# Interleukin 33

> Mediated Wiki article. Canonical URL: https://mediated.wiki/source/Interleukin_33
> Markdown URL: https://mediated.wiki/source/Interleukin_33.md
> Source: https://en.wikipedia.org/wiki/Interleukin_33
> Source revision: 1356960427
> License: Creative Commons Attribution-ShareAlike 4.0 International (https://creativecommons.org/licenses/by-sa/4.0/)

Protein that in humans is encoded by the IL33 gene

"IL-33" redirects here. For the road, see [Illinois Route 33](/source/Illinois_Route_33).

IL33 Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2KLL, 4KC3 Identifiers Aliases IL33, C9orf26, DVS27, IL1F11, NF-HEV, NFEHEV, Interleukin 33, IL-33, IL-1F11 External IDs OMIM: 608678; MGI: 1924375; HomoloGene: 14126; GeneCards: IL33; OMA:IL33 - orthologs Gene location (Human) Chr. Chromosome 9 (human)[1] Band 9p24.1 Start 6,215,786 bp[1] End 6,257,983 bp[1] Gene location (Mouse) Chr. Chromosome 19 (mouse)[2] Band 19|19 C1 Start 29,902,514 bp[2] End 29,938,118 bp[2] RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in Achilles tendon right coronary artery olfactory zone of nasal mucosa smooth muscle tissue left coronary artery Descending thoracic aorta gallbladder lymph node ascending aorta right auricle of heart Top expressed in ciliary body olfactory epithelium sciatic nerve renal capsule iris mucous cell of stomach substantia nigra epithelium of stomach endolymphatic duct esophagus More reference expression data BioGPS n/a Gene ontology Molecular function cytokine activity protein binding Cellular component transport vesicle chromosome cytoplasmic vesicle nucleus extracellular region extracellular space nucleoplasm Biological process negative regulation of interferon-gamma production positive regulation of inflammatory response positive regulation of interleukin-5 production extrinsic apoptotic signaling pathway positive regulation of macrophage activation negative regulation of T-helper 1 type immune response positive regulation of interleukin-4 production transcription, DNA-templated positive regulation of interleukin-13 production positive regulation of gene expression defense response to virus positive regulation of interleukin-6 production positive regulation of type 2 immune response negative regulation of leukocyte migration positive regulation of proteasomal ubiquitin-dependent protein catabolic process positive regulation of transcription by RNA polymerase II microglial cell proliferation macrophage activation involved in immune response microglial cell activation involved in immune response type 2 immune response protein deubiquitination regulation of signaling receptor activity interleukin-33-mediated signaling pathway positive regulation of neuroinflammatory response Sources:Amigo / QuickGO Orthologs Species Human Mouse Entrez 90865 77125 Ensembl ENSG00000137033 ENSMUSG00000024810 UniProt O95760 Q8BVZ5 RefSeq (mRNA) NM_001199640 NM_001199641 NM_001314044 NM_001314045 NM_001314046 NM_001314047 NM_001314048 NM_033439 NM_001353802 NM_001164724 NM_133775 NM_001360725 RefSeq (protein) NP_001186569 NP_001186570 NP_001300973 NP_001300974 NP_001300975 NP_001300976 NP_001300977 NP_254274 NP_001340731 NP_001158196 NP_598536 NP_001347654 Location (UCSC) Chr 9: 6.22 – 6.26 Mb Chr 19: 29.9 – 29.94 Mb PubMed search [3] [4] Wikidata View/Edit Human View/Edit Mouse

**Interleukin 33** (**IL-33**) is a [protein](/source/Protein) that in humans is encoded by the *IL33* [gene](/source/Gene).[5]

Interleukin 33 is a member of the [IL-1](/source/Interleukin_1) family that potently drives production of [T helper-2](/source/T_helper_cell) (Th2)-associated [cytokines](/source/Cytokine) (e.g., [IL-4](/source/Interleukin_4)). IL33 is a ligand for ST2 ([IL1RL1](/source/IL1RL1)), an IL-1 family [receptor](/source/Receptor_(biochemistry)) that is highly expressed on [Th2 cells](/source/Th2_cell), [mast cells](/source/Mast_cell) and [group 2 innate lymphocytes](/source/Innate_lymphoid_cell#Group_2_ILCs).[6]

IL-33 is expressed by a wide variety of cell types, including [fibroblasts](/source/Fibroblast), [mast cells](/source/Mast_cell), [dendritic cells](/source/Dendritic_cell), [macrophages](/source/Macrophage), [osteoblasts](/source/Osteoblast), [endothelial cells](/source/Endothelium), and [epithelial cells](/source/Epithelium).[7]

## Structure

IL-33 is a member of the IL-1 superfamily of cytokines, a determination based in part on the molecules β-trefoil structure, a conserved structure type described in other IL-1 cytokines, including IL-1α, IL-1β, IL-1Ra and [IL-18](/source/Interleukin_18). In this structure, the 12 β-strands of the β-trefoil are arranged in three pseudorepeats of four β-strand units, of which the first and last β-strands are antiparallel staves in a six-stranded β-barrel, while the second and third β-strands of each repeat form a [β-hairpin](/source/%CE%92-hairpin) sitting atop the β-barrel. IL-33 is a ligand that binds to a high-affinity receptor family member ST2. The complex of these two molecules with IL-1RAcP indicates a ternary complex formation. The binding area appears to be a mix of polar and non-polar regions that create a specific binding between ligand and receptor. The interface between the molecules has been shown to be extensive. Structural data on the IL-33 molecule was determined by solution NMR and small angle X-ray scattering.[8]

## Function

Interleukin 33 (IL-33) is a [cytokine](/source/Cytokine) belonging to the [IL-1](/source/Interleukin_1) superfamily. IL-33 induces [helper T cells](/source/Helper_T_cells), [mast cells](/source/Mast_cell), [eosinophils](/source/Eosinophil) and [basophils](/source/Basophil) to produce type 2 cytokines. This cytokine was previously named NF-HEV '[nuclear](/source/Cell_nucleus) factor (NF) in [high endothelial venules](/source/High_endothelial_venules)' (HEVs) since it was originally identified in these specialized cells.[9] IL-33 acts intracellularly as a nuclear factor and extracellularly as a cytokine.

### Role as alarmin

Alarmins, also known as [danger-associated molecular patterns](/source/Danger-associated_molecular_patterns) (DAMPs), are endogenous molecules that are released by stressed, damaged, or dying cells. They play a crucial role in the immune response by alerting the immune system to tissue damage or danger. The bioactive pro-inflammatory form of IL-33 is released from necrotic but not apoptotic cells, classifying it as alarmin. IL-33 released from damaged tissue during viral infection directly stimulates [cytotoxic CD8+ T cells](/source/Cytotoxic_T_cell) for the efficient generation of a memory–recall response and antiviral immunity.[10][11]

### Nuclear role

IL-33 is constitutively located in the nucleus of structural cells of humans and mice[12] and has a helix-turn-helix domain[9] presumably allowing it to bind to DNA. There is a paucity of research into the nuclear role of IL-33 but amino acids 40–58 in human IL-33 are sufficient for nuclear localisation and histone binding.[13] IL-33 also interacts with the [histone methyltransferase](/source/Histone_methyltransferase) [SUV39H1](/source/SUV39H1)[14] and murine appears to IL-33 interact to [NF-κB](/source/NF-%CE%BAB).[15]

### Cytokine role

As a cytokine, IL-33 interacts with the receptors ST2 (also known as [IL1RL1](/source/IL1RL1)) and IL-1 Receptor Accessory Protein ([IL1RAP](/source/IL1RAP)), activating intracellular molecules in the [NF-κB](/source/NF-%CE%BAB) and [MAP kinase](/source/MAP_kinase) signaling pathways that drive production of type 2 cytokines (e.g. [IL-5](/source/Interleukin_5) and [IL-13](/source/Interleukin_13)) from polarized [Th2](/source/Helper_T_cells) cells. The induction of type 2 cytokines by IL-33 *in vivo* is believed to induce the severe [pathological](/source/Pathological) changes observed in [mucosal](/source/Mucosal) organs following administration of IL-33.[16][17] IL-33 is also effective in reversing Alzheimer-like symptoms in APP/PS1 mice, by reversing the buildup and preventing the new formation of amyloid plaques.[18]

### Regulation

Extracellularly, IL-33 is rapidly oxidised. The oxidation process results in the formation of two disulphide bridges and a change in the conformation of the molecule, which prevents it from binding to its receptor, ST2. This is believed to limit the range and duration of the action of IL-33.[19]

## Clinical significance

IL-33 has been associated with several disease states through [Genome Wide Association Studies](/source/Genome-wide_association_study): asthma,[20] allergy,[21] [endometriosis](/source/Endometriosis),[22] and hay fever.[23] In particular, a [single-nucleotide polymorphism](/source/Single-nucleotide_polymorphism) rs928413 (A/G), is located in the 5′ upstream region of IL33 gene, and its minor "G" allele was identified as a susceptible variant for early childhood asthma [24] and atopic asthma [25] development. The rs928413(G) allele creates a binding site for the [cAMP responsive element-binding protein 1](/source/CREB1) transcription factor that may explain the negative effect of the rs928413 minor "G" allele on asthma development.[26] "T" allele of the polymorphism rs4742170 located in the second intron of IL33 gene was linked to specific wheezing phenotype (intermediate-onset wheeze).[27] Risk "T" rs4742170 allele disrupts binding of [GR](/source/Glucocorticoid_receptor) transcription factor to IL33 putative enhancer that may explain the negative effect of the rs4742170 (T) risk allele on the development of wheezing phenotype that strongly correlates with allergic sensitization in childhood.[28]

This protein is one of many that acts as a cytokine and signals inflammation in the body by acting upon macrophages, neutrophils, B cells, Th2 cells, eosinophils, basophils and mast cells.[29] This protein is also thought to cause the itching that is associated with [dermatitis](/source/Dermatitis). The IL-33 protein resides in [keratinocytes](/source/Keratinocyte) of the skin and when subjected to irritation or allergic conditions will communicate with nearby sensory neurons and initiate an itchy feeling.[30] In IL-33 knockout mice, it was discovered that nuclear IL-33 is associated with wound healing as mice without the protein healed significantly slower than mice with the IL-33 protein.[31] Elevated levels of IL-33 are associated with asthma.[32]

In mice, IL-33 was found to effect the production of [methionine-enkephalin peptides](/source/Methionine-enkephalin_peptide) in [group 2 innate lymphocytes](/source/ILC2), in turn promoting the emergence of beige [adipocytes](/source/Adipocyte), which leads to increased energy expenditure and decreased [adiposity](/source/Adiposity).[33]

Elevated levels of IL-33 have been reported in some patients with nonsmall cell lung carcinomas. The source of elevated serum levels of IL-33 during the early stages could be bronchial and vascular epithelium.[34] IL-33 knockdown showed lower growth of nonsmall cell lung carcinomas, while overexpression of IL-33 resulted in increased growth. Blocking of IL-33 reduced the growth of human nonsmall cell lung carcinomas. I mice model blocking of IL-33 inhibited tumor growth in immunodeficient mice.[35][36]

In the mouse colon carcinoma model, IL-33 was expressed by tumor stromal cells, while the colon carcinoma cells did not express ST2 with or without IL-33 stimulation. The IL-33 [knockout model](/source/Knockout_model) had higher tumor growth than wild type. Similarly, [IFN- γ](/source/Interferon_gamma) expression was increased in the IL-33 knockout model as well as the number of T regulatory cells and [CD8+ T cells.](/source/Cytotoxic_T_cell)[37]

Age-related macular degeneration is a retinal disease leading to neovascularization and thus impaired vision. Current treatment includes administration of anti-VEGF but is not sufficient. Retinal pigment epithelial cells can express IL-33 at both mRNA and protein levels. IL-33 expression is upregulated during inflammatory stimuli. IL-33 can inhibit fibroblasts and endothelial cells that express ST2, which can lead to reduced angiogenesis.[38]

In a mouse model of chronic asthma, anti-IL-33 administration decreased antigen-induced immune response. Similar results were found in ST2 deficient mice. IL-33 activated innate lymphoid cells 2 remained in the lymph nodes for several weeks. CD4 + Th2 cells were formed after repeated exposure to IL-33. This type of cells highly produced IL-5.[39]

Chronic inflammation is characteristic for [IBD ( inflammatory bowel disease)](/source/Inflammatory_bowel_disease). Under normal conditions, IL-33 is present in healthy intestinal tissue, but during inflammatory conditions its expression is increased. However, IL-33 has also a protective role under inflammatory conditions and is involved in wound healing.[40]

In brain, IL-33 is expressed in oligodendrocytes and astrocytes and is implicated in the pathophysiology of intracerebral hemorrhage.[41]

## References

1. ^ [***a***](#cite_ref-refGRCh38Ensembl_1-0) [***b***](#cite_ref-refGRCh38Ensembl_1-1) [***c***](#cite_ref-refGRCh38Ensembl_1-2) [GRCh38: Ensembl release 89: ENSG00000137033](http://May2017.archive.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000137033) – [Ensembl](/source/Ensembl_genome_database_project), May 2017

1. ^ [***a***](#cite_ref-refGRCm38Ensembl_2-0) [***b***](#cite_ref-refGRCm38Ensembl_2-1) [***c***](#cite_ref-refGRCm38Ensembl_2-2) [GRCm38: Ensembl release 89: ENSMUSG00000024810](http://May2017.archive.ensembl.org/Mus_musculus/Gene/Summary?db=core;g=ENSMUSG00000024810) – [Ensembl](/source/Ensembl_genome_database_project), May 2017

1. **[^](#cite_ref-3)** ["Human PubMed Reference:"](https://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Link&LinkName=gene_pubmed&from_uid=90865). *National Center for Biotechnology Information, U.S. National Library of Medicine*.

1. **[^](#cite_ref-4)** ["Mouse PubMed Reference:"](https://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Link&LinkName=gene_pubmed&from_uid=77125). *National Center for Biotechnology Information, U.S. National Library of Medicine*.

1. **[^](#cite_ref-entrez_5-0)** ["Entrez Gene: Interleukin 33"](https://www.ncbi.nlm.nih.gov/gene/90865).

1. **[^](#cite_ref-Yagami_2010_6-0)** Yagami A, Orihara K, Morita H, Futamura K, Hashimoto N, Matsumoto K, et al. (November 2010). ["IL-33 mediates inflammatory responses in human lung tissue cells"](https://doi.org/10.4049%2Fjimmunol.0903818). *Journal of Immunology*. **185** (10). Baltimore, Md.: 5743–5750. [doi](/source/Doi_(identifier)):[10.4049/jimmunol.0903818](https://doi.org/10.4049%2Fjimmunol.0903818). [PMID](/source/PMID_(identifier)) [20926795](https://pubmed.ncbi.nlm.nih.gov/20926795). [S2CID](/source/S2CID_(identifier)) [27317847](https://api.semanticscholar.org/CorpusID:27317847).

1. **[^](#cite_ref-7)** Mirchandani AS, Salmond RJ, Liew FY (August 2012). "Interleukin-33 and the function of innate lymphoid cells". *Trends in Immunology*. **33** (8): 389–396. [doi](/source/Doi_(identifier)):[10.1016/j.it.2012.04.005](https://doi.org/10.1016%2Fj.it.2012.04.005). [PMID](/source/PMID_(identifier)) [22609147](https://pubmed.ncbi.nlm.nih.gov/22609147).

1. **[^](#cite_ref-Lingel_2009_8-0)** Lingel A, Weiss TM, Niebuhr M, Pan B, Appleton BA, Wiesmann C, et al. (October 2009). ["Structure of IL-33 and its interaction with the ST2 and IL-1RAcP receptors--insight into heterotrimeric IL-1 signaling complexes"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2766095). *Structure*. **17** (10). London, England: 1398–1410. [doi](/source/Doi_(identifier)):[10.1016/j.str.2009.08.009](https://doi.org/10.1016%2Fj.str.2009.08.009). [PMC](/source/PMC_(identifier)) [2766095](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2766095). [PMID](/source/PMID_(identifier)) [19836339](https://pubmed.ncbi.nlm.nih.gov/19836339).

1. ^ [***a***](#cite_ref-Baekkevold_2003_9-0) [***b***](#cite_ref-Baekkevold_2003_9-1) Baekkevold ES, Roussigné M, Yamanaka T, Johansen FE, Jahnsen FL, Amalric F, et al. (July 2003). ["Molecular characterization of NF-HEV, a nuclear factor preferentially expressed in human high endothelial venules"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1868188). *The American Journal of Pathology*. **163** (1): 69–79. [doi](/source/Doi_(identifier)):[10.1016/S0002-9440(10)63631-0](https://doi.org/10.1016%2FS0002-9440%2810%2963631-0). [PMC](/source/PMC_(identifier)) [1868188](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1868188). [PMID](/source/PMID_(identifier)) [12819012](https://pubmed.ncbi.nlm.nih.gov/12819012).

1. **[^](#cite_ref-10)** Bonilla W (2012). ["The Alarmin Interleukin-33 Drives Protective Antiviral CD8+ T Cell Responses"](https://www.science.org/doi/full/10.1126/science.1215418). *Science*. **335** (6071): 984–989. [doi](/source/Doi_(identifier)):[10.1126/science.1215418](https://doi.org/10.1126%2Fscience.1215418). [PMID](/source/PMID_(identifier)) [22323740](https://pubmed.ncbi.nlm.nih.gov/22323740).

1. **[^](#cite_ref-11)** Baumann C (2019). ["Memory CD8+ T Cell Protection From Viral Reinfection Depends on Interleukin-33 Alarmin Signals"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692449). *Front. Immunol*. **10**: 1833. [doi](/source/Doi_(identifier)):[10.3389/fimmu.2019.01833](https://doi.org/10.3389%2Ffimmu.2019.01833). [PMC](/source/PMC_(identifier)) [6692449](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692449). [PMID](/source/PMID_(identifier)) [31447845](https://pubmed.ncbi.nlm.nih.gov/31447845).

1. **[^](#cite_ref-12)** Pichery M, Mirey E, Mercier P, Lefrancais E, Dujardin A, Ortega N, et al. (April 2012). ["Endogenous IL-33 is highly expressed in mouse epithelial barrier tissues, lymphoid organs, brain, embryos, and inflamed tissues: in situ analysis using a novel Il-33-LacZ gene trap reporter strain"](https://doi.org/10.4049%2Fjimmunol.1101977). *Journal of Immunology*. **188** (7). Baltimore, Md.: 3488–3495. [doi](/source/Doi_(identifier)):[10.4049/jimmunol.1101977](https://doi.org/10.4049%2Fjimmunol.1101977). [PMID](/source/PMID_(identifier)) [22371395](https://pubmed.ncbi.nlm.nih.gov/22371395). [S2CID](/source/S2CID_(identifier)) [42558099](https://api.semanticscholar.org/CorpusID:42558099).

1. **[^](#cite_ref-13)** Roussel L, Erard M, Cayrol C, Girard JP (October 2008). ["Molecular mimicry between IL-33 and KSHV for attachment to chromatin through the H2A-H2B acidic pocket"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2572127). *EMBO Reports*. **9** (10): 1006–1012. [doi](/source/Doi_(identifier)):[10.1038/embor.2008.145](https://doi.org/10.1038%2Fembor.2008.145). [PMC](/source/PMC_(identifier)) [2572127](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2572127). [PMID](/source/PMID_(identifier)) [18688256](https://pubmed.ncbi.nlm.nih.gov/18688256).

1. **[^](#cite_ref-14)** Shao D, Perros F, Caramori G, Meng C, Dormuller P, Chou PC, et al. (August 2014). "Nuclear IL-33 regulates soluble ST2 receptor and IL-6 expression in primary human arterial endothelial cells and is decreased in idiopathic pulmonary arterial hypertension". *Biochemical and Biophysical Research Communications*. **451** (1): 8–14. [doi](/source/Doi_(identifier)):[10.1016/j.bbrc.2014.06.111](https://doi.org/10.1016%2Fj.bbrc.2014.06.111). [hdl](/source/Hdl_(identifier)):[10044/1/32413](https://hdl.handle.net/10044%2F1%2F32413). [PMID](/source/PMID_(identifier)) [25003325](https://pubmed.ncbi.nlm.nih.gov/25003325).

1. **[^](#cite_ref-15)** Ali S, Mohs A, Thomas M, Klare J, Ross R, Schmitz ML, et al. (August 2011). ["The dual function cytokine IL-33 interacts with the transcription factor NF-κB to dampen NF-κB-stimulated gene transcription"](https://doi.org/10.4049%2Fjimmunol.1003080). *Journal of Immunology*. **187** (4). Baltimore, Md.: 1609–1616. [doi](/source/Doi_(identifier)):[10.4049/jimmunol.1003080](https://doi.org/10.4049%2Fjimmunol.1003080). [PMID](/source/PMID_(identifier)) [21734074](https://pubmed.ncbi.nlm.nih.gov/21734074). [S2CID](/source/S2CID_(identifier)) [27523266](https://api.semanticscholar.org/CorpusID:27523266).

1. **[^](#cite_ref-Schmitz_2005_16-0)** Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, et al. (November 2005). ["IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines"](https://doi.org/10.1016%2Fj.immuni.2005.09.015). *Immunity*. **23** (5): 479–490. [doi](/source/Doi_(identifier)):[10.1016/j.immuni.2005.09.015](https://doi.org/10.1016%2Fj.immuni.2005.09.015). [PMID](/source/PMID_(identifier)) [16286016](https://pubmed.ncbi.nlm.nih.gov/16286016).

1. **[^](#cite_ref-Chackerian_2007_17-0)** Chackerian AA, Oldham ER, Murphy EE, Schmitz J, Pflanz S, Kastelein RA (August 2007). ["IL-1 receptor accessory protein and ST2 comprise the IL-33 receptor complex"](https://doi.org/10.4049%2Fjimmunol.179.4.2551). *Journal of Immunology*. **179** (4). Baltimore, Md.: 2551–2555. [doi](/source/Doi_(identifier)):[10.4049/jimmunol.179.4.2551](https://doi.org/10.4049%2Fjimmunol.179.4.2551). [PMID](/source/PMID_(identifier)) [17675517](https://pubmed.ncbi.nlm.nih.gov/17675517). [S2CID](/source/S2CID_(identifier)) [9289093](https://api.semanticscholar.org/CorpusID:9289093).

1. **[^](#cite_ref-Fu_2016_18-0)** Fu AK, Hung KW, Yuen MY, Zhou X, Mak DS, Chan IC, et al. (May 2016). ["IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4868478). *Proceedings of the National Academy of Sciences of the United States of America*. **113** (19): E2705–E2713. [Bibcode](/source/Bibcode_(identifier)):[2016PNAS..113E2705F](https://ui.adsabs.harvard.edu/abs/2016PNAS..113E2705F). [doi](/source/Doi_(identifier)):[10.1073/pnas.1604032113](https://doi.org/10.1073%2Fpnas.1604032113). [PMC](/source/PMC_(identifier)) [4868478](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4868478). [PMID](/source/PMID_(identifier)) [27091974](https://pubmed.ncbi.nlm.nih.gov/27091974).

1. **[^](#cite_ref-Cohen_2015_19-0)** Cohen ES, Scott IC, Majithiya JB, Rapley L, Kemp BP, England E, et al. (September 2015). ["Oxidation of the alarmin IL-33 regulates ST2-dependent inflammation"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4579851). *Nature Communications*. **6**: 8327. [Bibcode](/source/Bibcode_(identifier)):[2015NatCo...6.8327C](https://ui.adsabs.harvard.edu/abs/2015NatCo...6.8327C). [doi](/source/Doi_(identifier)):[10.1038/ncomms9327](https://doi.org/10.1038%2Fncomms9327). [PMC](/source/PMC_(identifier)) [4579851](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4579851). [PMID](/source/PMID_(identifier)) [26365875](https://pubmed.ncbi.nlm.nih.gov/26365875).

1. **[^](#cite_ref-20)** Moffatt MF, Gut IG, Demenais F, Strachan DP, Bouzigon E, Heath S, et al. (September 2010). ["A large-scale, consortium-based genomewide association study of asthma"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260321). *The New England Journal of Medicine*. **363** (13): 1211–1221. [doi](/source/Doi_(identifier)):[10.1056/NEJMoa0906312](https://doi.org/10.1056%2FNEJMoa0906312). [PMC](/source/PMC_(identifier)) [4260321](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260321). [PMID](/source/PMID_(identifier)) [20860503](https://pubmed.ncbi.nlm.nih.gov/20860503).

1. **[^](#cite_ref-21)** Hinds DA, McMahon G, Kiefer AK, Do CB, Eriksson N, Evans DM, et al. (August 2013). ["A genome-wide association meta-analysis of self-reported allergy identifies shared and allergy-specific susceptibility loci"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753407). *Nature Genetics*. **45** (8): 907–911. [doi](/source/Doi_(identifier)):[10.1038/ng.2686](https://doi.org/10.1038%2Fng.2686). [PMC](/source/PMC_(identifier)) [3753407](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753407). [PMID](/source/PMID_(identifier)) [23817569](https://pubmed.ncbi.nlm.nih.gov/23817569).

1. **[^](#cite_ref-22)** Albertsen HM, Chettier R, Farrington P, Ward K (2013-01-01). ["Genome-wide association study link novel loci to endometriosis"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3589333). *PLOS ONE*. **8** (3) e58257. [Bibcode](/source/Bibcode_(identifier)):[2013PLoSO...858257A](https://ui.adsabs.harvard.edu/abs/2013PLoSO...858257A). [doi](/source/Doi_(identifier)):[10.1371/journal.pone.0058257](https://doi.org/10.1371%2Fjournal.pone.0058257). [PMC](/source/PMC_(identifier)) [3589333](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3589333). [PMID](/source/PMID_(identifier)) [23472165](https://pubmed.ncbi.nlm.nih.gov/23472165).

1. **[^](#cite_ref-23)** Ferreira MA, Matheson MC, Tang CS, Granell R, Ang W, Hui J, et al. (June 2014). ["Genome-wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4280183). *The Journal of Allergy and Clinical Immunology*. **133** (6): 1564–1571. [doi](/source/Doi_(identifier)):[10.1016/j.jaci.2013.10.030](https://doi.org/10.1016%2Fj.jaci.2013.10.030). [PMC](/source/PMC_(identifier)) [4280183](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4280183). [PMID](/source/PMID_(identifier)) [24388013](https://pubmed.ncbi.nlm.nih.gov/24388013).

1. **[^](#cite_ref-24)** Bønnelykke K, Sleiman P, Nielsen K, Kreiner-Møller E, Mercader JM, Belgrave D, et al. (January 2014). ["A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations"](http://orbit.dtu.dk/en/publications/a-genomewide-association-study-identifies-cdhr3-as-a-susceptibility-locus-for-early-childhood-asthma-with-severe-exacerbations(b0ec6ece-a73d-497e-b688-b5b810b430ba).html). *Nature Genetics*. **46** (1): 51–55. [doi](/source/Doi_(identifier)):[10.1038/ng.2830](https://doi.org/10.1038%2Fng.2830). [PMID](/source/PMID_(identifier)) [24241537](https://pubmed.ncbi.nlm.nih.gov/24241537). [S2CID](/source/S2CID_(identifier)) [20754856](https://api.semanticscholar.org/CorpusID:20754856).

1. **[^](#cite_ref-25)** Chen J, Zhang J, Hu H, Jin Y, Xue M (December 2015). "Polymorphisms of RAD50, IL33 and IL1RL1 are associated with atopic asthma in Chinese population". *Tissue Antigens*. **86** (6): 443–447. [doi](/source/Doi_(identifier)):[10.1111/tan.12688](https://doi.org/10.1111%2Ftan.12688). [PMID](/source/PMID_(identifier)) [26493291](https://pubmed.ncbi.nlm.nih.gov/26493291).

1. **[^](#cite_ref-26)** Gorbacheva AM, Korneev KV, Kuprash DV, Mitkin NA (September 2018). ["IL33 Promoter in Lung Epithelial Cells"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6212888). *International Journal of Molecular Sciences*. **19** (10) E2911. [doi](/source/Doi_(identifier)):[10.3390/ijms19102911](https://doi.org/10.3390%2Fijms19102911). [PMC](/source/PMC_(identifier)) [6212888](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6212888). [PMID](/source/PMID_(identifier)) [30257479](https://pubmed.ncbi.nlm.nih.gov/30257479).

1. **[^](#cite_ref-27)** Savenije OE, Mahachie John JM, Granell R, Kerkhof M, Dijk FN, de Jongste JC, et al. (July 2014). "Association of IL33-IL-1 receptor-like 1 (IL1RL1) pathway polymorphisms with wheezing phenotypes and asthma in childhood". *The Journal of Allergy and Clinical Immunology*. **134** (1): 170–177. [doi](/source/Doi_(identifier)):[10.1016/j.jaci.2013.12.1080](https://doi.org/10.1016%2Fj.jaci.2013.12.1080). [PMID](/source/PMID_(identifier)) [24568840](https://pubmed.ncbi.nlm.nih.gov/24568840).

1. **[^](#cite_ref-28)** Gorbacheva AM, Kuprash DV, Mitkin NA (December 2018). ["IL33 Enhancer and is Disrupted by rs4742170 (T) Allele Associated with Specific Wheezing Phenotype in Early Childhood"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321062). *International Journal of Molecular Sciences*. **19** (12) E3956. [doi](/source/Doi_(identifier)):[10.3390/ijms19123956](https://doi.org/10.3390%2Fijms19123956). [PMC](/source/PMC_(identifier)) [6321062](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321062). [PMID](/source/PMID_(identifier)) [30544846](https://pubmed.ncbi.nlm.nih.gov/30544846).

1. **[^](#cite_ref-29)** Tizard I (2012). *Veterinary immunology: an introduction* (9th ed.). St. Louis, Mo.: Elsevier/Saunders. [ISBN](/source/ISBN_(identifier)) [978-1-4557-0362-3](https://en.wikipedia.org/wiki/Special:BookSources/978-1-4557-0362-3).

1. **[^](#cite_ref-Liu_2016_30-0)** Liu B, Tai Y, Achanta S, Kaelberer MM, Caceres AI, Shao X, et al. (November 2016). ["IL-33/ST2 signaling excites sensory neurons and mediates itch response in a mouse model of poison ivy contact allergy"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127381). *Proceedings of the National Academy of Sciences of the United States of America*. **113** (47): E7572–E7579. [Bibcode](/source/Bibcode_(identifier)):[2016PNAS..113E7572L](https://ui.adsabs.harvard.edu/abs/2016PNAS..113E7572L). [doi](/source/Doi_(identifier)):[10.1073/pnas.1606608113](https://doi.org/10.1073%2Fpnas.1606608113). [PMC](/source/PMC_(identifier)) [5127381](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127381). [PMID](/source/PMID_(identifier)) [27821781](https://pubmed.ncbi.nlm.nih.gov/27821781).

1. **[^](#cite_ref-Oshio_2017_31-0)** Oshio T, Komine M, Tsuda H, Tominaga SI, Saito H, Nakae S, et al. (February 2017). "Nuclear expression of IL-33 in epidermal keratinocytes promotes wound healing in mice". *Journal of Dermatological Science*. **85** (2): 106–114. [doi](/source/Doi_(identifier)):[10.1016/j.jdermsci.2016.10.008](https://doi.org/10.1016%2Fj.jdermsci.2016.10.008). [PMID](/source/PMID_(identifier)) [27839630](https://pubmed.ncbi.nlm.nih.gov/27839630).

1. **[^](#cite_ref-Bahrami_Mahneh_2015_32-0)** Bahrami Mahneh S, Movahedi M, Aryan Z, Bahar MA, Rezaei A, Sadr M, et al. (2015). ["Serum IL-33 Is Elevated in Children with Asthma and Is Associated with Disease Severity"](https://doi.org/10.1159%2F000442413). *International Archives of Allergy and Immunology*. **168** (3): 193–196. [doi](/source/Doi_(identifier)):[10.1159/000442413](https://doi.org/10.1159%2F000442413). [PMID](/source/PMID_(identifier)) [26797312](https://pubmed.ncbi.nlm.nih.gov/26797312). [S2CID](/source/S2CID_(identifier)) [40501434](https://api.semanticscholar.org/CorpusID:40501434).

1. **[^](#cite_ref-33)** Brestoff JR, Kim BS, Saenz SA, Stine RR, Monticelli LA, Sonnenberg GF, et al. (March 2015). ["Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4447235). *Nature*. **519** (7542): 242–246. [Bibcode](/source/Bibcode_(identifier)):[2015Natur.519..242B](https://ui.adsabs.harvard.edu/abs/2015Natur.519..242B). [doi](/source/Doi_(identifier)):[10.1038/nature14115](https://doi.org/10.1038%2Fnature14115). [PMC](/source/PMC_(identifier)) [4447235](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4447235). [PMID](/source/PMID_(identifier)) [25533952](https://pubmed.ncbi.nlm.nih.gov/25533952).

1. **[^](#cite_ref-34)** Casciaro M, Cardia R, Di Salvo E, Tuccari G, Ieni A, Gangemi S (May 2019). ["Interleukin-33 Involvement in Nonsmall Cell Lung Carcinomas: An Update"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6572046). *Biomolecules*. **9** (5): 203. [doi](/source/Doi_(identifier)):[10.3390/biom9050203](https://doi.org/10.3390%2Fbiom9050203). [PMC](/source/PMC_(identifier)) [6572046](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6572046). [PMID](/source/PMID_(identifier)) [31130612](https://pubmed.ncbi.nlm.nih.gov/31130612).

1. **[^](#cite_ref-35)** Wang K, Shan S, Yang Z, Gu X, Wang Y, Wang C, et al. (September 2017). ["IL-33 blockade suppresses tumor growth of human lung cancer through direct and indirect pathways in a preclinical model"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620278). *Oncotarget*. **8** (40): 68571–68582. [doi](/source/Doi_(identifier)):[10.18632/oncotarget.19786](https://doi.org/10.18632%2Foncotarget.19786). [PMC](/source/PMC_(identifier)) [5620278](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620278). [PMID](/source/PMID_(identifier)) [28978138](https://pubmed.ncbi.nlm.nih.gov/28978138).

1. **[^](#cite_ref-36)** Wang C, Chen Z, Bu X, Han Y, Shan S, Ren T, et al. (October 2016). "IL-33 signaling fuels outgrowth and metastasis of human lung cancer". *Biochemical and Biophysical Research Communications*. **479** (3): 461–468. [doi](/source/Doi_(identifier)):[10.1016/j.bbrc.2016.09.081](https://doi.org/10.1016%2Fj.bbrc.2016.09.081). [PMID](/source/PMID_(identifier)) [27644880](https://pubmed.ncbi.nlm.nih.gov/27644880).

1. **[^](#cite_ref-37)** Xia Y, Ohno T, Nishii N, Bhingare A, Tachinami H, Kashima Y, et al. (August 2019). "+ T cell antitumor responses overcoming pro-tumor effects by regulatory T cells in a colon carcinoma model". *Biochemical and Biophysical Research Communications*. **518** (2): 331–336. [doi](/source/Doi_(identifier)):[10.1016/j.bbrc.2019.08.058](https://doi.org/10.1016%2Fj.bbrc.2019.08.058). [PMID](/source/PMID_(identifier)) [31421832](https://pubmed.ncbi.nlm.nih.gov/31421832). [S2CID](/source/S2CID_(identifier)) [201062815](https://api.semanticscholar.org/CorpusID:201062815).

1. **[^](#cite_ref-38)** Theodoropoulou S, Copland DA, Liu J, Wu J, Gardner PJ, Ozaki E, et al. (January 2017). ["Interleukin-33 regulates tissue remodelling and inhibits angiogenesis in the eye"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5683707). *The Journal of Pathology*. **241** (1): 45–56. [doi](/source/Doi_(identifier)):[10.1002/path.4816](https://doi.org/10.1002%2Fpath.4816). [PMC](/source/PMC_(identifier)) [5683707](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5683707). [PMID](/source/PMID_(identifier)) [27701734](https://pubmed.ncbi.nlm.nih.gov/27701734).

1. **[^](#cite_ref-39)** Drake LY, Kita H (July 2017). ["IL-33: biological properties, functions, and roles in airway disease"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5492954). *Immunological Reviews*. **278** (1): 173–184. [doi](/source/Doi_(identifier)):[10.1111/imr.12552](https://doi.org/10.1111%2Fimr.12552). [PMC](/source/PMC_(identifier)) [5492954](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5492954). [PMID](/source/PMID_(identifier)) [28658560](https://pubmed.ncbi.nlm.nih.gov/28658560).

1. **[^](#cite_ref-40)** Chen J, He Y, Tu L, Duan L (2019). ["Dual immune functions of IL-33 in inflammatory bowel disease"](https://web.archive.org/web/20190828213942/http://www.hh.um.es/Abstracts/Vol_/_/__18149.htm). *Histology and Histopathology*. **35** (2): 137–146. [doi](/source/Doi_(identifier)):[10.14670/HH-18-149](https://doi.org/10.14670%2FHH-18-149). [PMID](/source/PMID_(identifier)) [31294456](https://pubmed.ncbi.nlm.nih.gov/31294456). Archived from [the original](http://www.hh.um.es/Abstracts/Vol_/_/__18149.htm) on 2019-08-28. Retrieved 2019-08-28.

1. **[^](#cite_ref-41)** Zhu H, Wang Z, Yu J, Yang X, He F, Liu Z, et al. (March 2019). "Role and mechanisms of cytokines in the secondary brain injury after intracerebral hemorrhage". *Progress in Neurobiology*. **178**: 101610. [doi](/source/Doi_(identifier)):[10.1016/j.pneurobio.2019.03.003](https://doi.org/10.1016%2Fj.pneurobio.2019.03.003). [PMID](/source/PMID_(identifier)) [30923023](https://pubmed.ncbi.nlm.nih.gov/30923023). [S2CID](/source/S2CID_(identifier)) [85495400](https://api.semanticscholar.org/CorpusID:85495400).

## External links

- Overview of all the structural information available in the [PDB](/source/Protein_Data_Bank) for [UniProt](/source/UniProt): *[O95760](https://www.ebi.ac.uk/pdbe/pdbe-kb/proteins/O95760)* (Interleukin-33) at the [PDBe-KB](/source/PDBe-KB).

v t e Cell signaling: cytokines By family Chemokine CCL CCL1 CCL2/MCP1 CCL3/MIP1α CCL4/MIP1β CCL5/RANTES CCL6 CCL7 CCL8 CCL9 CCL11 CCL12 CCL13 CCL14 CCL15 CCL16 CCL17 CCL18/PARC/DCCK1/AMAC1/MIP4 CCL19 CCL20 CCL21 CCL22 CCL23 CCL24 CCL25 CCL26 CCL27 CCL28 CXCL CXCL1/KC CXCL2 CXCL3 CXCL4 CXCL5 CXCL6 CXCL7 CXCL8/IL8 CXCL9 CXCL10 CXCL11 CXCL12 CXCL13 CXCL14 CXCL15 CXCL16 CXCL17 CX3CL CX3CL1 XCL XCL1 XCL2 TNF TNFA Lymphotoxin TNFB/LTA TNFC/LTB TNFSF4 TNFSF5/CD40LG TNFSF6 TNFSF7 TNFSF8 TNFSF9 TNFSF10 TNFSF11 TNFSF13 TNFSF13B EDA Interleukin Type I (grouped by receptor subunit) γ chain IL2/IL15 IL4/IL13 IL7 IL9 IL21 β chain IL3 IL5 GMCSF IL6 like/gp130 IL6 IL11 IL27 IL30 IL31 +non IL OSM LIF CNTF CTF1 IL12 family/IL12RB1 IL12 IL23 IL27 IL35 Other IL14 IL16 IL32 IL34 Type II IL10 family IL10/IL22 IL19 IL20 IL24 IL26 Interferon type III IL28/IFNL2+3 IL29/IFNL1 Interferon I IFNA1 IFNA2 IFNA4 IFNA5 IFNA6 IFNA7 IFNA8 IFNA10 IFNA13 IFNA14 IFNA16 IFNA17 IFNA21 IFNB1 IFNK IFNW1 II IFNG Ig superfamily IL1 family: IL1A/IL1F1 IL1B/IL1F2 1Ra/IL1F3 IL1F5 IL1F6 IL1F7 IL1F8 IL1F9 IL1F10 33/IL1F11 18/IL1G IL17 family IL17/IL25 (IL17A) Other Hematopoietic KITLG Colony-stimulating factor SPP1 MIF By function/ cell proinflammatory cytokine IL1 TNFA Monokine Lymphokine Th1 IFNγ TNFβ Th2 IL4 IL5 IL6 IL10 IL13 Category Commons

v t e Interleukin receptor modulators IL-1 Agonists: Interleukin 1 (α, β) Mobenakin Pifonakin Antagonists: AF-12198 Anakinra IL-1RA Isunakinra Antibodies: Canakinumab Gevokizumab Lutikizumab Decoy receptors: Rilonacept (IL-1 Trap) IL-2 Agonists: Adargileukin alfa Aldesleukin Celmoleukin Denileukin diftitox Interleukin 2 Pegaldesleukin Teceleukin Tucotuzumab celmoleukin Antibodies: Basiliximab Daclizumab (dacliximab) Inolimomab IL-3 Agonists: Daniplestim Interleukin 3 Leridistim Milodistim Muplestim Promegapoietin IL-4 Agonists: Binetrakin Interleukin 4 Interleukin 13 Antagonists: Pitrakinra Antibodies: Dupilumab Pascolizumab IL-5 Agonists: Interleukin 5 Antagonists: YM-90709 Antibodies: Benralizumab Mepolizumab Reslizumab Antisense oligonucleotides: TPI ASM8 IL-6 Agonists: Atexakin alfa Interleukin 6 Antibodies: ARGX-109 Clazakizumab Elsilimomab mAb 1339 Olokizumab Sarilumab Siltuximab Sirukumab Tocilizumab Levilimab IL-7 Agonists: Interleukin 7 IL-8 See CXCR1 (IL-8Rα) and CXCR2 (IL-8Rβ) here instead. IL-9 Agonists: Interleukin 9 Antibodies: Enokizumab IL-10 Agonists: Ilodecakin Interleukin 10 (CSIF) IL-11 Agonists: Interleukin 11 (AGIF) Oprelvekin IL-12 Agonists: Edodekin alfa Interleukin 12 Antibodies: Briakinumab Ustekinumab IL-13 Agonists: Binetrakin Cintredekin besudotox Interleukin 4 Interleukin 13 Antibodies: Anrukinzumab Lebrikizumab Tralokinumab IL-15 Agonists: ALT-803 Interleukin 15 IL-17 Agonists: Interleukin 17 (A, B, C, D, E (interleukin 25), F) Antibodies: Brodalumab Ixekizumab Perakizumab Remtolumab Secukinumab Vunakizumab IL-18 Agonists: Iboctadekin Interleukin 18 Interleukin 37 Tadekinig Binding proteins: IL18BP IL-20 Agonists: Interleukin 19 Interleukin 20 Interleukin 24 Antibodies: Fletikumab (against IL-20) IL-21 Agonists: Denenicokin Interleukin 21 Antibodies: NNC0114-0005 NNC0114-0006 IL-22 Agonists: Interleukin 22 Antibodies: Fezakinumab (against IL-22) IL-23 Agonists: Interleukin 23 (SGRF) Antibodies: Brazikumab Briakinumab Guselkumab Risankizumab Tildrakizumab Ustekinumab IL-27 Agonists: Interleukin 27 (interleukin 30) IL-28 Agonists: Interferon λ4 (IFN-λ4) Interleukin 28 (A (IFN-λ2), B (IFN-λ3)) Interleukin-29 (IFN-λ1) IL-31 Agonists: Interleukin 31 IL1RL1 Agonists: Interleukin 33 IL1RL2 Agonists: Interleukin 36 (α, β, γ) Interleukin 38 Antagonists: IL-36RA Others JAK See here instead. Others Interleukin 14 (taxilin alpha, HMW-BCGF) Interleukin 16 (signals through CD4) Interleukin 24 (signals through IL-22Rα1/IL-20Rβ heterodimer) Interleukin 26 (signals through IL-20Rα/IL-10Rβ heterodimer) Interleukin 32 Interleukin 34 (signals through M-CSFR/CSF1R) Interleukin 35 Unsorted: Efavaleukin alfa Efineptakin alfa

*This article incorporates text from the [United States National Library of Medicine](/source/United_States_National_Library_of_Medicine), which is in the [public domain](/source/Public_domain).*

---
Adapted from the Wikipedia article [Interleukin 33](https://en.wikipedia.org/wiki/Interleukin_33) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/Interleukin_33?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.