Interleukin 5

Through binding to the interleukin-5 receptor, interleukin 5 stimulates B cell growth and increases immunoglobulin secretion—primarily IgA. It is also a key mediator in eosinophil activation.

IL-5 is a 115-amino acid (in human, 133 in the mouse) -long T_h2 cytokine that is part of the hematopoietic family. Unlike other members of this cytokine family (namely interleukin 3 and GM-CSF), this glycoprotein in its active form is a homodimer.{{cite journal | vauthors = Milburn MV, Hassell AM, Lambert MH, Jordan SR, Proudfoot AE, Graber P, Wells TN | title = A novel dimer configuration revealed by the crystal structure at 2.4 A resolution of human interleukin-5 | journal = Nature | volume = 363 | issue = 6425 | pages = 172–176 | date = May 1993 | pmid = 8483502 | doi = 10.1038/363172a0 | s2cid = 4254991 | bibcode = 1993Natur.363..172M }}

The IL-5 gene is located on chromosome 11 in the mouse, and chromosome 5 in humans, in close proximity to the genes encoding IL-3, IL-4, and granulocyte-macrophage colony-stimulating factor (GM-CSF),{{cite journal | vauthors = Lee JS, Campbell HD, Kozak CA, Young IG | title = The IL-4 and IL-5 genes are closely linked and are part of a cytokine gene cluster on mouse chromosome 11 | journal = Somatic Cell and Molecular Genetics | volume = 15 | issue = 2 | pages = 143–152 | date = March 1989 | pmid = 2784591 | doi = 10.1007/BF01535075 | s2cid = 41719900 | url = https://zenodo.org/record/1232944 }}{{cite journal | vauthors = van Leeuwen BH, Martinson ME, Webb GC, Young IG | title = Molecular organization of the cytokine gene cluster, involving the human IL-3, IL-4, IL-5, and GM-CSF genes, on human chromosome 5 | journal = Blood | volume = 73 | issue = 5 | pages = 1142–1148 | date = April 1989 | pmid = 2564789 | doi = 10.1182/blood.V73.5.1142.1142 | doi-access = free }} which are often co-expressed in T_h2 cells. IL-5 is also expressed by eosinophils{{cite journal | vauthors = Dubucquoi S, Desreumaux P, Janin A, Klein O, Goldman M, Tavernier J, Capron A, Capron M | display-authors = 6 | title = Interleukin 5 synthesis by eosinophils: association with granules and immunoglobulin-dependent secretion | journal = The Journal of Experimental Medicine | volume = 179 | issue = 2 | pages = 703–708 | date = February 1994 | pmid = 8294877 | pmc = 2191391 | doi = 10.1084/jem.179.2.703 }} and has been observed in the mast cells of asthmatic airways by immunohistochemistry.{{cite journal | vauthors = Bradding P, Roberts JA, Britten KM, Montefort S, Djukanovic R, Mueller R, Heusser CH, Howarth PH, Holgate ST | display-authors = 6 | title = Interleukin-4, -5, and -6 and tumor necrosis factor-alpha in normal and asthmatic airways: evidence for the human mast cell as a source of these cytokines | journal = American Journal of Respiratory Cell and Molecular Biology | volume = 10 | issue = 5 | pages = 471–480 | date = May 1994 | pmid = 8179909 | doi = 10.1165/ajrcmb.10.5.8179909 }} IL-5 expression is regulated by several transcription factors including GATA3.{{cite journal | vauthors = Kaminuma O, Mori A, Kitamura N, Hashimoto T, Kitamura F, Inokuma S, Miyatake S | title = Role of GATA-3 in IL-5 gene transcription by CD4+ T cells of asthmatic patients | journal = International Archives of Allergy and Immunology | volume = 137 | pages = 55–59 | year = 2005 | issue = Suppl 1 | pmid = 15947486 | doi = 10.1159/000085433 | s2cid = 25517499 }}

IL-5 has long been associated with the cause of several allergic diseases including allergic rhinitis and asthma, wherein a large increase in the number of circulating, airway tissue, and induced sputum eosinophils have been observed.{{cite journal | vauthors = Shen HH, Ochkur SI, McGarry MP, Crosby JR, Hines EM, Borchers MT, Wang H, Biechelle TL, O'Neill KR, Ansay TL, Colbert DC, Cormier SA, Justice JP, Lee NA, Lee JJ | display-authors = 6 | title = A causative relationship exists between eosinophils and the development of allergic pulmonary pathologies in the mouse | journal = Journal of Immunology | volume = 170 | issue = 6 | pages = 3296–3305 | date = March 2003 | pmid = 12626589 | doi = 10.4049/jimmunol.170.6.3296 | doi-access = free }} Given the high concordance of eosinophils and, in particular, allergic asthma pathology, it has been widely speculated that eosinophils have an important role in the pathology of this disease.{{cite journal | vauthors = Sanderson CJ | title = Interleukin-5, eosinophils, and disease | journal = Blood | volume = 79 | issue = 12 | pages = 3101–3109 | date = June 1992 | pmid = 1596561 | doi = 10.1182/blood.V79.12.3101.3101 | doi-access = free }}

As of 2019, there are two FDA-approved monoclonal antibodies that inhibit IL-5, mepolizumab and reslizumab. Additionally, the antibody benralizumab blocks the interleukin-5 receptor. All three drugs are used to treat severe eosinophilic asthma{{cite web |title=Anti-interleukin-5 therapy for severe asthma: A new therapeutic option | work = Mayo Clinic | date = 8 January 2019 |url=https://www.mayoclinic.org/medical-professionals/pulmonary-medicine/news/anti-interleukin-5-therapy-for-severe-asthma-a-new-therapeutic-option/mac-20451437 |access-date=14 December 2023 |language=en}} and eosinophilic granulomatosis with polyangiitis (EGPA).{{cite journal | vauthors = Berti A, Atzeni F, Dagna L, Del Giacco S, Emmi G, Salvarani C, Vaglio A | title = Targeting the interleukin-5 pathway in EGPA: evidence, uncertainties and opportunities | journal = Annals of the Rheumatic Diseases | volume = 82 | issue = 2 | pages = 164–168 | date = February 2023 | pmid = 36357156 | doi = 10.1136/ard-2022-223044 | s2cid = 253457684 }} Another antibody, depemokimab (GSK3511294), ultra-long acting IL-5 inhibitor, is under development.{{cite journal | vauthors = Singh D, Fuhr R, Bird NP, Mole S, Hardes K, Man YL, Cahn A, Yancey SW, Pouliquen IJ | display-authors = 6 | title = A Phase 1 study of the long-acting anti-IL-5 monoclonal antibody GSK3511294 in patients with asthma | journal = British Journal of Clinical Pharmacology | volume = 88 | issue = 2 | pages = 702–712 | date = February 2022 | pmid = 34292606 | doi = 10.1111/bcp.15002 | pmc = 9290054 }}

Some hydroxyethylaminomethylbenzimidazole analogs have shown IL-5 inhibition in vitro.{{cite journal | vauthors = Boggu PR, Kim Y, Jung SH | title = Discovery of benzimidazole analogs as a novel interleukin-5 inhibitors | journal = European Journal of Medicinal Chemistry | volume = 181 | pages = 111574 | date = November 2019 | pmid = 31400705 | doi = 10.1016/j.ejmech.2019.111574 | s2cid = 199527755 }}

Eosinophils are terminally differentiated granulocytes found in most mammals. The principal role of these cells, in a healthy host, is the elimination of antibody bound parasites through the release of cytotoxic granule proteins.{{cite journal | vauthors = Giembycz MA, Lindsay MA | title = Pharmacology of the eosinophil | journal = Pharmacological Reviews | volume = 51 | issue = 2 | pages = 213–340 | date = June 1999 | pmid = 10353986 }} Given that eosinophils are the primary IL-5Rα-expressing cells, it is not surprising that this cell type responds to IL-5. In fact, IL-5 was originally discovered as an eosinophil colony-stimulating factor,{{cite journal | vauthors = Lopez AF, Begley CG, Williamson DJ, Warren DJ, Vadas MA, Sanderson CJ | title = Murine eosinophil differentiation factor. An eosinophil-specific colony-stimulating factor with activity for human cells | journal = The Journal of Experimental Medicine | volume = 163 | issue = 5 | pages = 1085–1099 | date = May 1986 | pmid = 3486243 | pmc = 2188112 | doi = 10.1084/jem.163.5.1085 }} is a major regulator of eosinophil accumulation in tissues, and can modulate eosinophil behavior at every stage from maturation to survival. Mepolizumab is a monoclonal antibody antagonist IL-5 which can reduce excessive eosinophilia.

In Hodgkin lymphoma, the typically-observed eosinophilia is thought to be attributable to an increased production of IL-5.{{cite journal | vauthors = Di Biagio E, Sánchez-Borges M, Desenne JJ, Suárez-Chacón R, Somoza R, Acquatella G | title = Eosinophilia in Hodgkin's disease: a role for interleukin 5 | journal = International Archives of Allergy and Immunology | volume = 110 | issue = 3 | pages = 244–251 | date = July 1996 | pmid = 8688671 | doi = 10.1159/000237294 }}

IL-5 has been shown to interact with interleukin 5 receptor alpha subunit.{{cite journal | vauthors = Woodcock JM, Zacharakis B, Plaetinck G, Bagley CJ, Qiyu S, Hercus TR, Tavernier J, Lopez AF | display-authors = 6 | title = Three residues in the common beta chain of the human GM-CSF, IL-3 and IL-5 receptors are essential for GM-CSF and IL-5 but not IL-3 high affinity binding and interact with Glu21 of GM-CSF | journal = The EMBO Journal | volume = 13 | issue = 21 | pages = 5176–5185 | date = November 1994 | pmid = 7957082 | pmc = 395466 | doi = 10.1002/j.1460-2075.1994.tb06848.x }}{{cite journal | vauthors = Johanson K, Appelbaum E, Doyle M, Hensley P, Zhao B, Abdel-Meguid SS, Young P, Cook R, Carr S, Matico R | display-authors = 6 | title = Binding interactions of human interleukin 5 with its receptor alpha subunit. Large scale production, structural, and functional studies of Drosophila-expressed recombinant proteins | journal = The Journal of Biological Chemistry | volume = 270 | issue = 16 | pages = 9459–9471 | date = April 1995 | pmid = 7721873 | doi = 10.1074/jbc.270.16.9459 | doi-access = free }}{{cite journal | vauthors = Murata Y, Takaki S, Migita M, Kikuchi Y, Tominaga A, Takatsu K | title = Molecular cloning and expression of the human interleukin 5 receptor | journal = The Journal of Experimental Medicine | volume = 175 | issue = 2 | pages = 341–351 | date = February 1992 | pmid = 1732409 | pmc = 2119102 | doi = 10.1084/jem.175.2.341 }}

The IL-5 receptor is composed of an α and a βc chain.{{cite journal | vauthors = Tavernier J, Devos R, Cornelis S, Tuypens T, Van der Heyden J, Fiers W, Plaetinck G | title = A human high affinity interleukin-5 receptor (IL5R) is composed of an IL5-specific alpha chain and a beta chain shared with the receptor for GM-CSF | journal = Cell | volume = 66 | issue = 6 | pages = 1175–1184 | date = September 1991 | pmid = 1833065 | doi = 10.1016/0092-8674(91)90040-6 | s2cid = 54277241 }} The α subunit is specific for the IL-5 molecule, whereas the βc subunit also recognised by interleukin 3 (IL-3) and granulocyte-macrophage colony-stimulating factor (GM-CSF).{{cite journal | vauthors = Takaki S, Murata Y, Kitamura T, Miyajima A, Tominaga A, Takatsu K | title = Reconstitution of the functional receptors for murine and human interleukin 5 | journal = The Journal of Experimental Medicine | volume = 177 | issue = 6 | pages = 1523–1529 | date = June 1993 | pmid = 8496674 | pmc = 2191058 | doi = 10.1084/jem.177.6.1523 }} Glycosylation of the Asn196 residue of the Rα subunit appears to be essential for binding of IL-5.{{cite journal | vauthors = Ishino T, Economou NJ, McFadden K, Zaks-Zilberman M, Jost M, Baxter S, Contarino MR, Harrington AE, Loll PJ, Pasut G, Lievens S, Tavernier J, Chaiken I | display-authors = 6 | title = A protein engineering approach differentiates the functional importance of carbohydrate moieties of interleukin-5 receptor α | journal = Biochemistry | volume = 50 | issue = 35 | pages = 7546–7556 | date = September 2011 | pmid = 21770429 | doi = 10.1021/bi2009135 | url = https://biblio.ugent.be/publication/1965160/file/3111951 | url-access = subscription }}

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Category:Interleukins