Details for: IL4I1

Gene ID: 259307

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: IL4I1

Ensembl ID: ENSG00000104951

Description: interleukin 4 induced 1

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

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

  • group 3 innate lymphoid cell CL0001071
    CSI 18.24
    rCSI 13.7%
    PRS 97.89
  • dendritic cell, human CL0001056
    CSI 9.77
    rCSI 15%
    PRS 98.79
  • lung macrophage CL1001603
    CSI 8.96
    rCSI 20.02%
    PRS 98.72
  • CD4-positive helper T cell CL0000492
    CSI 8.13
    rCSI 6.15%
    PRS 99.51
  • monocyte CL0000576
    CSI 5.63
    rCSI 10.17%
    PRS 97.19
  • Langerhans cell CL0000453
    CSI 5.11
    rCSI 7.81%
    PRS 98.84
  • fallopian tube secretory epithelial cell CL4030006
    CSI 4.91
    rCSI 4.72%
    PRS 95.73
  • alternatively activated macrophage CL0000890
    CSI 4.5
    rCSI 5.66%
    PRS 98.98
  • CD1c-positive myeloid dendritic cell CL0002399
    CSI 4.23
    rCSI 5.11%
    PRS 98.57
  • innate lymphoid cell CL0001065
    CSI 3.57
    rCSI 7.37%
    PRS 91.44
  • inflammatory macrophage CL0000863
    CSI 3.4
    rCSI 5.81%
    PRS 99.52
  • CD34-positive, CD56-positive, CD117-positive common innate lymphoid precursor, human CL0001074
    CSI 3.34
    rCSI 38.75%
    PRS 98.87
  • elicited macrophage CL0000861
    CSI 3.17
    rCSI 2.91%
    PRS 98.55
  • T-helper 17 cell CL0000899
    CSI 2.97
    rCSI 2.36%
    PRS 99.5
  • myeloid leukocyte CL0000766
    CSI 2.93
    rCSI 2.7%
    PRS 97.57
  • mononuclear phagocyte CL0000113
    CSI 2.35
    rCSI 5.18%
    PRS 97.87
  • myeloid dendritic cell CL0000782
    CSI 1.76
    rCSI 2.55%
    PRS 99.37
  • follicular dendritic cell CL0000442
    CSI 1.05
    rCSI 16.8%
    PRS 97.65
  • colon macrophage CL0009038
    CSI 0.86
    rCSI 3.95%
    PRS 99.15

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.

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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 [IL4I1](/details-gene/259307) (Interleukin 4 Induced 1) is a protein-coding gene that encodes a secreted L-amino acid oxidase. This enzyme is involved in the catabolism of aromatic amino acids, including phenylalanine, tryptophan, and tyrosine. Functionally, [IL4I1](/details-gene/259307) plays a significant role in modulating immune responses, primarily through the negative regulation of T cell activation and proliferation, as supported by functional studies [Link](https://doi.org/10.1182/blood-2006-07-036210). It is also implicated in promoting the differentiation of regulatory T cells [Link](https://doi.org/10.1002/eji.201445000). Expression data indicates that [IL4I1](/details-gene/259307) is a key marker for several immune cell populations, with particularly high significance in myeloid cells like [dendritic cell, human](/details-cell/CL0001056) and [lung macrophage](/details-cell/CL1001603), as well as lymphoid cells such as [group 3 innate lymphoid cell](/details-cell/CL0001071). Its function as an immunosuppressive enzyme makes it an area of interest in cancer immunology and autoimmune disease research. ## Cellular Roles and Expression Landscape **Overall**, the expression profile of [IL4I1](/details-gene/259307) highlights its central role within the immune system, with high significance across both myeloid and lymphoid lineages. The gene shows the highest significance in [group 3 innate lymphoid cell](/details-cell/CL0001071) (CSI: 18.24), suggesting it may be a critical effector molecule for this cell type, which is known for its function at mucosal barriers. Its prominence in professional antigen-presenting cells is underscored by its high CSI scores in [dendritic cell, human](/details-cell/CL0001056) (CSI: 9.77), [Langerhans cell](/details-cell/CL0000453) (CSI: 5.11), and multiple macrophage subsets, including [lung macrophage](/details-cell/CL1001603) (CSI: 8.96), [alternatively activated macrophage](/details-cell/CL0000890) (CSI: 4.50), and [inflammatory macrophage](/details-cell/CL0000863) (CSI: 3.40). This is consistent with its reported expression in mature dendritic cells and its role in inhibiting T-cell proliferation [Link](https://doi.org/10.1182/blood-2006-07-036210). Within the lymphoid compartment, beyond its top ranking in ILC3s, [IL4I1](/details-gene/259307) is also a significant marker for [CD4-positive helper T cell](/details-cell/CL0000492) (CSI: 8.13), including the [T-helper 17 cell](/details-cell/CL0000899) subset (CSI: 2.97). This pattern, combined with its role in promoting regulatory T cells, suggests [IL4I1](/details-gene/259307) functions as a key enzymatic checkpoint that shapes adaptive immune responses. The notable, albeit lower, significance in [fallopian tube secretory epithelial cell](/details-cell/CL4030006) (CSI: 4.91) indicates potential roles outside of classical immunity, possibly in local tissue homeostasis or reproductive immunology. ## Pathways and Molecular Function The functions of [IL4I1](/details-gene/259307) are rooted in its enzymatic activity and its immunomodulatory consequences. **Molecular Function:** At the molecular level, [IL4I1](/details-gene/259307) is an L-amino acid oxidase ([GO:0001716](https://www.ebi.ac.uk/QuickGO/term/GO:0001716)) with specificity for L-phenylalanine ([GO:0106329](https://www.ebi.ac.uk/QuickGO/term/GO:0106329)). Its catalytic activity is central to several metabolic pathways, including the `Metabolism of amino acids and derivatives` ([R-HSA-71291](https://reactome.org/content/detail/R-HSA-71291)) and specifically `Phenylalanine and tyrosine metabolism` ([R-HSA-8963691](https://reactome.org/content/detail/R-HSA-8963691)). By catabolizing local amino acids, [IL4I1](/details-gene/259307) creates a microenvironment that is nutrient-poor for proliferating cells, such as activated T lymphocytes. **Biological Process:** This metabolic function directly translates into potent immunoregulatory effects. [IL4I1](/details-gene/259307) is a key participant in the `Adaptive immune response` ([GO:0002250](https://www.ebi.ac.uk/QuickGO/term/GO:0002250)), where it primarily acts as a suppressor. It is involved in the `Negative regulation of t cell activation` ([GO:0050868](https://www.ebi.ac.uk/QuickGO/term/GO:0050868)) and `Negative regulation of t cell mediated immune response to tumor cell` ([GO:0002841](https://www.ebi.ac.uk/QuickGO/term/GO:0002841)). This function is consistent with its high expression in antigen-presenting cells found within the tumor microenvironment, such as tumor-associated macrophages [Link](https://doi.org/10.1038/leu.2008.380). Furthermore, it contributes to immune tolerance by promoting `Positive regulation of regulatory t cell differentiation` ([GO:0045591](https://www.ebi.ac.uk/QuickGO/term/GO:0045591)). **Cellular Location:** As a secreted protein, [IL4I1](/details-gene/259307) functions primarily in the `Extracellular region` ([GO:0005576](https://www.ebi.ac.uk/QuickGO/term/GO:0005576)). Its localization to the `Immunological synapse` ([GO:0001772](https://www.ebi.ac.uk/QuickGO/term/GO:0001772)) and `Lysosome` ([GO:0005764](https://www.ebi.ac.uk/QuickGO/term/GO:0005764)) is consistent with a model where it is released by antigen-presenting cells to directly influence interacting T cells. ## Research Directions The role of [IL4I1](/details-gene/259307) as an enzymatic immune checkpoint, particularly its high expression in tumor-infiltrating myeloid cells and certain B-cell lymphomas [Link](https://doi.org/10.1038/leu.2008.380), positions it as a significant factor in tumor immune evasion. Its expression by diverse macrophage populations suggests a dynamic role in shaping tissue microenvironments during inflammation and cancer. **Proposed Hypotheses:** 1. Given its status as the top marker for [group 3 innate lymphoid cell](/details-cell/CL0001071), [IL4I1](/details-gene/259307) may be a critical effector molecule for ILC3s in maintaining mucosal homeostasis. It could achieve this by depleting specific amino acids to limit the expansion of pathogenic microbes or by modulating the activity of neighboring immune cells at barrier surfaces like the gut. 2. The expression of [IL4I1](/details-gene/259307) in functionally distinct macrophage subsets ([alternatively activated macrophage](/details-cell/CL0000890) and [inflammatory macrophage](/details-cell/CL0000863)) suggests its activity is not merely a marker of M2 polarization but a key functional tool used by macrophages to fine-tune inflammatory responses. In tumors, this activity likely contributes to the pro-tumoral, immunosuppressive phenotype of tumor-associated macrophages (TAMs). **Key Experiment:** To test the hypothesis that [IL4I1](/details-gene/259307) is a key effector of macrophage-mediated T cell suppression, a definitive experiment would involve genetic ablation. Primary human monocytes could be isolated and subjected to CRISPR-Cas9-mediated knockout of [IL4I1](/details-gene/259307). These monocytes, alongside control cells, would be differentiated into immunosuppressive M2-like macrophages using cytokines like IL-4 and IL-10. Subsequently, these macrophages would be co-cultured with autologous CD8+ T cells activated via their T-cell receptor. The primary readouts would be T cell proliferation (measured by CFSE dye dilution via flow cytometry) and effector function (quantification of IFN-gamma and granzyme B production by ELISA or intracellular staining). A significant rescue of T cell proliferation and effector function in co-cultures with [IL4I1](/details-gene/259307)-knockout macrophages compared to controls would confirm its critical role in this process. **Therapeutic Potential:** [IL4I1](/details-gene/259307) represents a highly promising target for cancer immunotherapy. As a secreted enzyme that suppresses T cell function, it acts as a metabolic checkpoint that helps tumors evade immune destruction. Therefore, **inhibition** of its enzymatic activity is the most logical therapeutic strategy. This could be pursued through the development of specific small molecule inhibitors or neutralizing monoclonal antibodies. Targeting [IL4I1](/details-gene/259307) could reverse the immunosuppressive microenvironment created by TAMs and other myeloid cells, potentially enhancing the efficacy of other immunotherapies such as PD-1/PD-L1 blockade. Its relatively restricted expression to the immune compartment may offer a favorable safety profile compared to targets with broader expression.

Genular Protein ID: 677367325

Symbol: OXLA_HUMAN

Name: N/A

UniProtKB Accession Codes:

Q96RQ9 Q1WMJ3 Q4GZN1 Q4GZN2 Q6P2Q3 Q8TEM5 Q96RQ8

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 2 CTD 1 ChEBI 38 ChEMBL 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 4 EC 2 EMBL 13 Ensembl 3 ExpressionAtlas 1 GO 21 Gene3D 3 GeneCards 1 GeneTree 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 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PRINTS 1 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 2 RNAct 1 Reactome 1 RefSeq 4 Rhea 10 SMR 1 STRING 1 SUPFAM 2 SignaLink 1 TreeFam 1 UCSC 1 UniPathway 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 12031486

Title: Characterization of the human homolog of the IL-4 induced gene-1 (Fig1).

PubMed ID: 12031486

DOI: 10.1016/s0167-4781(02)00295-6

PubMed ID: 16029492

Title: Alternative pre-mRNA processing regulates cell-type specific expression of the IL4l1 and NUP62 genes.

PubMed ID: 16029492

DOI: 10.1186/1741-7007-3-16

PubMed ID: 12975309

Title: The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment.

PubMed ID: 12975309

DOI: 10.1101/gr.1293003

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: 15340161

Title: Signal peptide prediction based on analysis of experimentally verified cleavage sites.

PubMed ID: 15340161

DOI: 10.1110/ps.04682504

PubMed ID: 12446450

Title: Interleukin 4-induced gene 1 is activated in primary mediastinal large B-cell lymphoma.

PubMed ID: 12446450

DOI: 10.1182/blood-2002-07-2215

PubMed ID: 17356132

Title: Human IL4I1 is a secreted L-phenylalanine oxidase expressed by mature dendritic cells that inhibits T-lymphocyte proliferation.

PubMed ID: 17356132

DOI: 10.1182/blood-2006-07-036210

PubMed ID: 19159218

Title: Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry.

PubMed ID: 19159218

DOI: 10.1021/pr8008012

PubMed ID: 19436310

Title: The novel immunosuppressive enzyme IL4I1 is expressed by neoplastic cells of several B-cell lymphomas and by tumor-associated macrophages.

PubMed ID: 19436310

DOI: 10.1038/leu.2008.380

PubMed ID: 23355881

Title: Antibacterial properties of the mammalian L-amino acid oxidase IL4I1.

PubMed ID: 23355881

DOI: 10.1371/journal.pone.0054589

PubMed ID: 25446972

Title: Differential expression of the immunosuppressive enzyme IL4I1 in human induced Aiolos+, but not natural Helios+, FOXP3+ Treg cells.

PubMed ID: 25446972

DOI: 10.1002/eji.201444897

PubMed ID: 25778793

Title: The immunosuppressive enzyme IL4I1 promotes FoxP3(+) regulatory T lymphocyte differentiation.

PubMed ID: 25778793

DOI: 10.1002/eji.201445000

PubMed ID: 25944712

Title: N-terminome analysis of the human mitochondrial proteome.

PubMed ID: 25944712

DOI: 10.1002/pmic.201400617

PubMed ID: 25767141

Title: Human spermatozoa possess an IL4I1 L-amino acid oxidase with a potential role in sperm function.

PubMed ID: 25767141

DOI: 10.1530/rep-14-0621

PubMed ID: 26673964

Title: Alterations of the immunosuppressive IL4I1 enzyme activity induced by naturally occurring SNP/mutations.

PubMed ID: 26673964

DOI: 10.1038/gene.2015.55

PubMed ID: 28891065

Title: IL4-induced gene 1 is secreted at the immune synapse and modulates TCR activation independently of its enzymatic activity.

PubMed ID: 28891065

DOI: 10.1002/eji.201646769

PubMed ID: 31812258

Title: Identification of inhibitors of the immunosuppressive enzyme IL4I1.

PubMed ID: 31812258

DOI: 10.1016/j.bioorg.2019.103463

PubMed ID: 32818467

Title: IL4I1 is a metabolic immune checkpoint that activates the AHR and promotes tumor progression.

PubMed ID: 32818467

DOI: 10.1016/j.cell.2020.07.038

PubMed ID: 32866000

Title: An endogenous indole pyruvate pathway for tryptophan metabolism mediated by IL4I1.

PubMed ID: 32866000

DOI: 10.1021/acs.jafc.0c03735

Sequence Information:

  • Length: 567
  • Mass: 62881
  • Checksum: FFF953CB28D22F19
  • Sequence:
    • MAPLALHLLV LVPILLSLVA SQDWKAERSQ DPFEKCMQDP DYEQLLKVVT WGLNRTLKPQ 
RVIVVGAGVA GLVAAKVLSD AGHKVTILEA DNRIGGRIFT YRDQNTGWIG ELGAMRMPSS 
HRILHKLCQG LGLNLTKFTQ YDKNTWTEVH EVKLRNYVVE KVPEKLGYAL RPQEKGHSPE 
DIYQMALNQA LKDLKALGCR KAMKKFERHT LLEYLLGEGN LSRPAVQLLG DVMSEDGFFY 
LSFAEALRAH SCLSDRLQYS RIVGGWDLLP RALLSSLSGL VLLNAPVVAM TQGPHDVHVQ 
IETSPPARNL KVLKADVVLL TASGPAVKRI TFSPPLPRHM QEALRRLHYV PATKVFLSFR 
RPFWREEHIE GGHSNTDRPS RMIFYPPPRE GALLLASYTW SDAAAAFAGL SREEALRLAL 
DDVAALHGPV VRQLWDGTGV VKRWAEDQHS QGGFVVQPPA LWQTEKDDWT VPYGRIYFAG 
EHTAYPHGWV ETAVKSALRA AIKINSRKGP ASDTASPEGH ASDMEGQGHV HGVASSPSHD 
LAKEEGSHPP VQGQLSLQNT THTRTSH