Interleukin 5 Explained

Interleukin 5 (IL-5) is an interleukin produced by type-2 T helper cells and mast cells.

Function

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.

Structure

IL-5 is a 115-amino acid (in human, 133 in the mouse) -long Th2 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.[1]

Tissue expression

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),[2] [3] which are often co-expressed in Th2 cells. IL-5 is also expressed by eosinophils[4] and has been observed in the mast cells of asthmatic airways by immunohistochemistry.[5] IL-5 expression is regulated by several transcription factors including GATA3.[6]

Clinical significance

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.[7] 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.[8]

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[9] and eosinophilic granulomatosis with polyangiitis (EGPA).[10] Another antibody, depemokimab (GSK3511294), is under development.[11]

Some hydroxyethylaminomethylbenzimidazole analogs have shown IL-5 inhibition in vitro.[12]

Effect on eosinophils

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.[13] 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,[14] 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.[15]

Interactions

IL-5 has been shown to interact with interleukin 5 receptor alpha subunit.[16] [17] [18]

Receptors

The IL-5 receptor is composed of an α and a βc chain.[19] 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).[19] [20] Glycosylation of the Asn196 residue of the Rα subunit appears to be essential for binding of IL-5.[21]

Notes and References

  1. Milburn MV, Hassell AM, Lambert MH, Jordan SR, Proudfoot AE, Graber P, Wells TN . A novel dimer configuration revealed by the crystal structure at 2.4 A resolution of human interleukin-5 . Nature . 363 . 6425 . 172–176 . May 1993 . 8483502 . 10.1038/363172a0 . 4254991 . 1993Natur.363..172M .
  2. Lee JS, Campbell HD, Kozak CA, Young IG . The IL-4 and IL-5 genes are closely linked and are part of a cytokine gene cluster on mouse chromosome 11 . Somatic Cell and Molecular Genetics . 15 . 2 . 143–152 . March 1989 . 2784591 . 10.1007/BF01535075 . 41719900 .
  3. van Leeuwen BH, Martinson ME, Webb GC, Young IG . Molecular organization of the cytokine gene cluster, involving the human IL-3, IL-4, IL-5, and GM-CSF genes, on human chromosome 5 . Blood . 73 . 5 . 1142–1148 . April 1989 . 2564789 . 10.1182/blood.V73.5.1142.1142 . free .
  4. Dubucquoi S, Desreumaux P, Janin A, Klein O, Goldman M, Tavernier J, Capron A, Capron M . 6 . Interleukin 5 synthesis by eosinophils: association with granules and immunoglobulin-dependent secretion . The Journal of Experimental Medicine . 179 . 2 . 703–708 . February 1994 . 8294877 . 2191391 . 10.1084/jem.179.2.703 .
  5. Bradding P, Roberts JA, Britten KM, Montefort S, Djukanovic R, Mueller R, Heusser CH, Howarth PH, Holgate ST . 6 . 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 . American Journal of Respiratory Cell and Molecular Biology . 10 . 5 . 471–480 . May 1994 . 8179909 . 10.1165/ajrcmb.10.5.8179909 .
  6. Kaminuma O, Mori A, Kitamura N, Hashimoto T, Kitamura F, Inokuma S, Miyatake S . Role of GATA-3 in IL-5 gene transcription by CD4+ T cells of asthmatic patients . International Archives of Allergy and Immunology . 137 . 55–59 . 2005 . Suppl 1 . 15947486 . 10.1159/000085433 . 25517499 .
  7. 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 . 6 . A causative relationship exists between eosinophils and the development of allergic pulmonary pathologies in the mouse . Journal of Immunology . 170 . 6 . 3296–3305 . March 2003 . 12626589 . 10.4049/jimmunol.170.6.3296 . free .
  8. Sanderson CJ . Interleukin-5, eosinophils, and disease . Blood . 79 . 12 . 3101–3109 . June 1992 . 1596561 . 10.1182/blood.V79.12.3101.3101 . free .
  9. Web site: Anti-interleukin-5 therapy for severe asthma: A new therapeutic option . Mayo Clinic . 8 January 2019 . 14 December 2023 . en.
  10. Berti A, Atzeni F, Dagna L, Del Giacco S, Emmi G, Salvarani C, Vaglio A . Targeting the interleukin-5 pathway in EGPA: evidence, uncertainties and opportunities . Annals of the Rheumatic Diseases . 82 . 2 . 164–168 . February 2023 . 36357156 . 10.1136/ard-2022-223044 . 253457684 .
  11. Singh D, Fuhr R, Bird NP, Mole S, Hardes K, Man YL, Cahn A, Yancey SW, Pouliquen IJ . 6 . A Phase 1 study of the long-acting anti-IL-5 monoclonal antibody GSK3511294 in patients with asthma . British Journal of Clinical Pharmacology . 88 . 2 . 702–712 . February 2022 . 34292606 . 10.1111/bcp.15002 . 9290054 .
  12. Boggu PR, Kim Y, Jung SH . Discovery of benzimidazole analogs as a novel interleukin-5 inhibitors . European Journal of Medicinal Chemistry . 181 . 111574 . November 2019 . 31400705 . 10.1016/j.ejmech.2019.111574 . 199527755 .
  13. Giembycz MA, Lindsay MA . Pharmacology of the eosinophil . Pharmacological Reviews . 51 . 2 . 213–340 . June 1999 . 10353986 .
  14. Lopez AF, Begley CG, Williamson DJ, Warren DJ, Vadas MA, Sanderson CJ . Murine eosinophil differentiation factor. An eosinophil-specific colony-stimulating factor with activity for human cells . The Journal of Experimental Medicine . 163 . 5 . 1085–1099 . May 1986 . 3486243 . 2188112 . 10.1084/jem.163.5.1085 .
  15. Di Biagio E, Sánchez-Borges M, Desenne JJ, Suárez-Chacón R, Somoza R, Acquatella G . Eosinophilia in Hodgkin's disease: a role for interleukin 5 . International Archives of Allergy and Immunology . 110 . 3 . 244–251 . July 1996 . 8688671 . 10.1159/000237294 .
  16. Woodcock JM, Zacharakis B, Plaetinck G, Bagley CJ, Qiyu S, Hercus TR, Tavernier J, Lopez AF . 6 . 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 . The EMBO Journal . 13 . 21 . 5176–5185 . November 1994 . 7957082 . 395466 . 10.1002/j.1460-2075.1994.tb06848.x .
  17. Johanson K, Appelbaum E, Doyle M, Hensley P, Zhao B, Abdel-Meguid SS, Young P, Cook R, Carr S, Matico R . 6 . Binding interactions of human interleukin 5 with its receptor alpha subunit. Large scale production, structural, and functional studies of Drosophila-expressed recombinant proteins . The Journal of Biological Chemistry . 270 . 16 . 9459–9471 . April 1995 . 7721873 . 10.1074/jbc.270.16.9459 . free .
  18. Murata Y, Takaki S, Migita M, Kikuchi Y, Tominaga A, Takatsu K . Molecular cloning and expression of the human interleukin 5 receptor . The Journal of Experimental Medicine . 175 . 2 . 341–351 . February 1992 . 1732409 . 2119102 . 10.1084/jem.175.2.341 .
  19. Tavernier J, Devos R, Cornelis S, Tuypens T, Van der Heyden J, Fiers W, Plaetinck G . 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 . Cell . 66 . 6 . 1175–1184 . September 1991 . 1833065 . 10.1016/0092-8674(91)90040-6 . 54277241 .
  20. Takaki S, Murata Y, Kitamura T, Miyajima A, Tominaga A, Takatsu K . Reconstitution of the functional receptors for murine and human interleukin 5 . The Journal of Experimental Medicine . 177 . 6 . 1523–1529 . June 1993 . 8496674 . 2191058 . 10.1084/jem.177.6.1523 .
  21. 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 . 6 . A protein engineering approach differentiates the functional importance of carbohydrate moieties of interleukin-5 receptor α . Biochemistry . 50 . 35 . 7546–7556 . September 2011 . 21770429 . 10.1021/bi2009135 .

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