GO:0140105 interleukin-10-mediated signaling pathway: Mechanism, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0140105 describes the molecular signaling cascade triggered when interleukin-10 (IL-10) binds its receptor on the cell surface, leading to regulation of downstream cellular processes such as transcription.
• The pathway is a master anti-inflammatory circuit that suppresses free radical generation in macrophages and limits immunopathology during infection.
• STAT3 is the central transcription factor activated downstream of the IL-10 receptor, and fibroblast-specific STAT3 signaling mediates regenerative tissue repair via hyaluronan metabolism.
• Pathogens can exploit IL-10 signaling to evade immunity; Yersinia V-antigen uses TLR2 and CD14 to induce IL-10-mediated immunosuppression, and Helicobacter pylori blocks dendritic cell maturation through IL-10-mediated STAT3 activation.
• IL-10 signaling also regulates B-1 B-cell autoregulation and contributes to lymphopenia during acute viral infection.
• CRISPR-based knockout, knock-in, and overexpression models are essential to dissect causal roles of IL-10 pathway components in inflammation, infection, and tissue repair.
Description
Interleukin-10 (IL-10) is a pleiotropic cytokine that plays a central role in limiting inflammatory responses and maintaining tissue homeostasis. The Gene Ontology term GO:0140105, interleukin-10-mediated signaling pathway, captures the series of molecular signals initiated by IL-10 binding to its receptor on the surface of a target cell and ending with regulation of a downstream cellular process, such as transcription. This pathway is highly conserved and is critical for preventing excessive inflammation while permitting effective pathogen clearance. Dysregulation of IL-10 signaling is associated with a broad spectrum of pathologies, including chronic infections, autoimmune disorders, and impaired tissue regeneration. Understanding the precise molecular events downstream of IL-10 receptor engagement is therefore essential for researchers in immunology, infectious disease, and regenerative medicine. The pathway is also a prime target for therapeutic modulation, as pathogens often hijack it to suppress host immunity. This article provides a research-grade overview of GO:0140105, integrating authoritative QuickGO annotation with real PubMed literature. We cover the core signaling stages, key genes and proteins, regulatory mechanisms, disease relevance, and state-of-the-art experimental methods, including CRISPR-based models, to support publication-ready investigations.
interleukin-10-mediated signaling pathway At A Glance
| GO ID | GO:0140105 |
|---|---|
| GO term | interleukin-10-mediated signaling pathway |
| Ontology | biological_process |
| Synonym | IL-10-mediated signaling pathway; interleukin-10-mediated signalling pathway |
| Major function | Transduces IL-10 signals from the cell surface to the nucleus, typically activating STAT3 and regulating anti-inflammatory and regenerative gene programs. |
| Key receptor | IL-10 receptor complex (IL10RA/IL10RB). |
| Major transcription factor | STAT3. |
| Physiological outcomes | Suppression of free radical generation, inhibition of dendritic cell maturation, B-1 B-cell autoregulation, and regenerative tissue repair. |
| Pathogen exploitation | Yersinia V-antigen and Helicobacter pylori exploit IL-10 signaling for immunosuppression. |
What Is GO:0140105?
GO:0140105, interleukin-10-mediated signaling pathway, is defined as the series of molecular signals initiated by interleukin-10 binding to its receptor on the surface of a target cell, and ending with the regulation of a downstream cellular process, e.g. transcription. In simpler terms, it is the entire communication line that starts when IL-10 docks onto its receptor and finishes with changes in gene expression or other cellular responses.
Why Is interleukin-10-mediated signaling pathway Important in Cell Biology?
The interleukin-10-mediated signaling pathway is a central brake on inflammation and a key driver of tissue repair, making it indispensable for host survival during infection and for preventing autoimmune pathology. Its dysregulation contributes to chronic infections, inflammatory diseases, and impaired regeneration, and it is a major mechanism by which pathogens evade immunity. Consequently, understanding GO:0140105 is critical for developing therapies that modulate inflammation without compromising host defense.
• Controls macrophage free radical generation, limiting oxidative tissue damage.
• Regulates dendritic cell maturation, influencing adaptive immune responses.
• Mediates regenerative postnatal tissue repair via fibroblast-specific STAT3 signaling and hyaluronan metabolism.
• Autoregulates B-1 B-cells, impacting innate-like B-cell homeostasis.
• Contributes to lymphopenia during acute viral infection, affecting disease severity.
• Is exploited by Yersinia V-antigen to suppress host immunity via TLR2 and CD14.
• Is subverted by Helicobacter pylori to block dendritic cell maturation through STAT3 activation.
• Represents a therapeutic target for inflammatory bowel disease, arthritis, and other chronic inflammatory conditions.
• Plays a role in cancer immunology by shaping the tumor microenvironment.
• Provides a paradigm for studying cytokine receptor signaling and negative feedback regulation.
What Happens During interleukin-10-mediated signaling pathway?
IL-10 Binding and Receptor Activation
In simple terms: IL-10 acts like a key that fits into a specific lock on the cell surface, called the IL-10 receptor.
The pathway begins when interleukin-10 binds to its heterodimeric receptor complex composed of IL10RA and IL10RB subunits on the target cell surface. This binding induces receptor oligomerization and activation of associated Janus kinases (JAKs), which phosphorylate the receptor intracellular domains. The QuickGO definition explicitly states that the series of molecular signals is initiated by interleukin-10 binding to its receptor.
JAK-STAT3 Signal Transduction
In simple terms: Once the receptor is activated, it turns on a messenger called STAT3 that travels to the nucleus to switch genes on or off.
Phosphorylated receptor tyrosines recruit STAT3, which is then phosphorylated by JAKs. Phosphorylated STAT3 dimerizes and translocates to the nucleus to regulate transcription of target genes. This STAT3 activation is a hallmark of IL-10 signaling and is required for many of its downstream effects, including inhibition of dendritic cell maturation by Helicobacter pylori and regenerative tissue repair.
Suppression of Inflammatory Mediators
In simple terms: The pathway puts the brakes on inflammation by reducing harmful molecules like free radicals.
IL-10-mediated signaling inhibits the generation of free radicals in macrophages, thereby limiting oxidative stress and tissue damage. This anti-inflammatory action is a key physiological outcome of the pathway and is dependent on STAT3 activation.
Regulation of Cell Survival and Autoregulation
In simple terms: The pathway also helps certain immune cells regulate themselves and survive.
In murine B-1 B-cells, IL-10-mediated signaling provides autoregulation, influencing B-cell homeostasis and responses during infection with Borrelia hermsii. Additionally, IL-10 signaling can induce lymphopenia during acute infection with foot-and-mouth disease virus in mice, highlighting its role in lymphocyte dynamics.
Tissue Repair and Regeneration
In simple terms: IL-10 signaling helps tissues heal after damage by controlling how cells build the matrix around them.
IL-10-mediated regenerative postnatal tissue repair depends on regulation of hyaluronan metabolism via fibroblast-specific STAT3 signaling. This demonstrates that the pathway extends beyond immune suppression to actively promote tissue remodeling and repair.
Key Genes Involved in GO:0140105 interleukin-10-mediated signaling pathway
The following genes and proteins are central to the interleukin-10-mediated signaling pathway, based on published literature and QuickGO annotations.
| Gene | Major Role | Research Relevance |
|---|---|---|
| IL10 | Ligand that initiates the pathway by binding to its receptor | Knockout models show exacerbated inflammation; overexpression used to study anti-inflammatory effects. |
| IL10RA | Alpha subunit of the IL-10 receptor; binds IL-10 | Mutations cause early-onset inflammatory bowel disease; target for CRISPR knock-in. |
| IL10RB | Beta subunit of the IL-10 receptor; shared with other cytokine receptors | Essential for signal transduction; knockout abolishes IL-10 responses. |
| STAT3 | Transcription factor activated downstream of IL-10 receptor; mediates anti-inflammatory and regenerative effects | Central node; knockout is lethal; conditional knockouts reveal tissue-specific roles. |
| JAK1 | Janus kinase that phosphorylates STAT3 upon receptor activation | Target for point mutations to dissect kinase activity. |
| TYK2 | Janus kinase associated with IL-10 receptor complex | Modulates signaling strength; knockout affects IL-10 responses. |
| SOCS3 | Negative feedback regulator of IL-10 signaling; inhibits JAK-STAT | Overexpression suppresses IL-10 signaling; knockout enhances it. |
| TLR2 | Toll-like receptor involved in Yersinia V-antigen-mediated IL-10 induction | Knockout reduces IL-10-mediated immunosuppression. |
| CD14 | Co-receptor for TLR2; required for Yersinia V-antigen-induced IL-10 | Knockout impairs IL-10 production. |
| HYAL1 | Hyaluronan synthase involved in hyaluronan metabolism during tissue repair | Regulated by IL-10-STAT3; knockout affects regeneration. |
| HYAL2 | Hyaluronidase involved in hyaluronan turnover | Modulated by IL-10 signaling in fibroblasts. |
| HAS1 | Hyaluronan synthase; produces hyaluronan | Target of STAT3; affects tissue repair. |
| HAS2 | Hyaluronan synthase; produces hyaluronan | Regulated by IL-10 in regenerative contexts. |
| B1 B-cell markers (e.g., CD5) | Markers of B-1 B-cells that undergo IL-10-mediated autoregulation | Used to study B-1 B-cell homeostasis. |
| FMDV proteins | Viral factors that induce IL-10-mediated lymphopenia | Infection models to study lymphocyte depletion. |
| H. pylori factors | Bacterial factors that activate IL-10-mediated STAT3 in dendritic cells | Infection models to study immune evasion. |
How Is interleukin-10-mediated signaling pathway Regulated?
The interleukin-10-mediated signaling pathway is tightly regulated by negative feedback mechanisms. SOCS3 is a key suppressor that inhibits JAK-STAT3 signaling downstream of the IL-10 receptor, preventing excessive anti-inflammatory responses. Additionally, the pathway can be modulated by other cytokines and pathogen-derived factors; for example, Yersinia V-antigen exploits TLR2 and CD14 to induce IL-10-mediated immunosuppression, while Helicobacter pylori activates STAT3 through IL-10 to block dendritic cell maturation. These regulatory layers ensure context-dependent outcomes and are critical for maintaining immune balance.
interleukin-10-mediated signaling pathway and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| IL10 | Inflammatory bowel disease; impaired tissue repair | IL10 knockout mouse; CRISPR knockout in human cell lines. |
| STAT3 | Chronic infection; autoimmunity; impaired regeneration | Conditional STAT3 knockout in fibroblasts; knock-in of phospho-mimetic. |
| TLR2 | Yersinia infection; immunosuppression | TLR2 knockout mouse; CRISPR knockout in macrophages. |
| CD14 | Yersinia infection; immunosuppression | CD14 knockout mouse; overexpression in cell lines. |
| IL10RA | Early-onset inflammatory bowel disease | Patient-derived iPSCs with point mutations; CRISPR correction. |
Infectious Diseases and Immune Evasion
Pathogens frequently exploit the interleukin-10-mediated signaling pathway to suppress host immunity. Yersinia V-antigen uses TLR2 and CD14 to induce IL-10-mediated immunosuppression, allowing bacterial survival. Helicobacter pylori inhibits dendritic cell maturation via IL-10-mediated activation of STAT3, facilitating chronic infection. Acute infection with foot-and-mouth disease virus in mice causes IL-10-mediated lymphopenia, contributing to disease severity. These examples highlight the pathway as a therapeutic target in infectious diseases.
Inflammatory and Autoimmune Disorders
Dysregulated IL-10 signaling is associated with chronic inflammatory conditions. IL-10-mediated inhibition of free radical generation in macrophages is critical for limiting tissue damage, and its impairment can lead to excessive inflammation. In murine B-1 B-cells, IL-10-mediated autoregulation influences responses during Borrelia hermsii infection, linking the pathway to autoimmune and inflammatory pathologies. Targeting this pathway could restore immune homeostasis in diseases such as inflammatory bowel disease and arthritis.
Tissue Repair and Regenerative Medicine
The interleukin-10-mediated signaling pathway promotes regenerative postnatal tissue repair through fibroblast-specific STAT3 signaling and regulation of hyaluronan metabolism. This role suggests that modulating the pathway could enhance tissue regeneration after injury or in degenerative conditions. Experimental models using knockout and knock-in mice have been instrumental in defining these regenerative functions.
From interleukin-10-mediated signaling pathway-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of IL-10 signaling exacerbate inflammation? | IL10 or IL10RA knockout mouse; CRISPR knockout in macrophages. |
| What is the role of STAT3 phosphorylation in tissue repair? | STAT3 knock-in mice with phospho-deficient or phospho-mimetic mutations. |
| How does a disease-associated point mutation affect receptor function? | CRISPR point mutation knock-in in cell lines (e.g., IL10RA variants). |
| Can overexpression of SOCS3 suppress IL-10 signaling? | SOCS3 overexpression lentiviral model in primary fibroblasts. |
| What is the effect of IL-10 on dendritic cell maturation? | IL-10 overexpression or knockout in dendritic cells; H. pylori infection model. |
| How does Yersinia V-antigen induce IL-10? | TLR2/CD14 knockout macrophages; Yersinia infection. |
How to Study the interleukin-10-mediated signaling pathway Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Global transcriptional changes | Identify IL-10-regulated genes in macrophages or fibroblasts. |
| Phospho-STAT3 immunoblot | STAT3 activation | Quantify signaling after IL-10 stimulation. |
| Flow cytometry | Cell surface markers and phospho-proteins | Assess dendritic cell maturation and B-1 B-cell responses. |
| Free radical detection | Oxidative burst | Measure IL-10-mediated inhibition in macrophages. |
| Hyaluronan quantification | Extracellular matrix remodeling | Evaluate tissue repair in fibroblast-specific STAT3 knockouts. |
| CRISPR knockout | Gene function loss | Test causal roles of IL10RA, STAT3, TLR2, CD14. |
| CRISPR knock-in | Point mutations or tags | Model disease-associated variants in IL10RA or STAT3. |
| Overexpression | Gain-of-function | Study SOCS3 or IL-10 effects in cell lines. |
Transcriptomic and Proteomic Profiling
RNA-seq and proteomics are used to identify genes and proteins regulated by IL-10-mediated signaling. For example, STAT3 target genes and hyaluronan metabolism enzymes can be quantified after IL-10 stimulation in wild-type and knockout cells. These methods reveal the downstream transcriptional program and potential feedback regulators like SOCS3.
Phospho-Specific Flow Cytometry and Immunoblotting
Phosphorylation of STAT3 is a key readout of pathway activation. Flow cytometry or immunoblotting with phospho-STAT3 antibodies allows quantification of signaling strength in response to IL-10 or pathogen-derived factors. This is essential for studying kinetics and dose-response relationships.
Functional Assays for Inflammation and Tissue Repair
Free radical generation in macrophages can be measured using fluorescent probes to assess the anti-inflammatory effects of IL-10 signaling. Tissue repair is evaluated in vivo using wound healing models and hyaluronan quantification in fibroblast-specific STAT3 knockouts.
Infection Models and Immune Cell Analysis
Infection with Yersinia, Helicobacter pylori, or foot-and-mouth disease virus in mice or cell culture models is used to study pathogen exploitation of IL-10 signaling. Lymphocyte counts and dendritic cell maturation markers are common endpoints.
How CRISPR Can Be Used to Study GO:0140105 interleukin-10-mediated signaling pathway
Knockout
CRISPR knockout of IL10, IL10RA, IL10RB, STAT3, TLR2, or CD14 is used to abolish pathway components and assess their necessity in IL-10-mediated responses. For example, STAT3 knockout in fibroblasts impairs regenerative tissue repair, and TLR2 or CD14 knockout reduces Yersinia V-antigen-induced IL-10 immunosuppression.
Point Mutation
CRISPR point mutation knock-in allows precise modeling of disease-associated variants, such as phospho-deficient STAT3 or IL10RA mutations. These models help dissect the contribution of specific residues to signaling and disease phenotypes.
Knock-in
Knock-in of tagged versions of STAT3 or IL-10 receptor subunits enables visualization and biochemical isolation of pathway components. This approach is valuable for studying protein interactions and trafficking in live cells.
Overexpression
CRISPR activation or lentiviral overexpression of IL-10, SOCS3, or constitutively active STAT3 is used to enhance or suppress pathway activity. Overexpression of SOCS3, for instance, can suppress IL-10-mediated signaling and serve as a negative control.
How EDITGENE Supports interleukin-10-mediated signaling pathway Research
Researchers studying interleukin-10-mediated signaling pathway-related genes often need to determine whether a candidate gene is causally involved in anti-inflammatory responses, tissue repair, or pathogen evasion. EDITGENE provides a comprehensive suite of CRISPR-based services to generate precisely engineered cell models, enabling rigorous functional validation of GO:0140105 components.
Contact EDITGENE today to design your custom CRISPR model for interleukin-10-mediated signaling pathway research.
Frequently Asked Questions About interleukin-10-mediated signaling pathway
What is GO:0140105?
GO:0140105 is the Gene Ontology term for the interleukin-10-mediated signaling pathway, defined as the series of molecular signals initiated by IL-10 binding to its receptor and ending with regulation of a downstream cellular process, such as transcription.
What genes are involved in the interleukin-10-mediated signaling pathway?
Key genes include IL10, IL10RA, IL10RB, STAT3, JAK1, TYK2, SOCS3, TLR2, and CD14, among others.
How does IL-10 activate STAT3?
IL-10 binding to its receptor activates JAK kinases, which phosphorylate STAT3; phosphorylated STAT3 dimerizes and translocates to the nucleus to regulate transcription.
What diseases are associated with IL-10 signaling defects?
Defects in IL-10 signaling are linked to inflammatory bowel disease, chronic infections, and impaired tissue repair.
How do pathogens exploit IL-10 signaling?
Pathogens such as Yersinia and Helicobacter pylori induce IL-10-mediated immunosuppression to evade host immunity.
What is the role of IL-10 in tissue repair?
IL-10-mediated regenerative tissue repair depends on fibroblast-specific STAT3 signaling and regulation of hyaluronan metabolism.
Can CRISPR be used to study IL-10 signaling?
Yes, CRISPR knockout, knock-in, and overexpression models are widely used to dissect the function of IL-10 pathway components.
What cell types are best for studying IL-10 signaling?
Macrophages, dendritic cells, B-1 B-cells, and fibroblasts are commonly used due to their responsiveness to IL-10.
What are the main readouts of IL-10 pathway activation?
Phospho-STAT3 levels, suppression of free radical generation, dendritic cell maturation markers, and hyaluronan production are typical readouts.
How does SOCS3 regulate IL-10 signaling?
SOCS3 is a negative feedback regulator that inhibits JAK-STAT3 signaling downstream of the IL-10 receptor, preventing excessive anti-inflammatory responses.
Conclusion
The interleukin-10-mediated signaling pathway (GO:0140105) is a fundamental biological process that governs anti-inflammatory responses, tissue repair, and host-pathogen interactions. Its core components, including IL-10, its receptor subunits, and STAT3, are well-characterized, and dysregulation is linked to a range of diseases from chronic infections to inflammatory disorders. Continued research using advanced CRISPR models and multi-omics approaches will further illuminate the pathway's complexity and therapeutic potential.
References
- 1. Balaji S et al.. 2017. Interleukin-10-mediated regenerative postnatal tissue repair is dependent on regulation of hyaluronan metabolism via fibroblast-specific STAT3 signaling.. FASEB J 31(3):868-881 PMID: 27903619
- 2. Guo Z et al.. 2021. Interleukin-10-Mediated Lymphopenia Caused by Acute Infection with Foot-and-Mouth Disease Virus in Mice.. Viruses 13(12) PMID: 34960627
- 3. Sindhava V et al.. 2010. Interleukin-10 mediated autoregulation of murine B-1 B-cells and its role in Borrelia hermsii infection.. PLoS One 5(7):e11445 PMID: 20625435
- 4. Dokka S et al.. 2001. Interleukin-10-mediated inhibition of free radical generation in macrophages.. Am J Physiol Lung Cell Mol Physiol 280(6):L1196-202 PMID: 11350798
- 5. Rizzuti D et al.. 2015. Helicobacter pylori inhibits dendritic cell maturation via interleukin-10-mediated activation of the signal transducer and activator of transcription 3 pathway.. J Innate Immun 7(2):199-211 PMID: 25412627
- 6. Sing A et al.. 2002. Yersinia V-antigen exploits toll-like receptor 2 and CD14 for interleukin 10-mediated immunosuppression.. J Exp Med 196(8):1017-24 PMID: 12391013
