GO:0019969 interleukin-10 binding: Mechanism, Genes and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0019969 (interleukin-10 binding) is a molecular function defined as binding to interleukin-10 (IL-10), the anti-inflammatory cytokine.
• IL-10 binding is mediated by the heterodimeric receptor complex IL-10R1/IL-10R2, which triggers JAK-STAT signaling, particularly STAT3 activation.
• Structural studies show that IL-10 binding can be decoupled from downstream pro- and anti-inflammatory signaling, offering therapeutic opportunities.
• IL-10 binding and signaling suppress inflammatory gene expression through epigenetic regulation of IRF transcription factors.
• Soluble and decoy proteins such as Ebi3 can bind IL-10 and limit its function, representing a regulatory layer.
• Dysregulated IL-10 binding is implicated in autoimmune diseases, chronic infections, and cancer immune evasion.
Description
Interleukin-10 (IL-10) is a pleiotropic cytokine that plays a central role in limiting inflammatory responses and maintaining immune homeostasis. The molecular function of interleukin-10 binding (GO:0019969) encompasses the specific interaction between IL-10 and its cognate receptors or binding proteins, a critical step in initiating downstream signaling. This binding event is the first committed step in IL-10-mediated suppression of pro-inflammatory cytokine production and is essential for preventing immunopathology. Understanding the structural and molecular basis of IL-10 binding is therefore fundamental to immunology and therapeutic development. Recent studies have elucidated the structural determinants of IL-10 binding to its receptor, revealing how distinct binding interfaces can differentially activate anti-inflammatory versus pro-inflammatory pathways. Furthermore, IL-10 binding to its receptor triggers a cascade of phosphorylation events that activate STAT transcription factors, particularly STAT3, which then translocate to the nucleus and modulate gene expression. The binding of IL-10 is also subject to regulation by soluble factors such as Ebi3, which can sequester IL-10 and limit its bioavailability. These findings underscore the importance of precise IL-10 binding in immune regulation and highlight its potential as a target for therapeutic intervention in inflammatory and autoimmune diseases.
interleukin-10 binding At A Glance
| GO ID | GO:0019969 |
|---|---|
| GO term | interleukin-10 binding |
| Ontology | molecular_function |
| Synonym | IL-10 binding |
| Definition | Binding to interleukin-10. |
| Major function | Mediates the initial recognition of IL-10 by its receptor complex, leading to JAK-STAT signaling activation. |
| Key receptors | IL-10R1 (IL10RA) and IL-10R2 (IL10RB) form the heterodimeric receptor that binds IL-10. |
| Regulatory proteins | Ebi3 can bind IL-10 and limit its function. |
| Associated diseases | Autoimmune diseases, chronic inflammatory conditions, and cancer. |
What Is GO:0019969?
GO:0019969, interleukin-10 binding, is a molecular function term defined as the binding to interleukin-10 (IL-10). This term describes the selective interaction between IL-10 and any molecule that recognizes it, including its cell surface receptors (IL-10R1 and IL-10R2), soluble decoy receptors, or other IL-10-binding proteins. The binding event is non-covalent and specific, and it is the initial step in IL-10 signal transduction.
Why Is interleukin-10 binding Important in Cell Biology?
Interleukin-10 binding is a critical molecular event that governs the anti-inflammatory actions of IL-10, a cytokine essential for immune homeostasis. Dysregulation of IL-10 binding and signaling is associated with a wide range of human diseases, including autoimmune disorders, chronic infections, and cancer. Understanding the precise molecular interactions involved in IL-10 binding provides a foundation for designing therapeutics that can selectively modulate IL-10 activity, either enhancing its anti-inflammatory effects or blocking its immunosuppressive functions in cancer.
• IL-10 binding initiates the anti-inflammatory signaling cascade that suppresses pro-inflammatory cytokine production.
• Structural insights into IL-10 binding enable the design of partial agonists or antagonists with tailored therapeutic effects.
• IL-10 binding to its receptor on somatosensory neurons controls CCL2 release and inflammatory pain responses.
• Epigenetic suppression of inflammatory genes by IL-10 requires initial receptor binding and downstream STAT3 activation.
• Bacterial components such as pseudaminic acid can modulate IL-10 binding through Siglec-10, affecting macrophage function.
• IL-10 binding is critical for regulatory T cell (Treg) suppressive function and mitochondrial integrity.
• Dysregulated IL-10 binding contributes to cancer immune evasion by suppressing anti-tumor immunity.
• The binding of IL-10 can be competitively inhibited by soluble factors like Ebi3, offering a regulatory mechanism.
• IL-10 binding is a potential target for treating autoimmune diseases and chronic inflammatory conditions.
• Understanding IL-10 binding at the molecular level aids in the development of biologics and small molecule modulators.
Molecular Mechanism of interleukin-10 binding
IL-10 Structure and Receptor Recognition
In simple terms: IL-10 is a dimeric cytokine that binds to a two-part receptor on the cell surface.
IL-10 is a homodimeric cytokine that adopts a classic four-helix bundle fold. Each monomer binds to two receptor chains: IL-10R1 (IL10RA) and IL-10R2 (IL10RB). The binding interface involves extensive hydrophobic and electrostatic interactions, with IL-10R1 providing the high-affinity binding site and IL-10R2 acting as a low-affinity co-receptor that stabilizes the complex. Structural studies have revealed that the IL-10/IL-10R1 interface is the primary determinant of specificity, while IL-10R2 recruitment is essential for signaling.
Receptor Complex Assembly and JAK Activation
In simple terms: When IL-10 binds, it brings together two receptor chains, which activates enzymes called JAKs.
Upon IL-10 binding, IL-10R1 and IL-10R2 are brought into close proximity, allowing their associated JAK kinases (JAK1 and TYK2) to trans-phosphorylate and activate each other. Activated JAKs then phosphorylate specific tyrosine residues on the intracellular domain of IL-10R1, creating docking sites for STAT3. This assembly is a prerequisite for downstream signaling and is tightly regulated by the binding affinity and kinetics of the IL-10-receptor interaction.
STAT3 Recruitment and Activation
In simple terms: The activated receptor recruits STAT3 proteins, which get phosphorylated and then move to the nucleus to turn genes on or off.
Phosphorylated tyrosine residues on IL-10R1 recruit STAT3 via its SH2 domain. JAK kinases then phosphorylate STAT3 on Tyr705, leading to STAT3 dimerization and nuclear translocation. In the nucleus, STAT3 dimers bind to specific DNA sequences and regulate the transcription of target genes, including those encoding pro-inflammatory cytokines and IRF transcription factors. Selective DNA-binding activity of IL-10-stimulated STAT molecules has been demonstrated in human monocytes.
Negative Regulation by Soluble Decoy Proteins
In simple terms: Some proteins can bind IL-10 and prevent it from reaching its receptor, acting as decoys.
Ebi3, a soluble subunit of the IL-27 and IL-35 cytokines, can bind to IL-10 and limit its function. This interaction sequesters IL-10, reducing its availability to bind to the signaling receptor complex. This represents an additional layer of regulation that fine-tunes IL-10 activity in the immune microenvironment.
Modulation by Microbial and Host Factors
In simple terms: Certain bacteria and host molecules can influence how IL-10 binds to cells, altering immune responses.
Bacterial pseudaminic acid can bind to Siglec-10 on macrophages, inducing an IL-10 response and suppressing phagocytosis. This indicates that microbial factors can indirectly modulate IL-10 binding and signaling. Additionally, lipid metabolism and mitochondrial integrity in Tregs can affect their suppressive function, which is partly dependent on IL-10 binding and signaling.
Key Genes Involved in GO:0019969 interleukin-10 binding
The following genes and proteins are directly involved in interleukin-10 binding and its downstream signaling.
| Gene | Major Role | Research Relevance |
|---|---|---|
| IL10 | Encodes the cytokine interleukin-10, the ligand for GO:0019969. | Central to anti-inflammatory responses; polymorphisms linked to autoimmune diseases. |
| IL10RA | Encodes the high-affinity receptor chain IL-10R1 that binds IL-10. | Mutations cause very early onset inflammatory bowel disease; target for therapeutic modulation. |
| IL10RB | Encodes the low-affinity co-receptor IL-10R2 that stabilizes the complex. | Shared with other cytokine receptors; essential for IL-10 signaling. |
| STAT3 | Transcription factor activated downstream of IL-10 binding. | Mediates anti-inflammatory gene expression; frequently mutated in cancer. |
| JAK1 | Kinase associated with IL-10R1 that phosphorylates STAT3. | Target of JAK inhibitors; critical for IL-10 signaling. |
| TYK2 | Kinase associated with IL-10R2 that contributes to signaling. | Deficiency leads to impaired IL-10 responses; drug target. |
| EBI3 | Soluble protein that binds IL-10 and limits its function. | Regulates IL-10 bioavailability; component of IL-27 and IL-35. |
| SIGLEC10 | Receptor on macrophages that can induce IL-10 production upon binding bacterial ligands. | Modulates macrophage polarization and phagocytosis. |
| IRF1 | Interferon regulatory factor suppressed by IL-10 signaling. | Epigenetic target of IL-10; involved in inflammatory gene regulation. |
| IRF5 | Interferon regulatory factor suppressed by IL-10 signaling. | Associated with autoimmune diseases; regulated by IL-10. |
| CCL2 | Chemokine whose release is controlled by IL-10 signaling in neurons. | Mediates inflammatory pain; modulated by IL-10 binding. |
| FOXP3 | Master transcription factor of regulatory T cells. | Treg suppressive function depends on IL-10 binding and signaling. |
| IL10RA | Receptor chain; also known as IL-10R1. | See above. |
| IL10RB | Receptor chain; also known as IL-10R2. | See above. |
| SOCS3 | Negative regulator of IL-10 signaling. | Inhibits JAK-STAT pathway; feedback control. |
| PIAS3 | Negative regulator of STAT3. | Modulates IL-10-induced gene expression. |
How Is interleukin-10 binding Regulated?
Interleukin-10 binding and signaling are tightly regulated at multiple levels. The expression of IL-10 itself is controlled by various transcription factors and epigenetic mechanisms in different immune cell types. The availability of IL-10 for binding is modulated by soluble decoy proteins such as Ebi3, which can sequester IL-10 and prevent receptor engagement. At the receptor level, the cell surface expression of IL-10R1 and IL-10R2 is regulated by internalization and degradation, affecting the sensitivity of cells to IL-10. Intracellularly, negative feedback loops involving SOCS3 and PIAS3 dampen STAT3 activation, thereby limiting the duration and magnitude of IL-10 signaling. Additionally, microbial factors such as pseudaminic acid can indirectly influence IL-10 binding through pattern recognition receptors like Siglec-10. These regulatory mechanisms ensure that IL-10 responses are appropriate to the context and prevent excessive immunosuppression.
interleukin-10 binding and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| IL10 | Autoimmune diseases, inflammatory bowel disease | IL10 knockout mice; overexpression in macrophages |
| IL10RA | Very early onset inflammatory bowel disease | Knock-in of patient mutations in cell lines; organoids |
| IL10RB | Inflammatory bowel disease, viral infections | IL10RB knockout cell lines; CRISPR point mutations |
| STAT3 | Cancer, autoimmune diseases | STAT3 knockout or point-mutant (Y705F) cells |
| EBI3 | Autoimmune diseases, cancer | EBI3 overexpression or knockout in immune cells |
Autoimmune and Inflammatory Diseases
Dysregulated IL-10 binding and signaling are strongly associated with autoimmune and inflammatory diseases. Polymorphisms in IL10 and its receptor genes have been linked to susceptibility to inflammatory bowel disease, rheumatoid arthritis, and systemic lupus erythematosus. Defects in IL-10 binding can lead to excessive inflammation, as seen in very early onset inflammatory bowel disease caused by mutations in IL10RA or IL10RB. Conversely, elevated IL-10 levels can contribute to chronic infections by suppressing protective immunity.
Cancer Immune Evasion
IL-10 binding and signaling play a complex role in cancer. While IL-10 can suppress inflammation that promotes tumorigenesis, it can also promote immune evasion by inhibiting anti-tumor T cell responses. Many tumors produce IL-10, which binds to receptors on immune cells and suppresses their activity. Recent studies have shown that IL-10 targets IRF transcription factors to suppress interferon and inflammatory response genes through epigenetic mechanisms, contributing to an immunosuppressive tumor microenvironment. Therefore, blocking IL-10 binding is being explored as a strategy to enhance anti-tumor immunity.
Neuroinflammatory and Pain Conditions
IL-10 binding in the nervous system has been implicated in the control of neuroinflammation and pain. Interleukin-10 signaling in somatosensory neurons controls CCL2 release and inflammatory responses, suggesting that IL-10 binding to neuronal receptors can modulate pain sensitivity. This opens potential avenues for treating chronic pain and neuroinflammatory conditions by targeting IL-10 binding.
From interleukin-10 binding-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does a candidate gene affect IL-10 binding affinity? | Knockout of the gene in IL-10-responsive cells followed by binding assays |
| What is the effect of a specific point mutation in IL10RA on IL-10 binding? | Point-mutation knock-in cell lines (e.g., HEK293 or primary immune cells) |
| Can a tagged IL-10 receptor be used to track binding dynamics? | Knock-in of fluorescent or epitope tags at the endogenous IL10RA locus |
| Does overexpression of EBI3 reduce IL-10 binding? | Overexpression of EBI3 in macrophages or dendritic cells |
| Which genes are essential for IL-10-mediated suppression? | Genome-wide CRISPR knockout library screening in IL-10-treated cells |
| How does IL-10 binding affect neuronal function? | Conditional knockout of IL10RA in somatosensory neurons in mice |
How to Study the interleukin-10 binding Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Surface plasmon resonance (SPR) | Binding affinity and kinetics (KD, kon, koff) | Characterizing IL-10 binding to IL-10R1/IL-10R2 |
| ELISA | Concentration of IL-10 or soluble receptors | Quantifying IL-10 in supernatants; measuring Ebi3-IL-10 interaction |
| CRISPR knockout screening | Genes required for IL-10 binding/signaling | Identifying novel regulators of IL-10 response |
| RNA-seq | Transcriptional changes upon IL-10 binding | Global gene expression profiling |
| ChIP-seq | STAT3 DNA binding sites | Mapping IL-10-induced STAT3 target genes |
| Flow cytometry | Cell surface IL-10 receptor expression and IL-10 binding | Analyzing receptor levels in immune cell subsets |
| Confocal microscopy | Intracellular trafficking of IL-10-receptor complexes | Visualizing internalization and localization |
| Western blot | Phosphorylation of STAT3 and JAKs | Assessing activation of signaling pathways |
Binding Assays (SPR, BLI, ELISA)
Surface plasmon resonance (SPR) and biolayer interferometry (BLI) are used to measure the binding kinetics and affinity between IL-10 and its receptors or other binding proteins. ELISA-based assays can quantify soluble IL-10 and its interaction with decoy proteins like Ebi3. These methods provide quantitative data on the strength and specificity of interleukin-10 binding.
CRISPR Screening for IL-10 Binding Modulators
Genome-wide CRISPR knockout or activation screens can identify genes that regulate IL-10 binding and downstream signaling. For example, cells can be treated with IL-10 and screened for survival or reporter gene expression to uncover novel regulators of the pathway. Such screens have the power to reveal previously unknown components of the IL-10 binding machinery.
Transcriptomics and Epigenomics
RNA-seq and ATAC-seq can be used to study the transcriptional and epigenetic changes induced by IL-10 binding. Studies have shown that IL-10 targets IRF transcription factors to suppress inflammatory genes via epigenetic mechanisms, which can be dissected using these techniques. ChIP-seq for STAT3 can identify direct binding sites in the genome following IL-10 stimulation.
Imaging and Flow Cytometry
Flow cytometry can measure cell surface expression of IL-10 receptors and binding of fluorescently labeled IL-10. Confocal microscopy can visualize the internalization and trafficking of IL-10-receptor complexes. These methods are useful for studying the dynamics of interleukin-10 binding in live cells.
How CRISPR Can Be Used to Study GO:0019969 interleukin-10 binding
Knockout
CRISPR knockout of IL10RA, IL10RB, or downstream signaling components (e.g., STAT3) can completely abolish interleukin-10 binding and signaling. These models are essential for studying the loss of IL-10 function in immune cells and for validating drug targets. For example, IL10RA knockout macrophages fail to respond to IL-10 and exhibit increased inflammatory cytokine production.
Point Mutation
Point mutations can be introduced into the IL-10 binding interface of IL10RA or IL10RB to dissect the specific residues required for high-affinity binding. Such models help in understanding the structural basis of IL-10 binding and can mimic patient mutations that cause inflammatory bowel disease. For instance, mutation of key tyrosine residues in IL-10R1 can prevent STAT3 recruitment without affecting ligand binding.
Knock-in
Knock-in of epitope tags (e.g., FLAG, HA) or fluorescent proteins (e.g., GFP) at the endogenous IL10RA locus allows for real-time tracking of receptor expression, localization, and binding dynamics. This approach is valuable for imaging studies and for isolating receptor complexes for biochemical analysis.
Overexpression
Overexpression of IL-10, IL-10 receptors, or decoy proteins like EBI3 can be achieved via CRISPR activation or lentiviral transduction. Overexpression models are useful for studying gain-of-function effects, such as enhanced IL-10 binding and signaling, and for producing large amounts of recombinant proteins for structural studies.
How EDITGENE Supports interleukin-10 binding Research
Researchers studying interleukin-10 binding-related genes often need to determine whether a candidate gene is causally involved in the binding event or downstream signaling. EDITGENE provides a comprehensive suite of CRISPR-based services to create precisely engineered cell models, enabling rigorous functional validation of genes implicated in IL-10 binding and its associated diseases.
Contact EDITGENE today to design your custom CRISPR model for interleukin-10 binding research.
Frequently Asked Questions About interleukin-10 binding
What is interleukin-10 binding?
Interleukin-10 binding (GO:0019969) is a molecular function defined as the binding to interleukin-10 (IL-10), a cytokine that suppresses inflammation. It typically involves the IL-10 receptor complex (IL-10R1/IL-10R2) and initiates signaling.
What genes are involved in interleukin-10 binding?
Key genes include IL10 (the ligand), IL10RA and IL10RB (receptor subunits), and downstream signaling molecules like JAK1, TYK2, and STAT3. Regulatory proteins such as EBI3 can also bind IL-10.
What is the GO term for IL-10 binding?
The Gene Ontology term for IL-10 binding is GO:0019969, with the official name 'interleukin-10 binding' and synonym 'IL-10 binding'.
How does IL-10 binding lead to anti-inflammatory effects?
IL-10 binding to its receptor activates JAK kinases, which phosphorylate STAT3. STAT3 then translocates to the nucleus and induces the expression of anti-inflammatory genes while suppressing pro-inflammatory ones.
What diseases are associated with defects in IL-10 binding?
Defects in IL-10 binding can cause very early onset inflammatory bowel disease, and dysregulated IL-10 signaling is linked to autoimmune diseases and cancer immune evasion.
Can IL-10 binding be targeted therapeutically?
Yes, therapeutic strategies aim to either enhance IL-10 binding for treating autoimmune diseases or block it to boost anti-tumor immunity. Structural studies have identified ways to decouple pro- and anti-inflammatory effects.
What experimental methods are used to study IL-10 binding?
Common methods include surface plasmon resonance (SPR), ELISA, flow cytometry, and CRISPR screening. Transcriptomics and ChIP-seq are used to study downstream effects.
What is the role of Ebi3 in IL-10 binding?
Ebi3 is a soluble protein that can bind IL-10 and limit its function by preventing it from interacting with the signaling receptor. This provides a regulatory mechanism.
How does IL-10 binding affect neurons?
IL-10 signaling in somatosensory neurons controls CCL2 release and inflammatory responses, suggesting a role in pain modulation.
What CRISPR models are available for studying IL-10 binding?
EDITGENE offers knockout, point mutation, knock-in, and overexpression models for genes involved in IL-10 binding, as well as CRISPR library screening and bioinformatics services.
Conclusion
Interleukin-10 binding (GO:0019969) is a fundamental molecular event that initiates the anti-inflammatory actions of IL-10. Its precise regulation is critical for immune homeostasis, and its dysregulation contributes to autoimmune diseases, chronic infections, and cancer. Advances in structural biology and CRISPR-based functional genomics continue to unravel the complexities of IL-10 binding, offering new opportunities for therapeutic intervention. EDITGENE's comprehensive CRISPR services empower researchers to dissect the molecular mechanisms of interleukin-10 binding and translate these findings into novel treatments.
References
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- 3. Mishra B et al.. 2025. IL-10 targets IRF transcription factors to suppress IFN and inflammatory response genes by epigenetic mechanisms.. Nat Immunol 26(5):748-759 PMID: 40263613
- 4. de Souza S et al.. 2024. Interleukin-10 signaling in somatosensory neurons controls CCL2 release and inflammatory response.. Brain Behav Immun 116:193-202 PMID: 38081433
- 5. Scott EN et al.. 2024. Ebi3 Binding to IFN-γ and IL-10 Limits Their Function.. J Immunol 213(8):1115-1124 PMID: 39240167
- 6. Lee IM et al.. 2024. Bacterial pseudaminic acid binding to Siglec-10 induces a macrophage interleukin-10 response and suppresses phagocytosis.. Chem Commun (Camb) 60(21):2930-2933 PMID: 38372418
- 7. Field CS et al.. 2020. Mitochondrial Integrity Regulated by Lipid Metabolism Is a Cell-Intrinsic Checkpoint for Treg Suppressive Function.. Cell Metab 31(2):422-437.e5 PMID: 31883840
- 8. Yamaoka K et al.. 1999. Selective DNA-binding activity of interleukin-10-stimulated STAT molecules in human monocytes.. J Interferon Cytokine Res 19(6):679-85 PMID: 10433370
