Details for: IL1RN

Gene ID: 3557

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: IL1RN

Ensembl ID: ENSG00000136689

Description: interleukin 1 receptor antagonist

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • conjunctival epithelial cell CL1000432
    CSI 21.35
    rCSI 32.61%
    PRS 91.37
  • elicited macrophage CL0000861
    CSI 20.02
    rCSI 18.38%
    PRS 95.89
  • squamous epithelial cell CL0000076
    CSI 15.33
    rCSI 36.39%
    PRS 89.44
  • promyelocyte CL0000836
    CSI 7.42
    rCSI 10.71%
    PRS 93.89
  • respiratory suprabasal cell CL4033048
    CSI 6.76
    rCSI 8.67%
    PRS 93.57
  • alveolar macrophage CL0000583
    CSI 6.48
    rCSI 10.67%
    PRS 93.98
  • corneal epithelial cell CL0000575
    CSI 5.94
    rCSI 16.99%
    PRS 93.27
  • Langerhans cell CL0000453
    CSI 5.72
    rCSI 8.74%
    PRS 96.84
  • mononuclear phagocyte CL0000113
    CSI 5.18
    rCSI 11.41%
    PRS 94.46
  • keratinocyte CL0000312
    CSI 4.89
    rCSI 4.1%
    PRS 92.05
  • Kupffer cell CL0000091
    CSI 4.06
    rCSI 9.29%
    PRS 93.24
  • Hofbauer cell CL3000001
    CSI 3.72
    rCSI 7.03%
    PRS 95.96
  • alternatively activated macrophage CL0000890
    CSI 3.62
    rCSI 4.55%
    PRS 96.63
  • enterocyte CL0000584
    CSI 3.61
    rCSI 5.81%
    PRS 89.67
  • goblet cell CL0000160
    CSI 3.55
    rCSI 3.36%
    PRS 90.33
  • periportal region hepatocyte CL0019026
    CSI 3.51
    rCSI 13.67%
    PRS 89.23
  • CD14-positive, CD16-positive monocyte CL0002397
    CSI 3.4
    rCSI 4.46%
    PRS 97.13
  • inflammatory macrophage CL0000863
    CSI 3.25
    rCSI 5.54%
    PRS 97.91
  • CD1c-positive myeloid dendritic cell CL0002399
    CSI 3.19
    rCSI 3.85%
    PRS 95.99
  • epithelial cell of esophagus CL0002252
    CSI 2.91
    rCSI 28.78%
    PRS 91.13
  • myeloid leukocyte CL0000766
    CSI 2.88
    rCSI 2.66%
    PRS 93.43
  • respiratory basal cell CL0002633
    CSI 2.56
    rCSI 2.65%
    PRS 93.54
  • monocyte CL0000576
    CSI 2.43
    rCSI 4.4%
    PRS 93.44
  • respiratory hillock cell CL4030023
    CSI 2.34
    rCSI 4.18%
    PRS 95.23
  • mucous neck cell CL0000651
    CSI 2.32
    rCSI 3.35%
    PRS 94.36
  • nasal mucosa goblet cell CL0002480
    CSI 2.26
    rCSI 2.63%
    PRS 92.44
  • club cell CL0000158
    CSI 2.19
    rCSI 3.21%
    PRS 88.51
  • epithelial cell CL0000066
    CSI 2.15
    rCSI 3.3%
    PRS 81.06
  • granulocyte CL0000094
    CSI 2.08
    rCSI 3.18%
    PRS 95.59
  • dendritic cell, human CL0001056
    CSI 2.08
    rCSI 3.19%
    PRS 96.59
  • lung macrophage CL1001603
    CSI 2.05
    rCSI 4.58%
    PRS 96
  • foveolar cell of stomach CL0002179
    CSI 1.64
    rCSI 3.49%
    PRS 93.75
  • pancreatic ductal cell CL0002079
    CSI 1.55
    rCSI 3.01%
    PRS 93.37
  • intermediate monocyte CL0002393
    CSI 1.54
    rCSI 2.33%
    PRS 95.7
  • neutrophil CL0000775
    CSI 1.52
    rCSI 8.51%
    PRS 89.76
  • tracheal goblet cell CL1000329
    CSI 1.35
    rCSI 2.95%
    PRS 93.98
  • promonocyte CL0000559
    CSI 1.3
    rCSI 2.23%
    PRS 93.74
  • epithelial cell of urethra CL1000296
    CSI 1.23
    rCSI 31.01%
    PRS 93.99
  • colon macrophage CL0009038
    CSI 1.21
    rCSI 5.57%
    PRS 97.25
  • basal cell of epidermis CL0002187
    CSI 1.14
    rCSI 2.02%
    PRS 65.23
  • CD14-positive, CD16-negative classical monocyte CL0002057
    CSI 0.65
    rCSI 3.9%
    PRS 96.53

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

Comma-separated if multiple.
Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [IL1RN](/details-gene/3557) (Interleukin 1 Receptor Antagonist) is a protein-coding gene located on chromosome 2q14.1. It encodes a secreted cytokine that is a key negative regulator of the pro-inflammatory interleukin-1 (IL-1) signaling pathway. Functionally, [IL1RN](/details-gene/3557) acts as a competitive inhibitor by binding to the IL-1 receptor without inducing a downstream signal, thereby dampening IL-1-mediated inflammation [Link](https://pubmed.ncbi.nlm.nih.gov/2139180/). **Overall**, expression data reveals that [IL1RN](/details-gene/3557) is a highly significant marker in both immune cells, particularly macrophages, and various epithelial cells at barrier surfaces. This dual expression pattern highlights its critical role in maintaining immune homeostasis and controlling inflammation at the interface between the body and the external environment. Its dysfunction is associated with inflammatory conditions, as noted in its clinical association ([OMIM: 147679](https://omim.org/entry/147679)). ## Cellular Roles and Expression Landscape The expression profile of [IL1RN](/details-gene/3557) underscores its specialized function in modulating inflammatory responses, primarily within epithelial and myeloid compartments. **Overall**, the gene shows the highest significance in [conjunctival epithelial cell](/details-cell/CL1000432) (CSI: 21.35) and [elicited macrophage](/details-cell/CL0000861) (CSI: 20.02), indicating it is a defining feature of these cell types. This pattern suggests a crucial role in regulating inflammation at mucosal surfaces and in professional phagocytes. Its high significance extends across a range of epithelial cell types, including [squamous epithelial cell](/details-cell/CL0000076), [corneal epithelial cell](/details-cell/CL0000575), [keratinocyte](/details-cell/CL0000312), and [enterocyte](/details-cell/CL0000584). The presence of various intracellular and secreted isoforms of [IL1RN](/details-gene/3557) has been specifically associated with epithelial tissues, suggesting a cell-intrinsic mechanism to prevent autoinflammation [Link](https://pubmed.ncbi.nlm.nih.gov/1827201/). Concurrently, [IL1RN](/details-gene/3557) is a key marker for the mononuclear phagocyte system. Beyond elicited macrophages, it is significantly expressed in tissue-resident macrophages such as the [alveolar macrophage](/details-cell/CL0000583) of the lung, the [Kupffer cell](/details-cell/CL0000091) of the liver, and the [Langerhans cell](/details-cell/CL0000453) of the skin. This widespread expression in macrophages strategically positioned throughout the body suggests [IL1RN](/details-gene/3557) is a fundamental component for setting the activation threshold of these key innate immune sentinels. ## Pathways and Molecular Function The function of [IL1RN](/details-gene/3557) is centered on the negative regulation of cytokine signaling, as detailed by its functional annotations. Its primary molecular function is [Interleukin-1 receptor antagonist activity (GO:0005152)](https://www.ebi.ac.uk/QuickGO/term/GO:0005152), which involves direct [Interleukin-1 receptor binding (GO:0005149)](https://www.ebi.ac.uk/QuickGO/term/GO:0005149) to block the pro-inflammatory effects of IL-1α and IL-1β [Link](https://pubmed.ncbi.nlm.nih.gov/2137200/). This inhibitory role is a central component of several critical biological processes. The gene is integral to the [Negative regulation of interleukin-1-mediated signaling pathway (GO:2000660)](https://www.ebi.ac.uk/QuickGO/term/GO:2000660), which is a key process within broader pathways such as the [Immune response (GO:0006955)](https://www.ebi.ac.uk/QuickGO/term/GO:0006955) and the [Acute-phase response (GO:0006953)](https://www.ebi.ac.uk/QuickGO/term/GO:0006953). This is further contextualized by its involvement in Reactome pathways like [Interleukin-1 signaling (R-HSA-9020702)](https://reactome.org/content/detail/R-HSA-9020702) and [Cytokine signaling in immune system (R-HSA-1280215)](https://reactome.org/content/detail/R-HSA-1280215). As a secreted protein found in the [Extracellular space (GO:0005615)](https://www.ebi.ac.uk/QuickGO/term/GO:0005615), its function is consistent with its expression in epithelial cells and macrophages, which can secrete it to create an anti-inflammatory microenvironment and limit bystander tissue damage during an immune response. ## Research Directions The expression and function of [IL1RN](/details-gene/3557) point to its central role as a rheostat for inflammation. Based on the data, several testable hypotheses can be proposed: 1. **Paracrine control at barrier surfaces:** Given its high expression in epithelial cells like [keratinocyte](/details-cell/CL0000312)s and its role as a secreted antagonist, we hypothesize that epithelial-derived [IL1RN](/details-gene/3557) acts in a paracrine fashion to maintain skin-resident immune cells, such as [Langerhans cell](/details-cell/CL0000453)s, in a quiescent state, thereby preventing inappropriate inflammatory responses to commensal microbes or minor environmental insults. 2. **Macrophage self-regulation:** The high expression in diverse macrophage populations ([elicited macrophage](/details-cell/CL0000861), [alveolar macrophage](/details-cell/CL0000583), [Kupffer cell](/details-cell/CL0000091)) suggests that [IL1RN](/details-gene/3557) functions as a critical autocrine feedback mechanism. Following activation and production of IL-1β, macrophages may co-express [IL1RN](/details-gene/3557) to limit the duration and magnitude of their own inflammatory response, a mechanism that could be dysregulated in chronic inflammatory diseases. A key experiment to test the second hypothesis would involve the use of primary human monocytes differentiated into macrophages. One could use CRISPR-Cas9 to knock out [IL1RN](/details-gene/3557) in these cells. Following stimulation with an inflammatory agent like lipopolysaccharide (LPS), the kinetics and magnitude of IL-1β and TNF-α secretion could be compared between knockout and wild-type macrophages using ELISA. Furthermore, RNA-sequencing could be performed to determine if the loss of this autocrine feedback loop leads to a prolonged or exaggerated pro-inflammatory transcriptional signature. **Therapeutic Potential:** The protein product of [IL1RN](/details-gene/3557) is already utilized as a biopharmaceutical (Anakinra) for treating autoinflammatory and rheumatoid conditions. Its mechanism is to supplement the body's natural IL-1 antagonism. Therefore, the therapeutic strategy is not inhibition but rather *activation* or *protein replacement*. Future therapeutic avenues could involve developing cell-type-specific delivery systems to increase local concentrations of [IL1RN](/details-gene/3557) at sites of inflammation, such as in the joints or skin, which might enhance efficacy and reduce systemic side effects compared to current treatments.

Genular Protein ID: 1419908218

Symbol: IL1RA_HUMAN

Name: Interleukin-1 receptor antagonist protein

UniProtKB Accession Codes:

P18510 A8K4G1 Q14628 Q53SC2 Q7RTZ4 Q96GD6 Q9UPC0

Database IDs:

AGR 1 Allergome 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 4 CDD 1 CPTC 1 CTD 1 ChEMBL 1 ChiTaRS 1 ComplexPortal 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 1 DrugCentral 1 EMBL 17 Ensembl 8 EvolutionaryTrace 1 ExpressionAtlas 1 GO 21 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyConnect 1 GlyCosmos 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 4 KEGG 1 MANE-Select 1 MIM 5 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PDB 5 PDBsum 5 PIR 2 PRIDE 1 PRINTS 2 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 4 RNAct 1 Reactome 2 RefSeq 7 SIGNOR 1 SMART 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 2139180

Title: Purification, cloning, expression and biological characterization of an interleukin-1 receptor antagonist protein.

PubMed ID: 2139180

DOI: 10.1038/344633a0

PubMed ID: 2137201

Title: Primary structure and functional expression from complementary DNA of a human interleukin-1 receptor antagonist.

PubMed ID: 2137201

DOI: 10.1038/343341a0

PubMed ID: 1828896

Title: Interleukin 1 receptor antagonist is a member of the interleukin 1 gene family: evolution of a cytokine control mechanism.

PubMed ID: 1828896

DOI: 10.1073/pnas.88.12.5232

PubMed ID: 1385987

Title: Cloning and chromosome mapping of the human interleukin-1 receptor antagonist gene.

PubMed ID: 1385987

DOI: 10.1016/1043-4666(92)90041-o

PubMed ID: 8992991

Title: Intracellular IL-1 receptor antagonist promoter: cell type-specific and inducible regulatory regions.

PubMed ID: 8992991

PubMed ID: 1827201

Title: cDNA cloning of an intracellular form of the human interleukin 1 receptor antagonist associated with epithelium.

PubMed ID: 1827201

DOI: 10.1073/pnas.88.9.3681

PubMed ID: 7629520

Title: Cloning and characterization of a new isoform of the interleukin 1 receptor antagonist.

PubMed ID: 7629520

DOI: 10.1084/jem.182.2.623

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 15815621

Title: Generation and annotation of the DNA sequences of human chromosomes 2 and 4.

PubMed ID: 15815621

DOI: 10.1038/nature03466

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 2137200

Title: Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor.

PubMed ID: 2137200

DOI: 10.1038/343336a0

PubMed ID: 2143761

Title: Purification and characterization of interleukin 1 receptor level antagonist proteins from THP-1 cells.

PubMed ID: 2143761

DOI: 10.1016/s0021-9258(18)77331-6

PubMed ID: 9514884

Title: Detection of an interleukin-1 intracellular receptor antagonist mRNA variant.

PubMed ID: 9514884

DOI: 10.1006/bbrc.1998.8217

PubMed ID: 7989776

Title: Elevated levels of shed type II IL-1 receptor in sepsis. Potential role for type II receptor in regulation of IL-1 responses.

PubMed ID: 7989776

PubMed ID: 7775431

Title: Molecular cloning and characterization of a second subunit of the interleukin 1 receptor complex.

PubMed ID: 7775431

DOI: 10.1074/jbc.270.23.13757

PubMed ID: 11991722

Title: A sequence-based map of the nine genes of the human interleukin-1 cluster.

PubMed ID: 11991722

DOI: 10.1006/geno.2002.6751

PubMed ID: 8786086

Title: Interleukin-1 receptor antagonist allele (IL1RN*2) associated with nephropathy in diabetes mellitus.

PubMed ID: 8786086

DOI: 10.1007/bf02185776

PubMed ID: 16335952

Title: Human plasma N-glycoproteome analysis by immunoaffinity subtraction, hydrazide chemistry, and mass spectrometry.

PubMed ID: 16335952

DOI: 10.1021/pr0502065

PubMed ID: 19494218

Title: An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist.

PubMed ID: 19494218

DOI: 10.1056/nejmoa0807865

PubMed ID: 32384874

Title: Serum level of IL-1ra was associated with the treatment of latent tuberculosis infection in a Chinese population.

PubMed ID: 32384874

DOI: 10.1186/s12879-020-05047-x

PubMed ID: 1534997

Title: Secondary structure and topology of interleukin-1 receptor antagonist protein determined by heteronuclear three-dimensional NMR spectroscopy.

PubMed ID: 1534997

DOI: 10.1021/bi00138a001

PubMed ID: 8045306

Title: Solution structure of human interleukin-1 receptor antagonist protein.

PubMed ID: 8045306

DOI: 10.1016/0014-5793(94)00643-1

PubMed ID: 8175703

Title: X-ray structure of interleukin-1 receptor antagonist at 2.0-A resolution.

PubMed ID: 8175703

DOI: 10.1016/s0021-9258(18)99957-6

PubMed ID: 7867645

Title: Refined crystal structure of the interleukin-1 receptor antagonist. Presence of a disulfide link and a cis-proline.

PubMed ID: 7867645

DOI: 10.1111/j.1432-1033.1995.tb20209.x

PubMed ID: 9062194

Title: A new cytokine-receptor binding mode revealed by the crystal structure of the IL-1 receptor with an antagonist.

PubMed ID: 9062194

DOI: 10.1038/386194a0

PubMed ID: 18987736

Title: DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome.

PubMed ID: 18987736

DOI: 10.1038/nature07485

Sequence Information:

  • Length: 177
  • Mass: 20055
  • Checksum: D1690776A7394057
  • Sequence:
    • MEICRGLRSH LITLLLFLFH SETICRPSGR KSSKMQAFRI WDVNQKTFYL RNNQLVAGYL 
QGPNVNLEEK IDVVPIEPHA LFLGIHGGKM CLSCVKSGDE TRLQLEAVNI TDLSENRKQD 
KRFAFIRSDS GPTTSFESAA CPGWFLCTAM EADQPVSLTN MPDEGVMVTK FYFQEDE