Interleukin 33

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. 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 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.{{cite journal | vauthors = Lingel A, Weiss TM, Niebuhr M, Pan B, Appleton BA, Wiesmann C, Bazan JF, Fairbrother WJ | title = Structure of IL-33 and its interaction with the ST2 and IL-1RAcP receptors--insight into heterotrimeric IL-1 signaling complexes | journal = Structure | location = London, England | volume = 17 | issue = 10 | pages = 1398–1410 | date = October 2009 | pmid = 19836339 | pmc = 2766095 | doi = 10.1016/j.str.2009.08.009 }}

Interleukin 33 (IL-33) is a cytokine belonging to the IL-1 superfamily. IL-33 induces helper T cells, mast cells, eosinophils and basophils to produce type 2 cytokines. This cytokine was previously named NF-HEV 'nuclear factor (NF) in high endothelial venules' (HEVs) since it was originally identified in these specialized cells.{{cite journal | vauthors = Baekkevold ES, Roussigné M, Yamanaka T, Johansen FE, Jahnsen FL, Amalric F, Brandtzaeg P, Erard M, Haraldsen G, Girard JP | title = Molecular characterization of NF-HEV, a nuclear factor preferentially expressed in human high endothelial venules | journal = The American Journal of Pathology | volume = 163 | issue = 1 | pages = 69–79 | date = July 2003 | pmid = 12819012 | pmc = 1868188 | doi = 10.1016/S0002-9440(10)63631-0 }} IL-33 acts intracellularly as a nuclear factor and extracellularly as a cytokine.

Alarmins, also known as 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 for the efficient generation of a memory–recall response and antiviral immunity. {{cite journal | vauthors = Bonilla W | title = The Alarmin Interleukin-33 Drives Protective Antiviral CD8+ T Cell Responses | journal = Science | date = 2012 | volume = 335 | issue = 6071 | pages = 984–989 | doi = 10.1126/science.1215418 | pmid = 22323740 | url = https://www.science.org/doi/full/10.1126/science.1215418 }}{{cite journal | vauthors = Baumann C | title = Memory CD8+ T Cell Protection From Viral Reinfection Depends on Interleukin-33 Alarmin Signals | journal = Front. Immunol | date = 2019 | volume = 10 | page = 1833 | pmid = 31447845 | doi = 10.3389/fimmu.2019.01833 | doi-access = free | pmc = 6692449 }}

IL-33 is constitutively located in the nucleus of structural cells of humans and mice{{cite journal | vauthors = Pichery M, Mirey E, Mercier P, Lefrancais E, Dujardin A, Ortega N, Girard JP | title = 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 | journal = Journal of Immunology | location = Baltimore, Md. | volume = 188 | issue = 7 | pages = 3488–3495 | date = April 2012 | pmid = 22371395 | doi = 10.4049/jimmunol.1101977 | s2cid = 42558099 | doi-access = free }} and has a helix-turn-helix domain 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.{{cite journal | vauthors = Roussel L, Erard M, Cayrol C, Girard JP | title = Molecular mimicry between IL-33 and KSHV for attachment to chromatin through the H2A-H2B acidic pocket | journal = EMBO Reports | volume = 9 | issue = 10 | pages = 1006–1012 | date = October 2008 | pmid = 18688256 | pmc = 2572127 | doi = 10.1038/embor.2008.145 }} IL-33 also interacts with the histone methyltransferase SUV39H1{{cite journal | vauthors = Shao D, Perros F, Caramori G, Meng C, Dormuller P, Chou PC, Church C, Papi A, Casolari P, Welsh D, Peacock A, Humbert M, Adcock IM, Wort SJ | title = 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 | journal = Biochemical and Biophysical Research Communications | volume = 451 | issue = 1 | pages = 8–14 | date = August 2014 | pmid = 25003325 | doi = 10.1016/j.bbrc.2014.06.111 | hdl = 10044/1/32413 | hdl-access = free }} and murine appears to IL-33 interact to NF-κB.{{cite journal | vauthors = Ali S, Mohs A, Thomas M, Klare J, Ross R, Schmitz ML, Martin MU | title = The dual function cytokine IL-33 interacts with the transcription factor NF-κB to dampen NF-κB-stimulated gene transcription | journal = Journal of Immunology | location = Baltimore, Md. | volume = 187 | issue = 4 | pages = 1609–1616 | date = August 2011 | pmid = 21734074 | doi = 10.4049/jimmunol.1003080 | s2cid = 27523266 | doi-access = free }}

As a cytokine, IL-33 interacts with the receptors ST2 (also known as IL1RL1) and IL-1 Receptor Accessory Protein (IL1RAP), activating intracellular molecules in the NF-κB and MAP kinase signaling pathways that drive production of type 2 cytokines (e.g. IL-5 and IL-13) from polarized Th₂ cells. The induction of type 2 cytokines by IL-33 in vivo is believed to induce the severe pathological changes observed in mucosal organs following administration of IL-33.{{cite journal | vauthors = Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, Zurawski G, Moshrefi M, Qin J, Li X, Gorman DM, Bazan JF, Kastelein RA | title = 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 | journal = Immunity | volume = 23 | issue = 5 | pages = 479–490 | date = November 2005 | pmid = 16286016 | doi = 10.1016/j.immuni.2005.09.015 | doi-access = free }}{{cite journal | vauthors = Chackerian AA, Oldham ER, Murphy EE, Schmitz J, Pflanz S, Kastelein RA | title = IL-1 receptor accessory protein and ST2 comprise the IL-33 receptor complex | journal = Journal of Immunology | location = Baltimore, Md. | volume = 179 | issue = 4 | pages = 2551–2555 | date = August 2007 | pmid = 17675517 | doi = 10.4049/jimmunol.179.4.2551 | s2cid = 9289093 | doi-access = free }} 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.{{cite journal | vauthors = Fu AK, Hung KW, Yuen MY, Zhou X, Mak DS, Chan IC, Cheung TH, Zhang B, Fu WY, Liew FY, Ip NY | title = IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 113 | issue = 19 | pages = E2705–E2713 | date = May 2016 | pmid = 27091974 | pmc = 4868478 | doi = 10.1073/pnas.1604032113 | bibcode = 2016PNAS..113E2705F | doi-access = free }}

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.{{cite journal | vauthors = Cohen ES, Scott IC, Majithiya JB, Rapley L, Kemp BP, England E, Rees DG, Overed-Sayer CL, Woods J, Bond NJ, Veyssier CS, Embrey KJ, Sims DA, Snaith MR, Vousden KA, Strain MD, Chan DT, Carmen S, Huntington CE, Flavell L, Xu J, Popovic B, Brightling CE, Vaughan TJ, Butler R, Lowe DC, Higazi DR, Corkill DJ, May RD, Sleeman MA, Mustelin T | title = Oxidation of the alarmin IL-33 regulates ST2-dependent inflammation | journal = Nature Communications | volume = 6 | pages = 8327 | date = September 2015 | pmid = 26365875 | pmc = 4579851 | doi = 10.1038/ncomms9327 | bibcode = 2015NatCo...6.8327C }}

IL-33 has been associated with several disease states through Genome Wide Association Studies: asthma,{{cite journal | vauthors = Moffatt MF, Gut IG, Demenais F, Strachan DP, Bouzigon E, Heath S, von Mutius E, Farrall M, Lathrop M, Cookson WO | title = A large-scale, consortium-based genomewide association study of asthma | journal = The New England Journal of Medicine | volume = 363 | issue = 13 | pages = 1211–1221 | date = September 2010 | pmid = 20860503 | pmc = 4260321 | doi = 10.1056/NEJMoa0906312 }} allergy,{{cite journal | vauthors = Hinds DA, McMahon G, Kiefer AK, Do CB, Eriksson N, Evans DM, St Pourcain B, Ring SM, Mountain JL, Francke U, Davey-Smith G, Timpson NJ, Tung JY | title = A genome-wide association meta-analysis of self-reported allergy identifies shared and allergy-specific susceptibility loci | journal = Nature Genetics | volume = 45 | issue = 8 | pages = 907–911 | date = August 2013 | pmid = 23817569 | pmc = 3753407 | doi = 10.1038/ng.2686 }} endometriosis,{{cite journal | vauthors = Albertsen HM, Chettier R, Farrington P, Ward K | title = Genome-wide association study link novel loci to endometriosis | journal = PLOS ONE | volume = 8 | issue = 3 | pages = e58257 | date = 2013-01-01 | pmid = 23472165 | pmc = 3589333 | doi = 10.1371/journal.pone.0058257 | bibcode = 2013PLoSO...858257A | doi-access = free }} and hay fever.{{cite journal | vauthors = Ferreira MA, Matheson MC, Tang CS, Granell R, Ang W, Hui J, Kiefer AK, Duffy DL, Baltic S, Danoy P, Bui M, Price L, Sly PD, Eriksson N, Madden PA, Abramson MJ, Holt PG, Heath AC, Hunter M, Musk B, Robertson CF, Le Souëf P, Montgomery GW, Henderson AJ, Tung JY, Dharmage SC, Brown MA, James A, Thompson PJ, Pennell C, Martin NG, Evans DM, Hinds DA, Hopper JL | title = Genome-wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype | journal = The Journal of Allergy and Clinical Immunology | volume = 133 | issue = 6 | pages = 1564–1571 | date = June 2014 | pmid = 24388013 | pmc = 4280183 | doi = 10.1016/j.jaci.2013.10.030 }} In particular, a 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 {{cite journal | vauthors = Bønnelykke K, Sleiman P, Nielsen K, Kreiner-Møller E, Mercader JM, Belgrave D, den Dekker HT, Husby A, Sevelsted A, Faura-Tellez G, Mortensen LJ, Paternoster L, Flaaten R, Mølgaard A, Smart DE, Thomsen PF, Rasmussen MA, Bonàs-Guarch S, Holst C, Nohr EA, Yadav R, March ME, Blicher T, Lackie PM, Jaddoe VW, Simpson A, Holloway JW, Duijts L, Custovic A, Davies DE, Torrents D, Gupta R, Hollegaard MV, Hougaard DM, Hakonarson H, Bisgaard H | title = A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations | journal = Nature Genetics | volume = 46 | issue = 1 | pages = 51–55 | date = January 2014 | pmid = 24241537 | doi = 10.1038/ng.2830 | s2cid = 20754856 | url = 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 }} and atopic asthma {{cite journal | vauthors = Chen J, Zhang J, Hu H, Jin Y, Xue M | title = Polymorphisms of RAD50, IL33 and IL1RL1 are associated with atopic asthma in Chinese population | journal = Tissue Antigens | volume = 86 | issue = 6 | pages = 443–447 | date = December 2015 | pmid = 26493291 | doi = 10.1111/tan.12688 }} development. The rs928413(G) allele creates a binding site for the cAMP responsive element-binding protein 1 transcription factor that may explain the negative effect of the rs928413 minor “G” allele on asthma development.{{cite journal | vauthors = Gorbacheva AM, Korneev KV, Kuprash DV, Mitkin NA | title = IL33 Promoter in Lung Epithelial Cells | journal = International Journal of Molecular Sciences | volume = 19 | issue = 10 | pages = E2911 | date = September 2018 | pmid = 30257479 | pmc = 6212888 | doi = 10.3390/ijms19102911 | doi-access = free }} “T” allele of the polymorphism rs4742170 located in the second intron of IL33 gene was linked to specific wheezing phenotype (intermediate-onset wheeze).{{cite journal | vauthors = Savenije OE, Mahachie John JM, Granell R, Kerkhof M, Dijk FN, de Jongste JC, Smit HA, Brunekreef B, Postma DS, Van Steen K, Henderson J, Koppelman GH | title = Association of IL33-IL-1 receptor-like 1 (IL1RL1) pathway polymorphisms with wheezing phenotypes and asthma in childhood | journal = The Journal of Allergy and Clinical Immunology | volume = 134 | issue = 1 | pages = 170–177 | date = July 2014 | pmid = 24568840 | doi = 10.1016/j.jaci.2013.12.1080 }} Risk “T” rs4742170 allele disrupts binding of GR 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.{{cite journal | vauthors = Gorbacheva AM, Kuprash DV, Mitkin NA | title = IL33 Enhancer and is Disrupted by rs4742170 (T) Allele Associated with Specific Wheezing Phenotype in Early Childhood | journal = International Journal of Molecular Sciences | volume = 19 | issue = 12 | pages = E3956 | date = December 2018 | pmid = 30544846 | pmc = 6321062 | doi = 10.3390/ijms19123956 | doi-access = free }}

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.{{cite book | vauthors = Tizard I | title = Veterinary immunology: an introduction | location = St. Louis, Mo. | date = 2012 | publisher = Elsevier/Saunders | isbn = 978-1-4557-0362-3 | edition = 9th }} This protein is also thought to cause the itching that is associated with dermatitis. The IL-33 protein resides in keratinocytes of the skin and when subjected to irritation or allergic conditions will communicate with nearby sensory neurons and initiate an itchy feeling.{{cite journal | vauthors = Liu B, Tai Y, Achanta S, Kaelberer MM, Caceres AI, Shao X, Fang J, Jordt SE | title = IL-33/ST2 signaling excites sensory neurons and mediates itch response in a mouse model of poison ivy contact allergy | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 113 | issue = 47 | pages = E7572–E7579 | date = November 2016 | pmid = 27821781 | pmc = 5127381 | doi = 10.1073/pnas.1606608113 | bibcode = 2016PNAS..113E7572L | doi-access = free }} 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.{{cite journal | vauthors = Oshio T, Komine M, Tsuda H, Tominaga SI, Saito H, Nakae S, Ohtsuki M | title = Nuclear expression of IL-33 in epidermal keratinocytes promotes wound healing in mice | journal = Journal of Dermatological Science | volume = 85 | issue = 2 | pages = 106–114 | date = February 2017 | pmid = 27839630 | doi = 10.1016/j.jdermsci.2016.10.008 }} Elevated levels of IL-33 are associated with asthma.{{cite journal | vauthors = Bahrami Mahneh S, Movahedi M, Aryan Z, Bahar MA, Rezaei A, Sadr M, Rezaei N | title = Serum IL-33 Is Elevated in Children with Asthma and Is Associated with Disease Severity | journal = International Archives of Allergy and Immunology | volume = 168 | issue = 3 | pages = 193–196 | year = 2015 | pmid = 26797312 | doi = 10.1159/000442413 | s2cid = 40501434 | doi-access = free }}

In mice, IL-33 was found to effect the production of methionine-enkephalin peptides in group 2 innate lymphocytes, in turn promoting the emergence of beige adipocytes, which leads to increased energy expenditure and decreased adiposity.{{cite journal | vauthors = Brestoff JR, Kim BS, Saenz SA, Stine RR, Monticelli LA, Sonnenberg GF, Thome JJ, Farber DL, Lutfy K, Seale P, Artis D | title = Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity | journal = Nature | volume = 519 | issue = 7542 | pages = 242–246 | date = March 2015 | pmid = 25533952 | pmc = 4447235 | doi = 10.1038/nature14115 | language = En | bibcode = 2015Natur.519..242B }}

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.{{cite journal | vauthors = Casciaro M, Cardia R, Di Salvo E, Tuccari G, Ieni A, Gangemi S | title = Interleukin-33 Involvement in Nonsmall Cell Lung Carcinomas: An Update | journal = Biomolecules | volume = 9 | issue = 5 | pages = 203 | date = May 2019 | pmid = 31130612 | pmc = 6572046 | doi = 10.3390/biom9050203 | doi-access = free }} 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.{{cite journal | vauthors = Wang K, Shan S, Yang Z, Gu X, Wang Y, Wang C, Ren T | title = IL-33 blockade suppresses tumor growth of human lung cancer through direct and indirect pathways in a preclinical model | journal = Oncotarget | volume = 8 | issue = 40 | pages = 68571–68582 | date = September 2017 | pmid = 28978138 | pmc = 5620278 | doi = 10.18632/oncotarget.19786 }}{{cite journal | vauthors = Wang C, Chen Z, Bu X, Han Y, Shan S, Ren T, Song W | title = IL-33 signaling fuels outgrowth and metastasis of human lung cancer | journal = Biochemical and Biophysical Research Communications | volume = 479 | issue = 3 | pages = 461–468 | date = October 2016 | pmid = 27644880 | doi = 10.1016/j.bbrc.2016.09.081 }}

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 had higher tumor growth than wild type. Similarly, IFN- γ expression was increased in the IL-33 knockout model as well as the number of T regulatory cells and CD8+ T cells.{{cite journal | vauthors = Xia Y, Ohno T, Nishii N, Bhingare A, Tachinami H, Kashima Y, Nagai S, Saito H, Nakae S, Azuma M | title = + T cell antitumor responses overcoming pro-tumor effects by regulatory T cells in a colon carcinoma model | journal = Biochemical and Biophysical Research Communications | volume = 518 | issue = 2 | pages = 331–336 | date = August 2019 | pmid = 31421832 | doi = 10.1016/j.bbrc.2019.08.058 | s2cid = 201062815 }}

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.{{cite journal | vauthors = Theodoropoulou S, Copland DA, Liu J, Wu J, Gardner PJ, Ozaki E, Doyle SL, Campbell M, Dick AD | title = Interleukin-33 regulates tissue remodelling and inhibits angiogenesis in the eye | journal = The Journal of Pathology | volume = 241 | issue = 1 | pages = 45–56 | date = January 2017 | pmid = 27701734 | pmc = 5683707 | doi = 10.1002/path.4816 }}

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.{{cite journal | vauthors = Drake LY, Kita H | title = IL-33: biological properties, functions, and roles in airway disease | journal = Immunological Reviews | volume = 278 | issue = 1 | pages = 173–184 | date = July 2017 | pmid = 28658560 | pmc = 5492954 | doi = 10.1111/imr.12552 }}

Chronic inflammation is characteristic for IBD ( 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.{{Cite journal | vauthors = Chen J, He Y, Tu L, Duan L | title = Dual immune functions of IL-33 in inflammatory bowel disease | journal = Histology and Histopathology | volume = 35 | issue = 2 | pages = 137–146 | date = 2019 | pmid = 31294456 | doi = 10.14670/HH-18-149 | url = http://www.hh.um.es/Abstracts/Vol_/_/__18149.htm | access-date = 2019-08-28 | archive-date = 2019-08-28 | archive-url = https://web.archive.org/web/20190828213942/http://www.hh.um.es/Abstracts/Vol_/_/__18149.htm | url-status = dead }}

In brain, IL-33 is expressed in oligodendrocytes and astrocytes and is implicated in the pathophysiology of intracerebral hemorrhage.{{cite journal | vauthors = Zhu H, Wang Z, Yu J, Yang X, He F, Liu Z, Che F, Chen X, Ren H, Hong M, Wang J | title = Role and mechanisms of cytokines in the secondary brain injury after intracerebral hemorrhage | journal = Progress in Neurobiology | volume = 178 | pages = 101610 | date = March 2019 | pmid = 30923023 | doi = 10.1016/j.pneurobio.2019.03.003 | s2cid = 85495400 }}

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Category:Interleukins