Interleukin 33

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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]


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]


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.

Nuclear role

IL-33 is constitutively located in the nucleus of structural cells of humans and mice[6] and has a helix-turn-helix domain[5] 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.[7] IL-33 also interacts with the histone methyltransferase SUV39H1[8] and murine appears to IL-33 interact to NF-κB.[9]

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.[10][11] 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.[12]


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.[13]

Clinical significance

IL-33 has been associated with several disease states through Genome Wide Association Studies: asthma,[14] allergy,[15] endometriosis,[16] and hay fever.[17]

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.[18] 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.[19] 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.[20] Elevated levels of IL-33 are associated with asthma.[21]

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.[22]


  1. "Entrez Gene: Interleukin 33".
  2. Yagami A, Orihara K, Morita H, Futamura K, Hashimoto N, Matsumoto K, Saito H, Matsuda A (November 2010). "IL-33 mediates inflammatory responses in human lung tissue cells". Journal of Immunology. 185 (10): 5743–50. doi:10.4049/jimmunol.0903818. PMID 20926795.
  3. Mirchandani AS, Salmond RJ, Liew FY (August 2012). "Interleukin-33 and the function of innate lymphoid cells". Trends in Immunology. 33 (8): 389–96. doi:10.1016/ PMID 22609147.
  4. Lingel A, Weiss TM, Niebuhr M, Pan B, Appleton BA, Wiesmann C, Bazan JF, Fairbrother WJ (October 2009). "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. doi:10.1016/j.str.2009.08.009. PMC 2766095. PMID 19836339.
  5. 5.0 5.1 Baekkevold ES, Roussigné M, Yamanaka T, Johansen FE, Jahnsen FL, Amalric F, Brandtzaeg P, Erard M, Haraldsen G, Girard JP (July 2003). "Molecular characterization of NF-HEV, a nuclear factor preferentially expressed in human high endothelial venules". The American Journal of Pathology. 163 (1): 69–79. doi:10.1016/S0002-9440(10)63631-0. PMC 1868188. PMID 12819012.
  6. Pichery M, Mirey E, Mercier P, Lefrancais E, Dujardin A, Ortega N, Girard JP (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". Journal of Immunology. 188 (7): 3488–95. doi:10.4049/jimmunol.1101977. PMID 22371395.
  7. 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". EMBO Reports. 9 (10): 1006–12. doi:10.1038/embor.2008.145. PMC 2572127. PMID 18688256.
  8. 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 (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:10.1016/j.bbrc.2014.06.111. PMID 25003325.
  9. Ali S, Mohs A, Thomas M, Klare J, Ross R, Schmitz ML, Martin MU (August 2011). "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. doi:10.4049/jimmunol.1003080. PMID 21734074.
  10. 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 (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". Immunity. 23 (5): 479–90. doi:10.1016/j.immuni.2005.09.015. PMID 16286016.
  11. 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". Journal of Immunology. 179 (4): 2551–5. doi:10.4049/jimmunol.179.4.2551. PMID 17675517.
  12. Fu AK, Hung KW, Yuen MY, Zhou X, Mak DS, Chan IC, Cheung TH, Zhang B, Fu WY, Liew FY, Ip NY (2016). "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. doi:10.1073/pnas.1604032113. PMC 4868478. PMID 27091974.
  13. Cohen ES, Scott IC, Majithiya JB, Rapley L, Kemp BP, England E, et al. (2015). "Oxidation of the alarmin IL-33 regulates ST2-dependent inflammation". Nature Communications. 6: 8327. doi:10.1038/ncomms9327. PMC 4579851. PMID 26365875.
  14. Moffatt MF, Gut IG, Demenais F, Strachan DP, Bouzigon E, Heath S, von Mutius E, Farrall M, Lathrop M, Cookson WO (September 2010). "A large-scale, consortium-based genomewide association study of asthma". The New England Journal of Medicine. 363 (13): 1211–21. doi:10.1056/NEJMoa0906312. PMC 4260321. PMID 20860503.
  15. 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 (August 2013). "A genome-wide association meta-analysis of self-reported allergy identifies shared and allergy-specific susceptibility loci". Nature Genetics. 45 (8): 907–11. doi:10.1038/ng.2686. PMC 3753407. PMID 23817569.
  16. Albertsen HM, Chettier R, Farrington P, Ward K (2013-01-01). "Genome-wide association study link novel loci to endometriosis". PLoS One. 8 (3): e58257. doi:10.1371/journal.pone.0058257. PMC 3589333. PMID 23472165.
  17. 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". The Journal of Allergy and Clinical Immunology. 133 (6): 1564–71. doi:10.1016/j.jaci.2013.10.030. PMC 4280183. PMID 24388013.
  18. Tizard I (2012). Veterinary immunology: an introduction (9th ed.). St. Louis, Mo.: Elsevier/Saunders. ISBN 978-1-4557-0362-3.
  19. Liu B, Tai Y, Achanta S, Kaelberer MM, Caceres AI, Shao X, Fang J, Jordt SE (2016). "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. doi:10.1073/pnas.1606608113. PMC 5127381. PMID 27821781.
  20. Oshio T, Komine M, Tsuda H, Tominaga SI, Saito H, Nakae S, Ohtsuki M (2017). "Nuclear expression of IL-33 in epidermal keratinocytes promotes wound healing in mice". Journal of Dermatological Science. 85 (2): 106–114. doi:10.1016/j.jdermsci.2016.10.008. PMID 27839630.
  21. Bahrami Mahneh S, Movahedi M, Aryan Z, Bahar MA, Rezaei A, Sadr M, Rezaei N (2015). "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. doi:10.1159/000442413. PMID 26797312.
  22. Brestoff JR, Kim BS, Saenz SA, Stine RR, Monticelli LA, Sonnenberg GF, Thome JJ, Farber DL, Lutfy K, Seale P, Artis D (March 2015). "Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity". Nature. 519 (7542): 242–6. doi:10.1038/nature14115. PMC 4447235. PMID 25533952.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.