GO:0032694 negative regulation of interleukin-11 production: Cytokine Control, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0032694 describes any process that stops, prevents, or reduces the frequency, rate, or extent of interleukin-11 (IL-11) production.
• IL-11 is a pleiotropic cytokine involved in hematopoiesis, thrombopoiesis, inflammation, and tissue remodeling [1,4].
• IL-6 is a key negative regulator of IL-11 production in vitro and in vivo, establishing a cytokine feedback loop.
• The transcription factor KLF15 suppresses IL-11 expression in adventitial fibroblasts via ERK1/2-dependent mechanisms.
• Dysregulated IL-11 production is implicated in thrombocytopenia, hypertension-associated vascular remodeling, and cancer [4,7,8].
• CRISPR-based knockout, knock-in, and overexpression models enable causal dissection of negative regulatory pathways controlling IL-11.
Description
Interleukin-11 (IL-11) is a member of the IL-6 family of cytokines that plays critical roles in hematopoiesis, thrombopoiesis, inflammation, and tissue remodeling [1,4]. The production of IL-11 is tightly controlled at multiple levels, and its dysregulation contributes to a range of pathological conditions including thrombocytopenia, chronic inflammation, and fibrosis [4,7,8]. The Gene Ontology term GO:0032694, negative regulation of interleukin-11 production, captures the biological processes that suppress the synthesis or secretion of this cytokine. Understanding these regulatory mechanisms is essential for researchers investigating cytokine networks, hematopoietic disorders, and inflammatory diseases. This article synthesizes current knowledge on the negative regulation of IL-11 production, drawing on authoritative QuickGO annotations and verified PubMed literature to provide a research-grade overview for experimental design and therapeutic targeting.
negative regulation of interleukin-11 production At A Glance
| GO ID | GO:0032694 |
|---|---|
| GO term | negative regulation of interleukin-11 production |
| Ontology | biological_process |
| Synonym | inhibition of interleukin-11 production; negative regulation of IL-11 production; negative regulation of interleukin-11 biosynthetic process; negative regulation of interleukin-11 secretion |
| Major function | Suppression of IL-11 cytokine synthesis and/or release |
| Related cytokine | Interleukin-11 (IL-11) |
| Key negative regulators | IL-6, KLF15, ERK1/2 signaling [7,8] |
| Associated diseases | Thrombocytopenia, hypertension-induced vascular remodeling, inflammation [4,7,8] |
What Is GO:0032694?
GO:0032694 (negative regulation of interleukin-11 production) is a biological process term defined as any process that stops, prevents, or reduces the frequency, rate, or extent of interleukin-11 production. This encompasses transcriptional, post-transcriptional, and secretory mechanisms that downregulate the biosynthesis or release of IL-11. The term includes synonyms such as inhibition of IL-11 production, negative regulation of IL-11 biosynthetic process, and negative regulation of IL-11 secretion, reflecting the multi-level control of this cytokine.
Why Is negative regulation of interleukin-11 production Important in Cell Biology?
The negative regulation of IL-11 production is critical for maintaining immune homeostasis and preventing pathological cytokine overproduction. IL-11 is a pleiotropic cytokine that stimulates platelet production and acute-phase responses, but excessive or sustained IL-11 activity contributes to thrombocytosis, chronic inflammation, and tissue fibrosis [1,4,7]. Understanding the mechanisms that suppress IL-11 production provides insights into normal hematopoiesis and offers therapeutic targets for diseases characterized by cytokine dysregulation. For example, IL-6-mediated suppression of IL-11 production represents a negative feedback loop that may be exploited to modulate inflammatory responses. Similarly, KLF15-dependent inhibition of IL-11 in adventitial fibroblasts links mechanical stress and hypertension to vascular remodeling. Thus, GO:0032694 is a focal point for research at the intersection of immunology, hematology, and cardiovascular biology.
• Maintains immune homeostasis by preventing excessive IL-11-driven inflammation.
• Regulates platelet production and thrombopoiesis, with implications for thrombocytopenia [1,4].
• Modulates vascular remodeling in hypertension via KLF15-IL-11 axis.
• Provides a negative feedback mechanism through IL-6 to control cytokine storms.
• Influences T-cell proliferation and p27(kip1) downregulation.
• Impacts adipose tissue biology and preadipocyte differentiation.
• Relevant to endometriosis-associated aromatase expression.
• Potential target for anti-fibrotic and anti-inflammatory therapies.
• Guides CRISPR-based functional genomics of cytokine regulatory networks.
• Enables development of cell models for cytokine production studies.
What Happens During negative regulation of interleukin-11 production?
Initiation by Negative Regulators
In simple terms: Certain molecules tell the cell to stop making IL-11.
Negative regulation of IL-11 production is initiated by extracellular or intracellular signals that activate repressive pathways. IL-6 has been shown to negatively regulate IL-11 production both in vitro and in vivo, establishing a cytokine-mediated feedback mechanism. In vascular smooth muscle cells, angiotensin II-induced hypertension triggers KLF15 expression, which subsequently suppresses IL-11 production. These initiators set off signaling cascades that converge on transcriptional or post-transcriptional control of the IL-11 gene (IL11).
Signal Transduction and Transcription Factor Activation
In simple terms: Signals are relayed inside the cell to switch on repressor proteins.
Upon initiation, intracellular signaling pathways such as the extracellular signal-regulated kinase (ERK) cascade are activated. In angiotensin II-induced hypertension, KLF15-mediated suppression of IL-11 depends on ERK1/2 activation. This suggests that phosphorylation events and transcription factor activation are critical steps in the negative regulation of IL-11 production. The activated transcription factors then bind to regulatory elements in the IL11 promoter or enhancer regions to repress transcription.
Transcriptional Repression of IL11
In simple terms: The gene for IL-11 is turned down or off.
Transcriptional repression is a central mechanism for reducing IL-11 production. KLF15 acts as a transcriptional repressor that directly or indirectly inhibits IL11 gene expression in adventitial fibroblasts. Similarly, IL-6-mediated negative regulation likely involves transcriptional changes, although the exact transcription factors remain to be fully elucidated. This step reduces the amount of IL11 mRNA available for translation.
Post-transcriptional and Secretory Control
In simple terms: Even if some mRNA is made, the cell can block its translation or stop releasing the protein.
Beyond transcription, negative regulation can occur at post-transcriptional levels, including mRNA stability and translational efficiency. The GO term includes negative regulation of IL-11 secretion, indicating that the export of IL-11 protein can also be suppressed [QuickGO]. While specific mechanisms are less characterized, general principles of cytokine regulation suggest that microRNAs or RNA-binding proteins may play roles. This multi-layered control ensures robust suppression of IL-11 production.
Feedback and Crosstalk with Other Cytokines
In simple terms: Other cytokines can tell the cell to make less IL-11.
IL-6 negatively regulates IL-11 production, demonstrating cytokine crosstalk. This feedback loop may prevent excessive IL-11 activity during inflammation. Additionally, tumor necrosis factor-alpha (TNF-alpha) induces IL-6 production via ERK1 activation in breast cancer cells, indirectly linking inflammatory signals to IL-11 suppression. Such crosstalk fine-tunes the overall cytokine milieu.
Key Genes Involved in GO:0032694 negative regulation of interleukin-11 production
The following genes and proteins are experimentally implicated in the negative regulation of interleukin-11 production or related cytokine pathways.
| Gene | Major Role | Research Relevance |
|---|---|---|
| IL6 | Negatively regulates IL-11 production in vitro and in vivo | Cytokine feedback loop; inflammation models |
| KLF15 | Transcription factor that suppresses IL-11 in adventitial fibroblasts | Hypertension and vascular remodeling |
| IL11 | Target gene whose production is negatively regulated [1,7,8] | Thrombopoiesis, fibrosis, inflammation |
| ERK1 (MAPK3) | Kinase involved in KLF15-mediated IL-11 suppression | Signal transduction studies |
| ERK2 (MAPK1) | Kinase involved in KLF15-mediated IL-11 suppression | Signal transduction studies |
| TNF | Induces IL-6, indirectly affecting IL-11 | Breast cancer inflammation |
| THPO | Thrombopoietin, co-regulated with IL-11 during thrombocytopenia | Platelet production |
| CDKN1B (p27) | Downregulated by IL-11 in T-cells | T-cell proliferation |
| CYP19A1 (aromatase) | Expressed in endometriosis; IL-11 may influence | Endometriosis biology |
| PREF1 (DLK1) | Preadipocyte factor-1, regulated during differentiation | Adipogenesis |
| STAT3 | Downstream of IL-6 family cytokines; potential mediator | Cytokine signaling |
| SOCS3 | Feedback inhibitor of cytokine signaling; may affect IL-11 | Negative feedback |
| NF-κB | Inflammatory transcription factor; crosstalk with IL-6 | Inflammation |
| AP-1 | Transcription factor downstream of ERK | Hypertension signaling |
| GATA | Potential transcription factor in megakaryopoiesis | Platelet production |
| RUNX1 | Transcription factor in hematopoiesis; may regulate IL11 | Thrombocytopenia |
| miRNAs (e.g., miR-1) | Potential post-transcriptional regulators | Fine-tuning of IL-11 |
How Is negative regulation of interleukin-11 production Regulated?
The negative regulation of IL-11 production is itself controlled by upstream signaling pathways. IL-6 acts as a direct negative regulator, likely through activation of STAT3 and subsequent induction of SOCS proteins. In hypertension, angiotensin II activates ERK1/2, which in turn promotes KLF15-mediated repression of IL-11. Additionally, TNF-alpha-induced ERK1 activation in breast cancer cells leads to IL-6 production, which may subsequently suppress IL-11. These interconnected pathways form a regulatory network that adjusts IL-11 levels according to physiological context.
negative regulation of interleukin-11 production and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| IL6 | Inflammation, cytokine storm | IL6 knockout mice; LPS-induced inflammation |
| KLF15 | Hypertension, vascular remodeling | KLF15 knockout mice; angiotensin II infusion |
| IL11 | Thrombocytopenia, fibrosis | IL11 knockout or transgenic mice; platelet counts |
| TNF | Breast cancer, inflammation | TNF knockout mice; breast cancer xenografts |
| CDKN1B | T-cell proliferation, autoimmunity | p27 knockout T-cells; proliferation assays |
Thrombocytopenia and Platelet Disorders
IL-11 is a thrombopoietic cytokine that stimulates platelet production [1,4]. Negative regulation of IL-11 production is crucial to prevent excessive platelet counts, but in thrombocytopenia, impaired IL-11 production may exacerbate low platelet levels. Studies show that endogenous levels of thrombopoietin and IL-11 are differentially regulated during thrombocytopenia, providing insight into platelet production control. Therapies aimed at increasing platelet production often target these pathways.
Hypertension and Vascular Remodeling
KLF15-mediated negative regulation of IL-11 in adventitial fibroblasts depends on ERK1/2 activation and is critical in angiotensin II-induced hypertension. Loss of this negative regulation leads to increased IL-11 production, promoting adventitial remodeling and vascular stiffness. This axis represents a potential therapeutic target for hypertension and associated cardiovascular diseases.
Inflammation and Cancer
IL-6 negatively regulates IL-11 production, and dysregulation of this feedback loop can contribute to chronic inflammation. In breast cancer cells, TNF-alpha induces IL-6 via ERK1, which may indirectly suppress IL-11. IL-11 itself promotes T-cell proliferation and downregulates p27(kip1), linking it to immune responses and potentially cancer progression. Understanding negative regulation may reveal strategies to modulate tumor microenvironment.
Endometriosis and Adipose Biology
IL-11 and related cytokines may influence aromatase expression in endometriosis and preadipocyte differentiation. Negative regulation of IL-11 production could therefore impact estrogen biosynthesis and adipose tissue development, though direct evidence is limited.
From negative regulation of interleukin-11 production-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does IL6 negatively regulate IL11 in vivo? | IL6 knockout mouse; measure IL-11 levels |
| Is KLF15 required for IL-11 suppression in hypertension? | KLF15 knockout mouse; angiotensin II treatment |
| Does ERK1/2 mediate KLF15-dependent IL-11 repression? | ERK1/2 double knockout or chemical inhibitors |
| What is the role of IL-11 in thrombopoiesis? | IL11 knockout mouse; platelet recovery after thrombocytopenia |
| Can overexpression of KLF15 reduce IL-11 production? | KLF15 overexpression in adventitial fibroblasts |
| Does a point mutation in IL11 promoter affect KLF15 binding? | CRISPR knock-in of promoter mutation in cell lines |
How to Study the negative regulation of interleukin-11 production Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Global transcriptome changes | Identify IL11 mRNA downregulation |
| qPCR | Specific mRNA levels | Validate IL11 repression |
| ELISA | Secreted IL-11 protein | Quantify cytokine production |
| Western blot | Intracellular IL-11 and signaling proteins | Assess protein levels and phosphorylation |
| Phospho-ERK immunoassay | ERK1/2 activation status | Link signaling to IL-11 suppression |
| CRISPR knockout screen | Genes affecting IL-11 production | Discover novel negative regulators |
| Luciferase reporter assay | IL11 promoter activity | Test transcriptional repression |
Transcriptional Profiling (RNA-seq, qPCR)
RNA sequencing and quantitative PCR are used to measure IL11 mRNA levels following experimental manipulation. These methods help identify transcriptional changes induced by negative regulators such as IL-6 or KLF15 [7,8]. They are essential for confirming that negative regulation occurs at the mRNA level.
Protein Quantification (ELISA, Western Blot)
ELISA and Western blot quantify secreted and intracellular IL-11 protein. These techniques validate that changes in mRNA translate to altered protein production. They are particularly useful for assessing negative regulation of IL-11 secretion [QuickGO].
Signaling Pathway Analysis (Phospho-ERK, Inhibitors)
Phospho-specific antibodies and pharmacological inhibitors (e.g., MEK inhibitors) are used to dissect ERK1/2 involvement in KLF15-mediated IL-11 suppression. This approach identifies upstream kinases and their contribution to negative regulation.
CRISPR-Based Genetic Screens
Genome-wide CRISPR knockout or activation screens can identify novel negative regulators of IL-11 production. By coupling IL-11 reporter systems with sgRNA libraries, researchers can uncover genes whose loss or gain alters IL-11 levels. This unbiased approach is powerful for discovering new components of GO:0032694.
How CRISPR Can Be Used to Study GO:0032694 negative regulation of interleukin-11 production
Knockout
CRISPR knockout of candidate negative regulators (e.g., IL6, KLF15) can be used to test whether their loss increases IL-11 production. For example, KLF15 knockout in adventitial fibroblasts would be expected to abolish angiotensin II-induced IL-11 suppression. Similarly, IL6 knockout mice show altered IL-11 levels. Knockout models provide causal evidence for gene function in GO:0032694.
Point Mutation
Point mutations can be introduced into regulatory elements of the IL11 gene or into signaling proteins to dissect specific phosphorylation sites. For instance, mutating ERK1/2 phosphorylation sites in KLF15 could test their requirement for IL-11 repression. CRISPR base editing enables precise single-nucleotide changes without indels.
Knock-in
Knock-in of reporter genes (e.g., luciferase or GFP) into the IL11 locus allows real-time monitoring of IL-11 production. Additionally, knock-in of epitope tags on KLF15 or IL-6 facilitates protein interaction studies. These models are valuable for high-throughput screening of negative regulators.
Overexpression
CRISPR activation (CRISPRa) or lentiviral overexpression can drive high-level expression of candidate negative regulators such as KLF15 or IL-6. Overexpression of KLF15 in fibroblasts is expected to suppress IL-11 production even under stimulatory conditions. This approach confirms sufficiency of a gene to mediate negative regulation.
How EDITGENE Supports negative regulation of interleukin-11 production Research
Researchers studying negative regulation of interleukin-11 production-related genes often need to determine whether a candidate gene is causally involved in suppressing IL-11 synthesis or secretion. EDITGENE provides comprehensive CRISPR-based services to generate precisely engineered cell models, enabling functional validation of genes within GO:0032694.
Contact EDITGENE today to design your custom CRISPR model for negative regulation of interleukin-11 production research.
Frequently Asked Questions About negative regulation of interleukin-11 production
What is negative regulation of interleukin-11 production?
It is a biological process (GO:0032694) that stops, prevents, or reduces the frequency, rate, or extent of interleukin-11 production, including its biosynthesis and secretion.
What genes are involved in negative regulation of interleukin-11 production?
Key genes include IL6, which negatively regulates IL-11 in vitro and in vivo, and KLF15, which suppresses IL-11 in adventitial fibroblasts via ERK1/2. Other potential regulators include SOCS3 and miRNAs.
How is IL-11 production negatively regulated?
IL-6 and KLF15 are known negative regulators. IL-6 acts through cytokine feedback, while KLF15 represses IL11 transcription in an ERK1/2-dependent manner. Post-transcriptional and secretory control also contribute.
What diseases are associated with dysregulated IL-11 production?
Thrombocytopenia, hypertension-induced vascular remodeling, inflammation, and cancer have been linked to altered IL-11 regulation [1,4,7,8].
What is the role of KLF15 in IL-11 regulation?
KLF15 is a transcription factor that suppresses IL-11 production in adventitial fibroblasts during angiotensin II-induced hypertension, depending on ERK1/2 activation.
Does IL-6 inhibit IL-11 production?
Yes, IL-6 negatively regulates IL-11 production both in vitro and in vivo, as demonstrated in endocrine studies.
How can CRISPR be used to study negative regulation of IL-11 production?
CRISPR knockout, knock-in, point mutation, and overexpression models allow causal testing of candidate genes. For example, knocking out KLF15 would test its requirement for IL-11 suppression.
What methods measure IL-11 production?
ELISA, Western blot, qPCR, RNA-seq, and luciferase reporter assays are commonly used to quantify IL-11 mRNA, protein, or promoter activity.
Is IL-11 production regulated at the transcriptional level?
Yes, transcriptional repression by factors like KLF15 is a key mechanism. Post-transcriptional and secretory control also occur.
What cell models are available for studying IL-11 negative regulation?
EDITGENE offers custom knockout, point mutation, knock-in, and overexpression cell models for genes in the IL-11 regulatory network, as well as CRISPR library screening.
Conclusion
GO:0032694 (negative regulation of interleukin-11 production) is a critical biological process that maintains cytokine homeostasis and prevents pathological IL-11 overproduction. Key regulators such as IL-6 and KLF15 have been identified through in vitro and in vivo studies [7,8]. Dysregulation of this process contributes to thrombocytopenia, hypertension, inflammation, and cancer. Advances in CRISPR-based genome editing now enable precise functional dissection of these regulatory pathways. EDITGENE provides comprehensive services to support researchers in modeling and understanding the negative regulation of IL-11 production.
References
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- 2. Curti A et al.. 2002. Interleukin-11 induces proliferation of human T-cells and its activity is associated with downregulation of p27(kip1).. Haematologica 87(4):373-80 PMID: 11940481
- 3. Noble LS et al.. 1996. Aromatase expression in endometriosis.. J Clin Endocrinol Metab 81(1):174-9 PMID: 8550748
- 4. Peeters K et al.. 2008. Emerging treatments for thrombocytopenia: increasing platelet production.. Drug Discov Today 13(17-18):798-806 PMID: 18602017
- 5. Boney CM et al.. 1996. Regulation of preadipocyte factor-1 gene expression during 3T3-L1 cell differentiation.. Endocrinology 137(7):2923-8 PMID: 8770915
- 6. Suarez-Cuervo C et al.. 2003. Tumor necrosis factor-alpha induces interleukin-6 production via extracellular-regulated kinase 1 activation in breast cancer cells.. Breast Cancer Res Treat 80(1):71-8 PMID: 12889600
- 7. Nakchbandi IA et al.. 2001. IL-6 negatively regulates IL-11 production in vitro and in vivo.. Endocrinology 142(9):3850-6 PMID: 11517162
- 8. Guo YT et al.. 2021. Krüppel-Like Factor 15/Interleukin 11 Axis-Mediated Adventitial Remodeling Depends on Extracellular Signal-Regulated Kinases 1 and 2 Activation in Angiotensin II-Induced Hypertension.. J Am Heart Assoc 10(16):e020554 PMID: 34350769
