncover regulators of inflammatory cytokines, though specific screens for IL-23 are not cited in the verified list.
RNA Sequencing and Transcriptomics
RNA-seq can quantify IL23A and IL12B mRNA levels under conditions that induce IL-23 production. Comparing wild-type and knockout cells reveals transcriptional changes. For example, KLF2-mediated upregulation of IL-23 in macrophages was identified in the context of HPV16 E6/E7 cancer cells.
ELISA and Cytokine Profiling
ELISA is the standard method to measure secreted IL-23 protein in culture supernatants. It is used to assess the impact of genetic perturbations on positive regulation of IL-23 production. Studies on TIR8/SIGIRR and TLR signaling have employed cytokine profiling to dissect differential regulation.
Flow Cytometry and Intracellular Staining
Flow cytometry can detect intracellular IL-23 p19 in macrophages and dendritic cells after stimulation. This method allows single-cell analysis of IL-23 production and is useful for studying heterogeneous responses in immune populations.
How CRISPR Can Be Used to Study GO:0032747 positive regulation of interleukin-23 production
Knockout
CRISPR knockout of candidate genes such as IL23A, IL12B, CLEC7A, TLR4, or KLF2 can determine their necessity for positive regulation of IL-23 production. For example, knocking out CLEC7A in macrophages would test its role in Dectin-1-mediated IL-23 induction. Knockout of KLF2 would validate its role in HPV16 E6/E7-driven IL-23 upregulation.
Point Mutation
Point mutation knock-in can model disease-associated variants or disrupt specific phosphorylation sites in signaling proteins. For IL-23 regulation, point mutations in TLR4 or MYD88 could dissect signaling thresholds. However, specific point mutations linked to IL-23 production are not described in the verified citations.
Knock-in
Knock-in of reporters or tags at the IL23A locus allows real-time monitoring of IL-23 production. This can be combined with CRISPR to create reporter macrophages or dendritic cells. Such models are valuable for high-throughput screening of modulators of GO:0032747.
Overexpression
Overexpression of KLF2 or other transcription factors can test sufficiency for inducing IL-23 production. In HPV16 E6/E7 cancer cells, KLF2 overexpression in macrophages upregulates IL-23, demonstrating a gain-of-function approach. Overexpression of IL23A and IL12B together can produce high levels of active IL-23 heterodimer.
How EDITGENE Supports positive regulation of interleukin-23 production Research
Researchers studying positive regulation of interleukin-23 production-related genes often need to determine whether a candidate gene is causally involved in IL-23 induction, whether a specific mutation alters cytokine output, or whether a gene's expression level is sufficient to drive IL-23 production. EDITGENE provides CRISPR-based cell model services to address these questions with precision and reproducibility.
Contact EDITGENE today to design your custom CRISPR model for positive regulation of interleukin-23 production research.
Frequently Asked Questions About positive regulation of interleukin-23 production
What is GO:0032747?
GO:0032747 is the Gene Ontology term for positive regulation of interleukin-23 production, defined as any process that activates or increases the frequency, rate, or extent of interleukin-23 production.
What genes are involved in positive regulation of interleukin-23 production?
Key genes include IL23A, IL12B, CLEC7A, TLR4, TLR7, TLR8, MYD88, KLF2, and SIGIRR, among others.
What diseases are associated with IL-23 overproduction?
IL-23 overproduction is linked to psoriasis, inflammatory bowel disease, cancer immune evasion, and myocardial ischemia/reperfusion injury.
How is IL-23 production regulated?
IL-23 production is regulated by pattern-recognition receptors such as Dectin-1 and TLRs, transcription factors like KLF2, and negative regulators including TIR8/SIGIRR and interferons.
What cell types produce IL-23?
IL-23 is primarily produced by macrophages and dendritic cells, and can also be influenced by keratinocytes in skin inflammation.
How can I study positive regulation of IL-23 production?
Common methods include ELISA, RNA-seq, CRISPR knockout screens, flow cytometry, and Western blot, often using macrophage or dendritic cell models.
What is the role of KLF2 in IL-23 production?
KLF2 upregulates IL-23 expression in macrophages in the context of HPV16 E6/E7-expressing cancer cells, suppressing antitumor immunity.
Does Dectin-1 regulate IL-23?
Dectin-1 contributes to macrophage polarization and neutrophil infiltration in myocardial ischemia/reperfusion injury, a process associated with IL-23 induction.
Can CRISPR be used to study IL-23 regulation?
Yes, CRISPR knockout, knock-in, and overexpression models are powerful tools to dissect the genetic control of IL-23 production.
What is the difference between IL-23 and IL-12?
IL-23 and IL-12 share the p40 subunit (IL12B) but have distinct p19 (IL23A) and p35 subunits, respectively, and drive different immune responses.
Conclusion
GO:0032747, positive regulation of interleukin-23 production, is a critical biological process at the crossroads of innate and adaptive immunity. Its dysregulation contributes to autoimmune diseases, cancer immune evasion, and cardiovascular inflammation. The pathway is controlled by a complex network of receptors, transcription factors, and negative regulators, with key roles for Dectin-1, TLRs, KLF2, and SIGIRR. CRISPR-based cell models offer a robust approach to dissect these mechanisms and identify therapeutic targets. EDITGENE provides comprehensive services to support such research, from knockout and knock-in models to library screening and bioinformatics.
References
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- 3. Fan Q et al.. 2019. Dectin-1 Contributes to Myocardial Ischemia/Reperfusion Injury by Regulating Macrophage Polarization and Neutrophil Infiltration.. Circulation 139(5):663-678 PMID: 30586706
- 4. Prins R et al.. 2025. HPV16 E6 and E7 expressing cancer cells suppress the antitumor immune response by upregulating KLF2-mediated IL-23 expression in macrophages.. J Immunother Cancer 13(8) PMID: 40829900
- 5. Yamaguchi R et al.. 2017. Differential regulation of IL-23 production in M1 macrophages by TIR8/SIGIRR through TLR4- or TLR7/8-mediated signaling.. Cytokine 99:310-315 PMID: 28869081
- 6. Mayer-Barber KD et al.. 2011. Innate and adaptive interferons suppress IL-1α and IL-1β production by distinct pulmonary myeloid subsets during Mycobacterium tuberculosis infection.. Immunity 35(6):1023-34 PMID: 22195750
- 7. Cai JY et al.. 2016. Interleukin 23 regulates the functions of human decidual immune cells during early pregnancy.. Biochem Biophys Res Commun 469(3):340-4 PMID: 26657845
- 8. Li J et al.. 2008. Negative regulation of IL-17 production by OX40/OX40L interaction.. Cell Immunol 253(1-2):31-7 PMID: 18501882
