IL33

HIGH

Interleukin 33

Chromosome: 9p24.1

Gene Overview

IL33 encodes interleukin-33, a dual-function cytokine and nuclear factor belonging to the IL-1 family. IL-33 functions as an epithelial alarmin: it is constitutively expressed in barrier tissues (lung, skin, gut) and released upon cell damage or stress, acting as a danger signal to activate innate and adaptive immune cells. Full-length IL-33 binds the ST2 (IL1RL1) receptor on group 2 innate lymphoid cells (ILC2s), mast cells, Th2 lymphocytes, and eosinophils, driving type 2 immunity. Proteolytic cleavage by allergens or inflammatory proteases generates mature forms with enhanced activity. Asthma-associated GWAS variants regulate IL33 expression through an enhancer-blocking element ~2.3 kb upstream, with differential OCT-1 (POU2F1) binding. IL-33 is upregulated by PM2.5, allergens, and viral infections, positioning it at the interface of environmental exposure and genetic susceptibility in asthma.

Molecular Function

  • cytokine activity
  • alarmin signaling
  • innate immune activation

Protein class: cytokine

Regulatory Annotation

Promoter activity: Promoter contains NF-κB and AP-1 binding sites; IL33 expression induced by NF-κB activation.

Enhancer associations: Asthma-associated variants (e.g., rs1888909) lie in a regulatory region 2.3 kb upstream; chromatin conformation capture shows looping to IL33 promoter.

eQTL tissues: lung, bronchial epithelium

Tissue Expression Context

lungTPM range: 5–25GTEx vv8
bronchial epitheliumTPM range: 10–40GTEx vv8
skinTPM range: 8–30
intestinal epitheliumTPM range: 5–20

Pathways

Linked Diseases & Exposures

Diseases

Exposures

Mechanistic Hypotheses

PM2.5-induced oxidative stress and NF-κB activation drive IL33 transcription and release from bronchial epithelium; genetic variants increasing basal IL33 expression amplify this response, explaining G×E interaction.

In vitro and in vivo studies show PM2.5 upregulates IL-33; asthma-risk alleles correlate with elevated IL-33.

HIGH

IL-33 released from damaged epithelial cells activates ILC2s and mast cells via ST2; sustained release under chronic PM2.5 exposure promotes eosinophilic inflammation and airway hyperresponsiveness.

IL-33/ST2 axis well-characterized; IL-33 blockade attenuates inflammation in models.

HIGH

Asthma-risk alleles at the IL33 enhancer increase IL-33 protein in plasma and airway; this genetically determined baseline modulates susceptibility to environmental triggers including allergens and pollution.

Alvarez et al. 2021 show enhancer-blocking mechanism; eQTL data support genotype-expression correlation.

HIGH

Confidence Rating

Overall evidence confidence for this gene entry: HIGH

References

  1. 1.Alvarez M, et al. (2021). Asthma-associated genetic variants induce IL33 differential expression through an enhancer-blocking regulatory region. Nature Communications. doi:10.1038/s41467-021-26347-z
  2. 2.Brandenburg AH, et al. (2014). Ambient particulate matter induces an exacerbation of airway inflammation in experimental asthma: role of interleukin-33. Clinical & Experimental Immunology. doi:10.1111/cei.12348
  3. 3.Liew FY, et al. (2016). IL-33 and the intestine: the role in intestinal inflammation and gut immunity. Mucosal Immunology. doi:10.1038/mi.2015.100
  4. 4.Cayrol C, Girard JP (2018). The IL-33/ST2 axis: Role in health and disease. Cytokine & Growth Factor Reviews. doi:10.1016/j.cytogfr.2018.01.001
  5. 5.GTEx Consortium (2020). GTEx Consortium. The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science. doi:10.1126/science.aaz1776