Interleukin 33 Explained

Interleukin 33 (IL-33) is a protein that in humans is encoded by the IL33 gene.[1]

Interleukin 33 is a member of the IL-1 family that potently drives production of T helper-2 (Th2)-associated cytokines (e.g., IL-4). IL33 is a ligand for ST2 (IL1RL1), an IL-1 family receptor that is highly expressed on Th2 cells, mast cells and group 2 innate lymphocytes.[2]

IL-33 is expressed by a wide variety of cell types, including fibroblasts, mast cells, dendritic cells, macrophages, osteoblasts, endothelial cells, and epithelial cells.[3]

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. 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.[4]

Function

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.[5] IL-33 acts intracellularly as a nuclear factor and extracellularly as a cytokine.

Role as alarmin

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. [6] [7]

Nuclear role

IL-33 is constitutively located in the nucleus of structural cells of humans and mice[8] 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.[9] IL-33 also interacts with the histone methyltransferase SUV39H1[10] and murine appears to IL-33 interact to NF-κB.[11]

Cytokine role

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.[12] [13] 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.[14]

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.[15]

Clinical significance

IL-33 has been associated with several disease states through Genome Wide Association Studies: asthma,[16] allergy,[17] endometriosis,[18] and hay fever.[19] 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 [20] and atopic asthma [21] 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.[22] “T” allele of the polymorphism rs4742170 located in the second intron of IL33 gene was linked to specific wheezing phenotype (intermediate-onset wheeze).[23] 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.[24]

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.[25] 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.[26] 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.[27] Elevated levels of IL-33 are associated with asthma.[28]

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.[29]

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.[30] 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.[31] [32]

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.[33]

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.[34]

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.[35]

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.[36]

In brain, IL-33 is expressed in oligodendrocytes and astrocytes and is implicated in the pathophysiology of intracerebral hemorrhage.[37]

Notes and References

  1. Web site: Entrez Gene: Interleukin 33 .
  2. Yagami A, Orihara K, Morita H, Futamura K, Hashimoto N, Matsumoto K, Saito H, Matsuda A . 6 . IL-33 mediates inflammatory responses in human lung tissue cells . Journal of Immunology . 185 . 10 . 5743–50 . November 2010 . 20926795 . 10.4049/jimmunol.0903818 . 27317847 . free .
  3. Mirchandani AS, Salmond RJ, Liew FY . Interleukin-33 and the function of innate lymphoid cells . Trends in Immunology . 33 . 8 . 389–96 . August 2012 . 22609147 . 10.1016/j.it.2012.04.005 .
  4. Lingel A, Weiss TM, Niebuhr M, Pan B, Appleton BA, Wiesmann C, Bazan JF, Fairbrother WJ . 6 . Structure of IL-33 and its interaction with the ST2 and IL-1RAcP receptors--insight into heterotrimeric IL-1 signaling complexes . Structure . 17 . 10 . 1398–410 . October 2009 . 19836339 . 2766095 . 10.1016/j.str.2009.08.009 .
  5. Baekkevold ES, Roussigné M, Yamanaka T, Johansen FE, Jahnsen FL, Amalric F, Brandtzaeg P, Erard M, Haraldsen G, Girard JP . 6 . Molecular characterization of NF-HEV, a nuclear factor preferentially expressed in human high endothelial venules . The American Journal of Pathology . 163 . 1 . 69–79 . July 2003 . 12819012 . 1868188 . 10.1016/S0002-9440(10)63631-0 .
  6. Bonilla . Weldy . The Alarmin Interleukin-33 Drives Protective Antiviral CD8+ T Cell Responses . Science . 2012 . 10.1126/science.121548 .
  7. Baumann . Claudia . Memory CD8+ T Cell Protection From Viral Reinfection Depends on Interleukin-33 Alarmin Signals . Front. Immunol. . 2019 .
  8. Pichery M, Mirey E, Mercier P, Lefrancais E, Dujardin A, Ortega N, Girard JP . 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 of Immunology . 188 . 7 . 3488–95 . April 2012 . 22371395 . 10.4049/jimmunol.1101977 . 42558099 . free .
  9. Roussel L, Erard M, Cayrol C, Girard JP . Molecular mimicry between IL-33 and KSHV for attachment to chromatin through the H2A-H2B acidic pocket . EMBO Reports . 9 . 10 . 1006–12 . October 2008 . 18688256 . 2572127 . 10.1038/embor.2008.145 .
  10. 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 . 6 . 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 . August 2014 . 25003325 . 10.1016/j.bbrc.2014.06.111 . 10044/1/32413 . free .
  11. Ali S, Mohs A, Thomas M, Klare J, Ross R, Schmitz ML, Martin MU . The dual function cytokine IL-33 interacts with the transcription factor NF-κB to dampen NF-κB-stimulated gene transcription . Journal of Immunology . 187 . 4 . 1609–16 . August 2011 . 21734074 . 10.4049/jimmunol.1003080 . 27523266 . free .
  12. 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 . 6 . 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 . Immunity . 23 . 5 . 479–90 . November 2005 . 16286016 . 10.1016/j.immuni.2005.09.015 . free .
  13. Chackerian AA, Oldham ER, Murphy EE, Schmitz J, Pflanz S, Kastelein RA . IL-1 receptor accessory protein and ST2 comprise the IL-33 receptor complex . Journal of Immunology . 179 . 4 . 2551–5 . August 2007 . 17675517 . 10.4049/jimmunol.179.4.2551 . 9289093 . free .
  14. Fu AK, Hung KW, Yuen MY, Zhou X, Mak DS, Chan IC, Cheung TH, Zhang B, Fu WY, Liew FY, Ip NY . 6 . IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline . Proceedings of the National Academy of Sciences of the United States of America . 113 . 19 . E2705-13 . May 2016 . 27091974 . 4868478 . 10.1073/pnas.1604032113 . 2016PNAS..113E2705F . free .
  15. 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 . 6 . Oxidation of the alarmin IL-33 regulates ST2-dependent inflammation . Nature Communications . 6 . 8327 . September 2015 . 26365875 . 4579851 . 10.1038/ncomms9327 . 2015NatCo...6.8327C .
  16. Moffatt MF, Gut IG, Demenais F, Strachan DP, Bouzigon E, Heath S, von Mutius E, Farrall M, Lathrop M, Cookson WO . 6 . A large-scale, consortium-based genomewide association study of asthma . The New England Journal of Medicine . 363 . 13 . 1211–1221 . September 2010 . 20860503 . 4260321 . 10.1056/NEJMoa0906312 .
  17. 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 . 6 . A genome-wide association meta-analysis of self-reported allergy identifies shared and allergy-specific susceptibility loci . Nature Genetics . 45 . 8 . 907–11 . August 2013 . 23817569 . 3753407 . 10.1038/ng.2686 .
  18. Albertsen HM, Chettier R, Farrington P, Ward K . Genome-wide association study link novel loci to endometriosis . PLOS ONE . 8 . 3 . e58257 . 2013-01-01 . 23472165 . 3589333 . 10.1371/journal.pone.0058257 . 2013PLoSO...858257A . free .
  19. 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 . 6 . Genome-wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype . The Journal of Allergy and Clinical Immunology . 133 . 6 . 1564–71 . June 2014 . 24388013 . 4280183 . 10.1016/j.jaci.2013.10.030 .
  20. 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 . 6 . A genome-wide association study identifies CDHR3 as a susceptibility locus for early childhood asthma with severe exacerbations . Nature Genetics . 46 . 1 . 51–5 . January 2014 . 24241537 . 10.1038/ng.2830 . 20754856 .
  21. Chen J, Zhang J, Hu H, Jin Y, Xue M . Polymorphisms of RAD50, IL33 and IL1RL1 are associated with atopic asthma in Chinese population . Tissue Antigens . 86 . 6 . 443–7 . December 2015 . 26493291 . 10.1111/tan.12688 .
  22. Gorbacheva AM, Korneev KV, Kuprash DV, Mitkin NA . IL33 Promoter in Lung Epithelial Cells . International Journal of Molecular Sciences . 19 . 10 . E2911 . September 2018 . 30257479 . 6212888 . 10.3390/ijms19102911 . free .
  23. 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 . 6 . 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 . 170–7 . July 2014 . 24568840 . 10.1016/j.jaci.2013.12.1080 .
  24. Gorbacheva AM, Kuprash DV, Mitkin NA . IL33 Enhancer and is Disrupted by rs4742170 (T) Allele Associated with Specific Wheezing Phenotype in Early Childhood . International Journal of Molecular Sciences . 19 . 12 . E3956 . December 2018 . 30544846 . 6321062 . 10.3390/ijms19123956 . free .
  25. Book: Tizard . Ian . vanc . Veterinary immunology: an introduction . 2012 . Elsevier/Saunders . St. Louis, Mo. . 978-1-4557-0362-3 . 9th .
  26. Liu B, Tai Y, Achanta S, Kaelberer MM, Caceres AI, Shao X, Fang J, Jordt SE . 6 . IL-33/ST2 signaling excites sensory neurons and mediates itch response in a mouse model of poison ivy contact allergy . Proceedings of the National Academy of Sciences of the United States of America . 113 . 47 . E7572–E7579 . November 2016 . 27821781 . 5127381 . 10.1073/pnas.1606608113 . 2016PNAS..113E7572L . free .
  27. Oshio T, Komine M, Tsuda H, Tominaga SI, Saito H, Nakae S, Ohtsuki M . Nuclear expression of IL-33 in epidermal keratinocytes promotes wound healing in mice . Journal of Dermatological Science . 85 . 2 . 106–114 . February 2017 . 27839630 . 10.1016/j.jdermsci.2016.10.008 .
  28. Bahrami Mahneh S, Movahedi M, Aryan Z, Bahar MA, Rezaei A, Sadr M, Rezaei N . Serum IL-33 Is Elevated in Children with Asthma and Is Associated with Disease Severity . International Archives of Allergy and Immunology . 168 . 3 . 193–6 . 2015 . 26797312 . 10.1159/000442413 . 40501434 . free .
  29. Brestoff JR, Kim BS, Saenz SA, Stine RR, Monticelli LA, Sonnenberg GF, Thome JJ, Farber DL, Lutfy K, Seale P, Artis D . 6 . Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity . En . Nature . 519 . 7542 . 242–6 . March 2015 . 25533952 . 4447235 . 10.1038/nature14115 . 2015Natur.519..242B .
  30. Casciaro M, Cardia R, Di Salvo E, Tuccari G, Ieni A, Gangemi S . Interleukin-33 Involvement in Nonsmall Cell Lung Carcinomas: An Update . Biomolecules . 9 . 5 . 203 . May 2019 . 31130612 . 6572046 . 10.3390/biom9050203 . free .
  31. Wang K, Shan S, Yang Z, Gu X, Wang Y, Wang C, Ren T . IL-33 blockade suppresses tumor growth of human lung cancer through direct and indirect pathways in a preclinical model . Oncotarget . 8 . 40 . 68571–68582 . September 2017 . 28978138 . 5620278 . 10.18632/oncotarget.19786 .
  32. Wang C, Chen Z, Bu X, Han Y, Shan S, Ren T, Song W . IL-33 signaling fuels outgrowth and metastasis of human lung cancer . Biochemical and Biophysical Research Communications . 479 . 3 . 461–468 . October 2016 . 27644880 . 10.1016/j.bbrc.2016.09.081 .
  33. Xia Y, Ohno T, Nishii N, Bhingare A, Tachinami H, Kashima Y, Nagai S, Saito H, Nakae S, Azuma M . 6 . + 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 . August 2019 . 31421832 . 10.1016/j.bbrc.2019.08.058 . 201062815 .
  34. Theodoropoulou S, Copland DA, Liu J, Wu J, Gardner PJ, Ozaki E, Doyle SL, Campbell M, Dick AD . 6 . Interleukin-33 regulates tissue remodelling and inhibits angiogenesis in the eye . The Journal of Pathology . 241 . 1 . 45–56 . January 2017 . 27701734 . 5683707 . 10.1002/path.4816 .
  35. Drake LY, Kita H . IL-33: biological properties, functions, and roles in airway disease . Immunological Reviews . 278 . 1 . 173–184 . July 2017 . 28658560 . 5492954 . 10.1111/imr.12552 .
  36. 2019. Dual immune functions of IL-33 in inflammatory bowel disease. Histology and Histopathology. 35. 2. 137–146. 10.14670/HH-18-149. 31294456. Chen. J.. He. Y.. Tu. L.. Duan. L.. 2019-08-28. 2019-08-28. https://web.archive.org/web/20190828213942/http://www.hh.um.es/Abstracts/Vol_/_/__18149.htm. dead.
  37. Zhu H, Wang Z, Yu J, Yang X, He F, Liu Z, Che F, Chen X, Ren H, Hong M, Wang J . Role and mechanisms of cytokines in the secondary brain injury after intracerebral hemorrhage . Prog. Neurobiol. . 178 . 101610 . March 2019 . 30923023 . 10.1016/j.pneurobio.2019.03.003. 85495400 .

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Interleukin 33".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2024, A B Cryer, All Rights Reserved. Cookie policy.