IL10RA Human
Description
Protein Structure
IL10RA is a single-pass type I membrane protein containing:
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Extracellular domain: Composed of two fibronectin type III domains (D1 and D2) critical for IL-10 binding.
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Transmembrane domain: A hydrophobic helix anchoring the protein to the cell membrane.
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Intracellular domain: Interacts with Janus kinases (JAK1 and TYK2) for signal transduction .
| Domain | Function | Key Features |
|---|---|---|
| Extracellular | Binds IL-10 via conserved motifs (e.g., WSXWS-like sequence) | Contains phosphorylation sites (Tyr57, 91, 157) |
| Transmembrane | Anchors receptor to membrane | Hydrophobic helix structure |
| Intracellular | Activates JAK1/TYK2-STAT3 signaling pathway | Tyrosine residues for kinase interaction |
Gene and Transcription
The IL10RA gene spans 11q23.3, comprising 7 exons that produce multiple splice variants:
| Transcript | Length (bp) | Protein Status | Biotype |
|---|---|---|---|
| ENST00000227752.8 | 3,695 | 578 aa (63 kDa) | Protein-coding |
| ENST00000534574.5 | 2,275 | Nonsense-mediated decay | Non-coding |
| ENST00000526544.5 | 1,179 | Nonsense-mediated decay | Non-coding |
Key variants are associated with pathogenic mutations disrupting IL-10 signaling .
Signaling Pathways
IL10RA forms a heterotetramer with IL10RB to bind IL-10, triggering:
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JAK1/TYK2 Activation: Tyrosine phosphorylation of intracellular domains.
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STAT3 Recruitment: Homodimerization and nuclear translocation to induce anti-inflammatory genes (e.g., SOCS3) .
| Pathway Component | Mechanism | Outcome |
|---|---|---|
| JAK1/TYK2 Kinases | Phosphorylate IL10RA intracellular domain | STAT3 activation |
| STAT3 | Binds DNA and regulates gene transcription | Suppression of pro-inflammatory cytokines |
Immunological Effects
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Anti-inflammatory: Inhibits TNF-α, IL-6, and IL-1β production .
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Tissue Protection: Prevents intestinal inflammation (e.g., in inflammatory bowel disease) .
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Pathogen Modulation: Limits excessive immune responses to infections (e.g., SARS-CoV-2) .
Pathogenic Mutations
Mutations in IL10RA are linked to early-onset inflammatory bowel disease (IBD) and impaired IL-10 responsiveness:
| Variant | Effect | Disease Association |
|---|---|---|
| p.R117C, p.R117H | Disrupts IL-10 binding in extracellular domain | Spontaneous enterocolitis, IBD28 |
| p.T84I, p.R101W | Abrogates phosphorylation and STAT3 activation | Severe immunodeficiency |
Global studies reveal regional allele frequencies: high prevalence in populations with high infectious disease burdens (e.g., malaria-endemic regions) .
Disease Links
| Disease | Mechanism | Genetic Evidence |
|---|---|---|
| Inflammatory Bowel Disease (IBD) | Loss-of-function mutations impair IL-10 signaling | IBD28 (OMIM 614291) |
| Systemic Lupus Erythematosus (SLE) | Polymorphisms alter receptor activity | Haplotype CAA linked to SLE susceptibility |
| COVID-19 | Elevated IL-10 levels correlate with severe ARDS | Hyporesponsiveness to IL-10 in critical cases |
Therapeutic Potential
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Recombinant IL10RA: Used in studies to modulate IL-10 activity (e.g., in Sf9 insect cell systems) .
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Targeted Therapies: JAK inhibitors being explored to modulate IL-10 signaling in autoimmune diseases .
Population Genetics
Product Specs
Q&A
FAQs for IL10RA Human Research
Advanced Research Challenges
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How do researchers address contradictions in IL10RA’s dual immunosuppressive and immunostimulatory roles?
IL10RA signaling paradoxically suppresses macrophages while enhancing B cell antibody production and Th2 responses . -
What are the key challenges in studying IL10RA-IL10RB complex dynamics?
The receptor’s tetrameric assembly and transient phosphorylation complicate structural studies . -
How do IL10RA polymorphisms impact translational research?
Certain SNPs (e.g., IBD-linked variants) reduce IL-10 binding affinity, altering clinical outcomes in autoimmune diseases .
Methodological Comparisons
Therapeutic Implications
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Can IL10RA-targeted therapies balance immunosuppression and anti-tumor immunity?
Preclinical studies show PEG-rHuIL-10 (AM0010) enhances CD8+ T cell cytotoxicity (↑Granzyme B, FasL) while suppressing TGFβ . -
How does IL10RA interact with checkpoint inhibitors (e.g., PD-1)?
IL10RA+ Tregs exhibit upregulated PD-1/LAG3, suggesting co-blockade may synergize with anti-PD-1 therapies .
Product Science Overview
IL-10RA is a subunit of the type II cytokine receptor family. The receptor complex for IL-10 is a heterodimer consisting of IL-10RA and IL-10RB. The IL-10RA subunit is primarily expressed on hematopoietic cells such as B cells, T cells, natural killer (NK) cells, monocytes, and macrophages . It is not typically found in non-hematopoietic cells like fibroblasts or endothelial cells .
The recombinant human IL-10RA protein is often produced in expression hosts such as HEK293 cells or insect cells. The recombinant protein typically includes a polyhistidine tag for purification purposes and is lyophilized for stability .
IL-10 is a pleiotropic cytokine with multiple immunostimulatory and immunosuppressive effects. It regulates immune responses by acting on various cell types, including T cells, B cells, macrophages, and antigen-presenting cells (APCs). IL-10 generally skews the immune response from a TH1 to a TH2 profile, suppressing the production of pro-inflammatory cytokines such as IL-1, IL-6, IL-8, TNF-α, GM-CSF, and G-CSF in activated monocytes and macrophages .
The biological effects of IL-10 are mediated through its binding to the IL-10 receptor complex. Upon binding, the receptor complex activates intracellular signaling pathways, including the JAK-STAT pathway, leading to the phosphorylation of JAK1 and TYK2 kinases .
Recombinant human IL-10RA is used in various research applications to study the immunosuppressive effects of IL-10 and its role in immune regulation. It is also utilized in assays to measure the biological activity of IL-10 by its ability to inhibit IL-10 dependent proliferation of certain cell lines .
