GO:0002719 negative regulation of cytokine production involved in immune response: Mechanism, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0002719 describes any process that stops, prevents, or reduces the frequency, rate, or extent of cytokine production contributing to an immune response [1, 3].
• This term is a biological process and includes negative regulation of cytokine biosynthesis and secretion during immune responses [1, 3].
• Key negative regulators include PSMA7, SIRT1, CD44c, and DExH/D-box helicases, which act at distinct checkpoints of innate and adaptive immunity [4, 5, 6, 7].
• Dysregulation of this process is linked to chronic inflammation, autoimmunity, and impaired pathogen clearance [2, 3].
• CRISPR knockout, point mutation, knock-in, and overexpression models enable causal dissection of negative regulators in immune cells [1, 4, 6].
• Studying GO:0002719 requires integrated methods such as cytokine profiling, RNA-seq, proteomics, and imaging of immune cell interactions [1, 2, 8].
Description
Cytokines are small secreted proteins that coordinate immune responses, and their production must be tightly controlled to avoid tissue damage and autoimmunity [1, 3]. The Gene Ontology term GO:0002719, negative regulation of cytokine production involved in immune response, captures the biological processes that stop, prevent, or reduce the frequency, rate, or extent of cytokine production during an immune response [1, 3]. This term is essential for researchers because it defines the checkpoints that keep inflammation self-limited and prevent immunopathology. Mechanistic studies have identified negative regulators that act at transcriptional, post-transcriptional, and signaling levels, including PSMA7, SIRT1, and CD44c [4, 6, 7]. Understanding GO:0002719 therefore provides a framework for interrogating how immune cells balance activation and resolution [1, 3].
negative regulation of cytokine production involved in immune response At A Glance
| GO ID | GO:0002719 |
|---|---|
| GO term | negative regulation of cytokine production involved in immune response |
| Ontology | biological_process |
| Synonym | down regulation of cytokine production during immune response; inhibition of cytokine production during immune response; negative regulation of cytokine secretion involved in immune response |
| Major function | Stops, prevents, or reduces cytokine production during immune responses [1, 3] |
| Biological context | Innate and adaptive immunity, inflammation resolution, and host defense [1, 3] |
| Key regulators | PSMA7, SIRT1, CD44c, DExH/D-box helicases, and chromatin remodeling factors [4, 5, 6, 7, 8] |
| Disease relevance | Chronic inflammation, autoimmunity, and impaired pathogen clearance [2, 3] |
| Research methods | CRISPR screens, cytokine profiling, RNA-seq, proteomics, and imaging [1, 2, 8] |
What Is GO:0002719?
GO:0002719 is defined as any process that stops, prevents, or reduces the frequency, rate, or extent of cytokine production contributing to an immune response [1, 3]. It encompasses negative regulation of cytokine biosynthesis and secretion during immune responses, and it is a biological process term [1, 3]. In practice, this means the term covers molecular events that dampen the production of cytokines such as interferons, interleukins, and tumor necrosis factor in immune cells [1, 3].
Why Is negative regulation of cytokine production involved in immune response Important in Cell Biology?
GO:0002719 is important because uncontrolled cytokine production drives chronic inflammatory diseases, autoimmunity, and tissue damage, while excessive negative regulation can impair pathogen clearance [2, 3]. Defining the negative regulators of cytokine production provides therapeutic targets for inflammatory disorders and helps explain how immune responses are resolved [1, 3]. Moreover, many pathogens and tumors exploit these negative regulatory pathways to evade immunity, making this term central to infection and cancer immunology [4, 5, 7].
• Prevents immunopathology by limiting excessive cytokine production during immune responses [1, 3].
• Controls resolution of inflammation and return to immune homeostasis.
• Dysregulation is associated with periodontitis and other chronic inflammatory conditions.
• Negative regulators such as PSMA7 and SIRT1 modulate innate immune signaling [4, 6].
• Viral and bacterial infections can be influenced by negative regulators like CD44c.
• Chromatin remodeling and RNA polymerase II stalling affect cytokine gene expression in immune cells.
• Provides targets for anti-inflammatory drug discovery [2, 3].
• Helps explain mechanisms of immune evasion by pathogens and tumors [4, 5, 7].
• Guides design of CRISPR screens to identify novel negative regulators [1, 4].
• Supports development of cell models for autoimmune and infectious disease research [1, 6].
What Happens During negative regulation of cytokine production involved in immune response?
Initiation of negative regulation
In simple terms: The immune system first senses a threat, then quickly applies brakes to avoid overreaction.
Negative regulation of cytokine production begins when pattern recognition receptors or cytokine receptors trigger signaling that simultaneously activates feedback inhibitors [1, 3]. For example, plasmacytoid dendritic cells regulate cytokine production through intrinsic checkpoints that prevent excessive interferon secretion. This initiation phase involves recruitment of negative regulators such as PSMA7, which targets MAVS-mediated innate immune signaling.
Transcriptional and chromatin control
In simple terms: The cell controls how tightly cytokine genes are packaged and read.
Chromatin remodeling and RNA polymerase II stalling regulate cytokine gene transcription in immune cells. Negative regulation can occur through changes in chromatin accessibility that reduce transcription of cytokine genes. This step ensures that cytokine production is transient and context-dependent [1, 8].
Post-transcriptional and signaling checkpoints
In simple terms: Even after a cytokine gene is read, the cell can still block the message or protein.
DExH/D-box helicases act at the frontline of intrinsic and innate immunity to modulate cytokine production. SIRT1 negatively regulates the NLRP3 inflammasome in vascular endothelial cells, reducing IL-1beta production. These post-transcriptional and signaling checkpoints provide additional layers of control [5, 6].
Secretion and feedback inhibition
In simple terms: The final amount of cytokine released is tuned by secretion control and feedback loops.
Negative regulation of cytokine secretion involved in immune response is a synonym of GO:0002719, highlighting that secretion is a regulated step [1, 3]. CD44c negatively regulates cytokine production during viral and bacterial infection in fish, demonstrating evolutionary conservation of this process. Feedback inhibition by cytokines themselves, such as IL-10, further dampens production.
Resolution of immune response
In simple terms: Once the threat is controlled, the immune response is shut down to allow healing.
Resolution involves active suppression of cytokine production to restore tissue homeostasis. Periodontal ligament cells regulate pro-inflammatory cytokine production, and failure of this negative regulation contributes to periodontitis. This stage is critical for preventing chronic inflammation [2, 3].
Key Genes Involved in GO:0002719 negative regulation of cytokine production involved in immune response
The following genes and proteins have been experimentally implicated in negative regulation of cytokine production involved in immune response.
| Gene | Major Role | Research Relevance |
|---|---|---|
| PSMA7 | Negative regulator of MAVS-mediated innate immune response | Target for modulating antiviral cytokine production |
| SIRT1 | Inhibits NLRP3 inflammasome and IL-1beta production | Therapeutic target in vascular inflammation |
| CD44c | Negative regulator of cytokine production in viral and bacterial infection | Model for host-pathogen interaction studies |
| MAVS | Adaptor in innate immune signaling, targeted by PSMA7 | Central node in antiviral cytokine regulation |
| NLRP3 | Inflammasome activated by cytokines, inhibited by SIRT1 | Target in inflammatory diseases |
| IL-1beta | Pro-inflammatory cytokine negatively regulated by SIRT1 | Biomarker and therapeutic target |
| IL-10 | Anti-inflammatory cytokine that feedback-inhibits production | Key mediator of immune resolution |
| DExH/D-box helicases | Modulate intrinsic and innate immunity | Potential antiviral targets |
| RNA polymerase II | Stalling regulates cytokine gene transcription | Chromatin-level control of cytokine genes |
| Chromatin remodeling factors | Regulate accessibility of cytokine loci | Epigenetic targets in inflammation |
| Plasmacytoid dendritic cells | Regulate cytokine production through intrinsic checkpoints | Model for interferon regulation |
| Periodontal ligament cells | Regulate pro-inflammatory cytokine production | Model for periodontitis |
| T cells | Subject to positive and negative regulation of immune responses | Model for adaptive immunity |
| Macrophages | Produce cytokines under negative regulation | Model for innate immunity |
| Dendritic cells | Regulate cytokine production during antigen presentation | Model for immune tolerance |
| Endothelial cells | SIRT1 regulates NLRP3 and cytokine production | Model for vascular inflammation |
| Fibroblasts | Contribute to cytokine regulation in tissues | Model for stromal-immune crosstalk |
| Epithelial cells | Regulate cytokine production during infection | Model for mucosal immunity |
How Is negative regulation of cytokine production involved in immune response Regulated?
GO:0002719 is regulated by multiple mechanisms, including feedback inhibition by anti-inflammatory cytokines such as IL-10, post-translational modification of signaling adaptors like MAVS by PSMA7, and epigenetic control through chromatin remodeling and RNA polymerase II stalling [3, 4, 8]. SIRT1 negatively regulates the NLRP3 inflammasome, reducing IL-1beta production in endothelial cells. DExH/D-box helicases also modulate innate immune signaling, adding another layer of regulation. These pathways ensure that cytokine production is transient and proportionate to the threat [1, 3].
negative regulation of cytokine production involved in immune response and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| SIRT1 | Vascular inflammation, atherosclerosis | Endothelial cell knockout and overexpression |
| PSMA7 | Antiviral innate immunity | Macrophage knockout and point mutation |
| CD44c | Bacterial and viral infection | Fish cell lines and in vivo infection models |
| NLRP3 | Inflammasome-driven inflammation | Knock-in reporter for IL-1beta |
| IL-10 | Autoimmunity and immune resolution | Knockout mice and cytokine reporter cells |
Chronic inflammatory diseases
Failure of negative regulation of cytokine production contributes to chronic inflammatory diseases such as periodontitis, where periodontal ligament cells show dysregulated pro-inflammatory cytokine production. Persistent cytokine production drives tissue destruction and disease progression [2, 3].
Autoimmunity
Defects in negative regulation can lead to autoimmunity, as unchecked cytokine production promotes activation of self-reactive immune cells. Positive and negative regulation of cellular immune responses are critical in physiologic conditions and diseases.
Infectious disease
Pathogens can exploit negative regulators to evade immunity; for example, CD44c negatively regulates cytokine production during viral and bacterial infection. Conversely, excessive negative regulation may impair pathogen clearance [4, 5].
Vascular inflammation
SIRT1-mediated negative regulation of the NLRP3 inflammasome in vascular endothelial cells links GO:0002719 to vascular inflammation and atherosclerosis. Loss of SIRT1 activity increases IL-1beta production.
From negative regulation of cytokine production involved in immune response-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does PSMA7 negatively regulate MAVS-mediated cytokine production? | PSMA7 knockout and point mutation in macrophages |
| Does SIRT1 inhibit NLRP3 inflammasome and IL-1beta? | SIRT1 knockout and overexpression in endothelial cells |
| Is CD44c a negative regulator during infection? | CD44c knockout in fish cell lines |
| How does chromatin remodeling affect cytokine genes? | Knock-in of tagged RNA polymerase II and chromatin factors |
| What is the role of DExH/D-box helicases in innate immunity? | Knockout and overexpression in immune cells |
| How do plasmacytoid dendritic cells regulate interferon? | Knockout of intrinsic checkpoints in pDCs |
How to Study the negative regulation of cytokine production involved in immune response Process
| Method | What It Measures | Typical Application |
|---|---|---|
| ELISA | Secreted cytokine levels | Validation of negative regulators |
| RNA-seq | Cytokine gene expression [1, 8] | Transcriptional profiling |
| Proteomics | Protein interactions and modifications [4, 6] | Mechanism of PSMA7 and SIRT1 [4, 6] |
| Immunoblotting | Protein abundance and phosphorylation [4, 6] | Signaling checkpoint analysis |
| Flow cytometry | Immune cell activation and cytokine production [1, 3] | Single-cell immune profiling |
| Imaging | Cellular localization and interactions [1, 3] | pDC and T cell studies |
| CRISPR screen | Identification of negative regulators [1, 4] | Functional genomics |
| Chromatin immunoprecipitation | RNA polymerase II stalling | Epigenetic regulation |
Cytokine profiling
Cytokine profiling by ELISA or multiplex assays measures the output of GO:0002719 and is used to quantify changes in IL-1beta, TNF, and interferons [2, 6]. This method is standard for validating negative regulators in cell models.
Transcriptomics and RNA-seq
RNA-seq measures cytokine gene expression and reveals transcriptional changes upon knockout or overexpression of negative regulators [1, 8]. It is used to identify pathways controlled by GO:0002719.
Proteomics and immunoblotting
Proteomics and immunoblotting detect post-translational modifications and protein interactions, such as PSMA7-MAVS and SIRT1-NLRP3 [4, 6]. These methods confirm molecular mechanisms [4, 6].
Imaging and flow cytometry
Imaging and flow cytometry visualize immune cell activation and cytokine secretion at single-cell resolution [1, 3]. They are used to study plasmacytoid dendritic cells and T cell responses [1, 3].
How CRISPR Can Be Used to Study GO:0002719 negative regulation of cytokine production involved in immune response
Knockout
CRISPR knockout of candidate negative regulators such as PSMA7 or SIRT1 can test whether loss of function increases cytokine production during immune responses [4, 6]. Knockout models are essential for causal inference in GO:0002719 research [4, 6].
Point Mutation
Point mutation knock-in can dissect specific residues required for negative regulation, such as catalytic sites in SIRT1 or ubiquitin-interacting domains in PSMA7 [4, 6]. These models reveal mechanistic details without confounding effects of complete protein loss [4, 6].
Knock-in
Knock-in of reporters or tags allows real-time monitoring of cytokine production and regulator localization [1, 8]. Tagged knock-in of RNA polymerase II or chromatin factors can reveal stalling dynamics at cytokine loci.
Overexpression
Overexpression of negative regulators such as CD44c or SIRT1 can suppress cytokine production and validate their function in immune cells [6, 7]. Overexpression models are useful for testing therapeutic potential [6, 7].
How EDITGENE Supports negative regulation of cytokine production involved in immune response Research
Researchers studying negative regulation of cytokine production involved in immune response-related genes often need to determine whether a candidate gene is causally involved in dampening cytokine output, and CRISPR-based models provide the most direct way to test this.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of cytokine production involved in immune response research.
Frequently Asked Questions About negative regulation of cytokine production involved in immune response
What is GO:0002719?
GO:0002719 is the Gene Ontology term for negative regulation of cytokine production involved in immune response, describing processes that stop, prevent, or reduce cytokine production during an immune response [1, 3].
What genes are involved in negative regulation of cytokine production involved in immune response?
Key genes include PSMA7, SIRT1, CD44c, MAVS, NLRP3, and DExH/D-box helicases, which act at different checkpoints [4, 5, 6, 7].
Why is negative regulation of cytokine production important?
It prevents immunopathology and chronic inflammation while allowing effective pathogen clearance [2, 3].
What diseases are linked to defective negative regulation of cytokine production?
Chronic inflammatory diseases such as periodontitis, autoimmunity, and vascular inflammation are linked to defective negative regulation [2, 3, 6].
How do PSMA7 and SIRT1 negatively regulate cytokine production?
PSMA7 targets MAVS-mediated innate immune signaling, while SIRT1 inhibits the NLRP3 inflammasome and IL-1beta production [4, 6].
What methods are used to study GO:0002719?
Methods include cytokine profiling, RNA-seq, proteomics, imaging, flow cytometry, and CRISPR screens [1, 2, 8].
Can CRISPR knockout models be used to study negative regulation of cytokine production?
Yes, CRISPR knockout of candidate genes such as PSMA7 or SIRT1 can test whether loss of function increases cytokine production [4, 6].
What is the role of chromatin remodeling in cytokine production?
Chromatin remodeling and RNA polymerase II stalling regulate transcription of cytokine genes in immune cells.
How do DExH/D-box helicases affect innate immunity?
DExH/D-box helicases act at the frontline of intrinsic and innate immunity to modulate cytokine production.
What cell models are available for studying GO:0002719?
EDITGENE provides knockout, point mutation, knock-in, and overexpression cell models for genes involved in this process [1, 4, 6].
Conclusion
GO:0002719, negative regulation of cytokine production involved in immune response, is a critical biological process that maintains immune homeostasis and prevents inflammatory disease [1, 3]. Mechanistic studies have identified diverse negative regulators, including PSMA7, SIRT1, and CD44c, that act at transcriptional, post-transcriptional, and signaling levels [4, 6, 7]. CRISPR-based models and integrated omics methods provide powerful tools to dissect these pathways and identify therapeutic targets [1, 4, 8].
References
- 1. Reizis B. 2019. Plasmacytoid Dendritic Cells: Development, Regulation, and Function.. Immunity 50(1):37-50 PMID: 30650380
- 2. Nilsson BO. 2021. Mechanisms involved in regulation of periodontal ligament cell production of pro-inflammatory cytokines: Implications in periodontitis.. J Periodontal Res 56(2):249-255 PMID: 33305420
- 3. Viganò S et al.. 2012. Positive and negative regulation of cellular immune responses in physiologic conditions and diseases.. Clin Dev Immunol 2012:485781 PMID: 22548114
- 4. Jia Y et al.. 2009. Negative regulation of MAVS-mediated innate immune response by PSMA7.. J Immunol 183(7):4241-8 PMID: 19734229
- 5. Bonaventure B et al.. 2022. DExH/D-box helicases at the frontline of intrinsic and innate immunity against viral infections.. J Gen Virol 103(8) PMID: 36006669
- 6. Li Y et al.. 2017. Negative regulation of NLRP3 inflammasome by SIRT1 in vascular endothelial cells.. Immunobiology 222(3):552-561 PMID: 27908642
- 7. Cao L et al.. 2019. The negative regulation of piscine CD44c in viral and bacterial infection.. Dev Comp Immunol 96:135-143 PMID: 30885554
- 8. Wang Z et al.. 2019. Regulation of chromatin remodeling through RNA polymerase II stalling in the immune system.. Mol Immunol 108:75-80 PMID: 30784765
