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 andIL-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 aβ-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]
Interleukin 33 (IL-33) is acytokine belonging to theIL-1 superfamily. IL-33 induceshelper T cells,mast cells,eosinophils andbasophils to produce type 2 cytokines. This cytokine was previously named NF-HEV 'nuclear factor (NF) inhigh 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.
Alarmins, also known asdanger-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 stimulatescytotoxic CD8+ T cells for the efficient generation of a memory–recall response and antiviral immunity.[10][11]
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 thehistone methyltransferaseSUV39H1[14] and murine appears to IL-33 interact toNF-κB.[15]
As a cytokine, IL-33 interacts with the receptors ST2 (also known asIL1RL1) and IL-1 Receptor Accessory Protein (IL1RAP), activating intracellular molecules in theNF-κB andMAP kinase signaling pathways that drive production of type 2 cytokines (e.g.IL-5 andIL-13) from polarizedTh2 cells. The induction of type 2 cytokines by IL-33in vivo is believed to induce the severepathological changes observed inmucosal 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]
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]
IL-33 has been associated with several disease states throughGenome Wide Association Studies: asthma,[20] allergy,[21]endometriosis,[22] and hay fever.[23] In particular, asingle-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 thecAMP responsive element-binding protein 1 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 ofGR 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 withdermatitis. The IL-33 protein resides inkeratinocytes 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]
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 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 andCD8+ T cells.[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 forIBD ( 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]
^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:10.1016/j.it.2012.04.005.PMID22609147.
^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:10.1016/j.bbrc.2014.06.111.hdl:10044/1/32413.PMID25003325.
^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:10.1111/tan.12688.PMID26493291.
^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:10.1016/j.jaci.2013.12.1080.PMID24568840.
^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:10.1016/j.bbrc.2016.09.081.PMID27644880.
^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:10.1016/j.bbrc.2019.08.058.PMID31421832.S2CID201062815.
^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:10.1016/j.pneurobio.2019.03.003.PMID30923023.S2CID85495400.
