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]
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 endothelialvenules' (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]
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.[13]
Interleukin 33 (IL-33) is a protein produced by the IL-33 gene. 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 conditions. 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] IL-33 has many effects on the body, and new associations are still being discovered. For example, links between elevated IL-33 levels and patients suffering with asthma are surfacing.[21]
↑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. PMID20926795.
↑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/j.it.2012.04.005. PMID22609147.
↑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. PMID22371395.
↑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. PMID25003325.
↑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. PMID21734074.
↑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. PMID16286016.
↑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. PMID17675517.
↑Tizard, I. R. (2013). Veterinary immunology. Louis: Elsevier Saunders.
↑Liu, B., Tai, Y., Achanta, S., Kaelberer, M. M., Caceres, A. I., Shao, X., . . . Jordt, S. (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, 113(47). doi:10.1073/pnas.1606608113
↑Oshio, T., Komine, M., Tsuda, H., Tominaga, S., 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
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Rezaei, N. (2016). Serum IL-33 Is Elevated in Children with Asthma and Is Associated with Disease Severity. International Archives of Allergy and Immunology, 168(3), 193-196. doi:10.1159/000442413