Biology:Interleukin 33

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Short description: IL-33 induces helper T cells, mast cells, eosinophils and basophils to produce type 2 cytokines.


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.

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]

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] 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 [18] and atopic asthma [19] 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.[20] “T” allele of the polymorphism rs4742170 located in the second intron of IL33 gene was linked to specific wheezing phenotype (intermediate-onset wheeze).[21] 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.[22]

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.[23] 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.[24] 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.[25] Elevated levels of IL-33 are associated with asthma.[26]

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.[27]

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.[28] 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.[29][30]

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.[31]

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.[32]

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.[33]

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.[34]

In brain, IL-33 is expressed in oligodendrocytes and astrocytes and is implicated in the pathophysiology of intracerebral hemorrhage.[35]

References

  1. ↑ "Entrez Gene: Interleukin 33". https://www.ncbi.nlm.nih.gov/gene/90865. 
  2. ↑ "IL-33 mediates inflammatory responses in human lung tissue cells". Journal of Immunology 185 (10): 5743–50. November 2010. doi:10.4049/jimmunol.0903818. PMID 20926795. 
  3. ↑ "Interleukin-33 and the function of innate lymphoid cells". Trends in Immunology 33 (8): 389–96. August 2012. doi:10.1016/j.it.2012.04.005. PMID 22609147. 
  4. ↑ "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. doi:10.1016/j.str.2009.08.009. PMID 19836339. 
  5. ↑ 5.0 5.1 "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. doi:10.1016/S0002-9440(10)63631-0. PMID 12819012. 
  6. ↑ "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. doi:10.4049/jimmunol.1101977. PMID 22371395. 
  7. ↑ "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. doi:10.1038/embor.2008.145. PMID 18688256. 
  8. ↑ "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. doi:10.1016/j.bbrc.2014.06.111. PMID 25003325. 
  9. ↑ "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. doi:10.4049/jimmunol.1003080. PMID 21734074. 
  10. ↑ "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. doi:10.1016/j.immuni.2005.09.015. PMID 16286016. 
  11. ↑ "IL-1 receptor accessory protein and ST2 comprise the IL-33 receptor complex". Journal of Immunology 179 (4): 2551–5. August 2007. doi:10.4049/jimmunol.179.4.2551. PMID 17675517. 
  12. ↑ "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. doi:10.1073/pnas.1604032113. PMID 27091974. Bibcode: 2016PNAS..113E2705F. 
  13. ↑ "Oxidation of the alarmin IL-33 regulates ST2-dependent inflammation". Nature Communications 6: 8327. September 2015. doi:10.1038/ncomms9327. PMID 26365875. Bibcode: 2015NatCo...6.8327C. 
  14. ↑ "A large-scale, consortium-based genomewide association study of asthma". The New England Journal of Medicine 363 (13): 1211–1221. September 2010. doi:10.1056/NEJMoa0906312. PMID 20860503. 
  15. ↑ "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. doi:10.1038/ng.2686. PMID 23817569. 
  16. ↑ "Genome-wide association study link novel loci to endometriosis". PLOS ONE 8 (3): e58257. 2013-01-01. doi:10.1371/journal.pone.0058257. PMID 23472165. Bibcode: 2013PLoSO...858257A. 
  17. ↑ "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. doi:10.1016/j.jaci.2013.10.030. PMID 24388013. 
  18. ↑ "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. doi:10.1038/ng.2830. PMID 24241537. 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. 
  19. ↑ "Polymorphisms of RAD50, IL33 and IL1RL1 are associated with atopic asthma in Chinese population". Tissue Antigens 86 (6): 443–7. December 2015. doi:10.1111/tan.12688. PMID 26493291. 
  20. ↑ "IL33 Promoter in Lung Epithelial Cells". International Journal of Molecular Sciences 19 (10): E2911. September 2018. doi:10.3390/ijms19102911. PMID 30257479. 
  21. ↑ "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. doi:10.1016/j.jaci.2013.12.1080. PMID 24568840. 
  22. ↑ "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. doi:10.3390/ijms19123956. PMID 30544846. 
  23. ↑ Tizard, Ian (2012). Veterinary immunology: an introduction (9th ed.). St. Louis, Mo.: Elsevier/Saunders. ISBN 978-1-4557-0362-3. 
  24. ↑ "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. doi:10.1073/pnas.1606608113. PMID 27821781. Bibcode: 2016PNAS..113E7572L. 
  25. ↑ "Nuclear expression of IL-33 in epidermal keratinocytes promotes wound healing in mice". Journal of Dermatological Science 85 (2): 106–114. February 2017. doi:10.1016/j.jdermsci.2016.10.008. PMID 27839630. 
  26. ↑ "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. doi:10.1159/000442413. PMID 26797312. 
  27. ↑ "Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity" (in En). Nature 519 (7542): 242–6. March 2015. doi:10.1038/nature14115. PMID 25533952. Bibcode: 2015Natur.519..242B. 
  28. ↑ "Interleukin-33 Involvement in Nonsmall Cell Lung Carcinomas: An Update". Biomolecules 9 (5): 203. May 2019. doi:10.3390/biom9050203. PMID 31130612. 
  29. ↑ "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. doi:10.18632/oncotarget.19786. PMID 28978138. 
  30. ↑ "IL-33 signaling fuels outgrowth and metastasis of human lung cancer". Biochemical and Biophysical Research Communications 479 (3): 461–468. October 2016. doi:10.1016/j.bbrc.2016.09.081. PMID 27644880. 
  31. ↑ "+ 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. doi:10.1016/j.bbrc.2019.08.058. PMID 31421832. 
  32. ↑ "Interleukin-33 regulates tissue remodelling and inhibits angiogenesis in the eye". The Journal of Pathology 241 (1): 45–56. January 2017. doi:10.1002/path.4816. PMID 27701734. 
  33. ↑ "IL-33: biological properties, functions, and roles in airway disease". Immunological Reviews 278 (1): 173–184. July 2017. doi:10.1111/imr.12552. PMID 28658560. 
  34. ↑ Chen, J.; He, Y.; Tu, L.; Duan, L. (2019). "Dual immune functions of IL-33 in inflammatory bowel disease". Histology and Histopathology 35 (2): 137–146. doi:10.14670/HH-18-149. PMID 31294456. http://www.hh.um.es/Abstracts/Vol_/_/__18149.htm. 
  35. ↑ "Role and mechanisms of cytokines in the secondary brain injury after intracerebral hemorrhage". Prog. Neurobiol. 178: 101610. March 2019. doi:10.1016/j.pneurobio.2019.03.003. PMID 30923023. 

External links

  • Overview of all the structural information available in the PDB for UniProt: O95760 (Interleukin-33) at the PDBe-KB.

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





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