Interleukin 25 Explained

Interleukin-25 (IL-25) – also known as interleukin-17E (IL-17E)^[1] – is a protein that in humans is encoded by the IL25 gene on chromosome 14.^[2] IL-25 was discovered in 2001 and is made up of 177 amino acids.^[3]

IL-25 and IL-17 family

IL-25 is a cytokine that belongs to the IL-17 cytokine family together with IL-17A (named also IL-17), IL-17B, IL-17C, IL-17D and IL-17F. This is why IL-25 has the alternative name IL-17E. All members have homologous amino acid sequence segments and spatially conserved cysteines. It is the IL-25 that differs from other members in its function and structure.^[4]

IL-25 signals through a heterohexameric receptor complex containing IL-17RA and IL-17RB. In this complex, IL-25 forms a homodimer with IL-17RB, which then binds to IL-17RA.^[5] The IL-17RA subunit is common for IL-17A and IL-17F, and IL-17RB is common for IL-17B. Both IL-17RA and IL-17RB are essential for IL-25 functions. IL-25 does not bind directly to IL-17RA, but this subunit is necessary for its functions - as well as IL-17RB which directly bind IL-25.^{[6] [7]}

Function

IL-25 is produced by many cell types. These cells include T cells, dendritic cells, macrophages, mast cells, basophils, eosinophils, epithelial cells and Paneth cells.^{[8] [9]}

This cytokine can induce NF-κB activation, and stimulate the production of IL-8 (named also CXCL8), which is the major chemotactic substance of neutrophils.

Another important function of interleukin 25 is to support the Th2 immune response. IL-25 has been shown to induce the production of IL-4, IL-5 and IL-13. Evidence is the expression of IL-17RB on Th2 cells, not on Th1 and Th17.^[10] In addition, IL-25 is responsible for the decrease in IFN gamma.

Because IL-25 promotes the development of a Th2 immune response, it acts to protect against several bowel infections caused by helminths.^[11] This role of IL-25 has been demonstrated in these intestinal parasites - Nippostrongylus brasiliensis , Trichuris muris , Trichinella spiralis ^[12] a Heligmosomoides polygyrus bekeri.

IL-25 is also referred to as the regulator of IL-9 production. IL-25 has been shown to increase the production of IL-9 in Th9 cells. Th9 cells can arise not only from naive T cells but also from differentiated Th2 cells.^[13]

Another function of IL-25 is the activation of natural lymphoid cells 2 (ILC2). IL-25 and IL-33 are the most potent activators of ILC2.^{[14] [15]}

Clinical significance

IL-25 induces the production of other cytokines, including IL-4, IL-5 and IL-13 in multiple tissues, which stimulate the expansion of eosinophils. This cytokine is an important molecule controlling immunity of the gut^[16] and has been implicated in chronic inflammation associated with the gastrointestinal tract. IL-25 can kill some types of breast cancer cells.^[17]

Further, the IL-25 gene has been identified in a chromosomal region associated with diseases of the gut such as inflammatory bowel disease (IBD), although no direct evidence suggests that IL-25 plays any role in this disease.^[18]

IL-25 has potent antitumor activity in vivo in several human cancers including melanoma, breast, lung, colon, and pancreatic cancers, suggesting the potential clinical use of IL-17E as an anticancer agent.^[19]

IL-25 and allergy

IL-25 works pathologically in allergies. It is a cytokine that supports the Th2 response. IL-25 induces IL-4, IL-5 a IL-13, cytokines which play important role in allergies.^{[20] [21]}

Many studies suggest that blocking IL-25 activity might be useful in the treatment of allergies. Research studies suggest the blocking of IL-25 activity by the neutralizing antibody against IL-25. A delayed Th2 differentiation and delayed production of cytokines IL-4, IL-5 and IL-13 have been demonstrated in the IL-25 knockout mouse.^[22]

IL-25 influences the development of nasal polyps, and may also be involved in the etiology of chronic rhinitis with nasal polyps. A 2018 study found that after using a non-neutralizing antibody against IL-25, IL-4, IL-5, and IL-13 decreased, and the number of nasal polyps decreased.^[23]

Another proposed option of treating allergies with IL-25 is a combination of neutralizing antibodies against IL-25, IL-33 and TSLP (thymic stromal lymphopoietin). All three of these cytokines support the Th2 immune response.^[24]

Further reading

• Fallon PG, Ballantyne SJ, Mangan NE, Barlow JL, Dasvarma A, Hewett DR, McIlgorm A, Jolin HE, McKenzie AN . Identification of an interleukin (IL)-25-dependent cell population that provides IL-4, IL-5, and IL-13 at the onset of helminth expulsion . The Journal of Experimental Medicine . 203 . 4 . 1105–16 . April 2006 . 16606668 . 2118283 . 10.1084/jem.20051615 . Andrew N. J. McKenzie .
• Pan G, French D, Mao W, Maruoka M, Risser P, Lee J, Foster J, Aggarwal S, Nicholes K, Guillet S, Schow P, Gurney AL . Forced expression of murine IL-17E induces growth retardation, jaundice, a Th2-biased response, and multiorgan inflammation in mice . Journal of Immunology . 167 . 11 . 6559–67 . December 2001 . 11714825 . 10.4049/jimmunol.167.11.6559 . free .
• Kim MR, Manoukian R, Yeh R, Silbiger SM, Danilenko DM, Scully S, Sun J, DeRose ML, Stolina M, Chang D, Van GY, Clarkin K, Nguyen HQ, Yu YB, Jing S, Senaldi G, Elliott G, Medlock ES . Transgenic overexpression of human IL-17E results in eosinophilia, B-lymphocyte hyperplasia, and altered antibody production . Blood . 100 . 7 . 2330–40 . October 2002 . 12239140 . 10.1182/blood-2002-01-0012 . 253678 . free .
• Zhang Z, Henzel WJ . Signal peptide prediction based on analysis of experimentally verified cleavage sites . Protein Science . 13 . 10 . 2819–24 . October 2004 . 15340161 . 2286551 . 10.1110/ps.04682504 .
• Létuvé S, Lajoie-Kadoch S, Audusseau S, Rothenberg ME, Fiset PO, Ludwig MS, Hamid Q . IL-17E upregulates the expression of proinflammatory cytokines in lung fibroblasts . The Journal of Allergy and Clinical Immunology . 117 . 3 . 590–6 . March 2006 . 16522458 . 10.1016/j.jaci.2005.10.025 .
• Tamachi T, Maezawa Y, Ikeda K, Kagami S, Hatano M, Seto Y, Suto A, Suzuki K, Watanabe N, Saito Y, Tokuhisa T, Iwamoto I, Nakajima H . IL-25 enhances allergic airway inflammation by amplifying a TH2 cell-dependent pathway in mice . The Journal of Allergy and Clinical Immunology . 118 . 3 . 606–14 . September 2006 . 16950278 . 10.1016/j.jaci.2006.04.051 . free .
• Wang YH, Angkasekwinai P, Lu N, Voo KS, Arima K, Hanabuchi S, Hippe A, Corrigan CJ, Dong C, Homey B, Yao Z, Ying S, Huston DP, Liu YJ . IL-25 augments type 2 immune responses by enhancing the expansion and functions of TSLP-DC-activated Th2 memory cells . The Journal of Experimental Medicine . 204 . 8 . 1837–47 . August 2007 . 17635955 . 2118667 . 10.1084/jem.20070406 .

Notes and References

1. http://www.ebioscience.com/knowledge-center/antigen/il-17e-il-25-overview.htm Product reference for IL-17E
2. Web site: Entrez Gene: IL25 interleukin 25.
3. Lee J, Ho WH, Maruoka M, Corpuz RT, Baldwin DT, Foster JS, Goddard AD, Yansura DG, Vandlen RL, Wood WI, Gurney AL . IL-17E, a novel proinflammatory ligand for the IL-17 receptor homolog IL-17Rh1 . The Journal of Biological Chemistry . 276 . 2 . 1660–4 . January 2001 . 11058597 . 10.1074/jbc.M008289200 . free .
4. Moseley TA, Haudenschild DR, Rose L, Reddi AH . Interleukin-17 family and IL-17 receptors . Cytokine & Growth Factor Reviews . 14 . 2 . 155–74 . April 2003 . 12651226 . 10.1016/S1359-6101(03)00002-9 .
5. Wilson SC, Caveney NA, Yen M, Pollmann C, Xiang X, Jude KM, Hafer M, Tsutsumi N, Piehler J, Garcia KC . 6 . Organizing structural principles of the IL-17 ligand-receptor axis . Nature . 609 . 7927 . 622–629 . September 2022 . 35863378 . 10.1038/s41586-022-05116-y . 9477748 . 2022Natur.609..622W .
6. Rickel EA, Siegel LA, Yoon BR, Rottman JB, Kugler DG, Swart DA, Anders PM, Tocker JE, Comeau MR, Budelsky AL . 6 . Identification of functional roles for both IL-17RB and IL-17RA in mediating IL-25-induced activities . Journal of Immunology . 181 . 6 . 4299–4310 . September 2008 . 18768888 . 10.4049/jimmunol.181.6.4299 . free .
7. Reynolds JM, Lee YH, Shi Y, Wang X, Angkasekwinai P, Nallaparaju KC, Flaherty S, Chang SH, Watarai H, Dong C . 6 . Interleukin-17B Antagonizes Interleukin-25-Mediated Mucosal Inflammation . Immunity . 42 . 4 . 692–703 . April 2015 . 25888259 . 5811222 . 10.1016/j.immuni.2015.03.008 .
8. Iwakura Y, Ishigame H, Saijo S, Nakae S . Functional specialization of interleukin-17 family members . Immunity . 34 . 2 . 149–62 . February 2011 . 21349428 . 10.1016/j.immuni.2011.02.012 . free .
9. Song X, Qian Y . IL-17 family cytokines mediated signaling in the pathogenesis of inflammatory diseases . Cellular Signalling . 25 . 12 . 2335–47 . December 2013 . 23917206 . 10.1016/j.cellsig.2013.07.021 .
10. Angkasekwinai P, Park H, Wang YH, Wang YH, Chang SH, Corry DB, Liu YJ, Zhu Z, Dong C . Interleukin 25 promotes the initiation of proallergic type 2 responses . The Journal of Experimental Medicine . 204 . 7 . 1509–17 . July 2007 . 17562814 . 2118650 . 10.1084/jem.20061675 .
11. Pei C, Zhao C, Wang AJ, Fan AX, Grinchuk V, Smith A, Sun R, Xie Y, Lu N, Urban JF, Shea-Donohue T, Zhao A, Yang Z . Critical Role for Interleukin-25 in Host Protective Th2 Memory Response against Heligmosomoides polygyrus bakeri . Infection and Immunity . 84 . 12 . 3328–3337 . December 2016 . 27620722 . 5116711 . 10.1128/IAI.00180-16 .
12. Angkasekwinai P, Srimanote P, Wang YH, Pootong A, Sakolvaree Y, Pattanapanyasat K, Chaicumpa W, Chaiyaroj S, Dong C . Interleukin-25 (IL-25) promotes efficient protective immunity against Trichinella spiralis infection by enhancing the antigen-specific IL-9 response . Infection and Immunity . 81 . 10 . 3731–41 . October 2013 . 23897610 . 3811766 . 10.1128/IAI.00646-13 .
13. Angkasekwinai P, Chang SH, Thapa M, Watarai H, Dong C . Regulation of IL-9 expression by IL-25 signaling . Nature Immunology . 11 . 3 . 250–6 . March 2010 . 20154671 . 2827302 . 10.1038/ni.1846 .
14. Spits H, Artis D, Colonna M, Diefenbach A, Di Santo JP, Eberl G, Koyasu S, Locksley RM, McKenzie AN, Mebius RE, Powrie F, Vivier E . Innate lymphoid cells--a proposal for uniform nomenclature . Nature Reviews. Immunology . 13 . 2 . 145–9 . February 2013 . 23348417 . 10.1038/nri3365 . 2228459 . free .
15. Neill DR, Wong SH, Bellosi A, Flynn RJ, Daly M, Langford TK, Bucks C, Kane CM, Fallon PG, Pannell R, Jolin HE, McKenzie AN . Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity . Nature . 464 . 7293 . 1367–70 . April 2010 . 20200518 . 2862165 . 10.1038/nature08900 . 2010Natur.464.1367N .
16. Owyang AM, Zaph C, Wilson EH, Guild KJ, McClanahan T, Miller HR, Cua DJ, Goldschmidt M, Hunter CA, Kastelein RA, Artis D . Interleukin 25 regulates type 2 cytokine-dependent immunity and limits chronic inflammation in the gastrointestinal tract . The Journal of Experimental Medicine . 203 . 4 . 843–9 . April 2006 . 16606667 . 1800834 . 10.1084/jem.20051496 .
17. Furuta S, Jeng YM, Zhou L, Huang L, Kuhn I, Bissell MJ, Lee WH . IL-25 causes apoptosis of IL-25R-expressing breast cancer cells without toxicity to nonmalignant cells . Science Translational Medicine . 3 . 78 . 78ra31 . April 2011 . 21490275 . 3199022 . 10.1126/scitranslmed.3001374 .
18. Büning C, Genschel J, Weltrich R, Lochs H, Schmidt H . The interleukin-25 gene located in the inflammatory bowel disease (IBD) 4 region: no association with inflammatory bowel disease . European Journal of Immunogenetics . 30 . 5 . 329–33 . October 2003 . 14641539 . 10.1046/j.1365-2370.2003.00411.x .
19. Benatar T, Cao MY, Lee Y, Lightfoot J, Feng N, Gu X, Lee V, Jin H, Wang M, Wright JA, Young AH . IL-17E, a proinflammatory cytokine, has antitumor efficacy against several tumor types in vivo . Cancer Immunology, Immunotherapy . 59 . 6 . 805–17 . June 2010 . 20012860 . 10.1007/s00262-009-0802-8 . 1895002 . 11030851 .
20. Fort MM, Cheung J, Yen D, Li J, Zurawski SM, Lo S, Menon S, Clifford T, Hunte B, Lesley R, Muchamuel T, Hurst SD, Zurawski G, Leach MW, Gorman DM, Rennick DM . IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo . Immunity . 15 . 6 . 985–95 . December 2001 . 11754819 . 10.1016/S1074-7613(01)00243-6 . free .
21. Yao X, Sun Y, Wang W, Sun Y . Interleukin (IL)-25: Pleiotropic roles in asthma . Respirology . 21 . 4 . 638–47 . May 2016 . 26699081 . 10.1111/resp.12707 . free .
22. Fallon PG, Ballantyne SJ, Mangan NE, Barlow JL, Dasvarma A, Hewett DR, McIlgorm A, Jolin HE, McKenzie AN . 6 . Identification of an interleukin (IL)-25-dependent cell population that provides IL-4, IL-5, and IL-13 at the onset of helminth expulsion . The Journal of Experimental Medicine . 203 . 4 . 1105–1116 . April 2006 . 16606668 . The Rockefeller University Press . 10.1084/jem.20051615 . 2118283 . 679042420 .
23. Tang W, Smith SG, Du W, Gugilla A, Du J, Oliveria JP, Howie K, Salter BM, Gauvreau GM, O'Byrne PM, Sehmi R . Interleukin-25 and eosinophils progenitor cell mobilization in allergic asthma . Clinical and Translational Allergy . 8 . 5 . 2018 . 29456832 . 5809891 . 10.1186/s13601-018-0190-2 . free .
24. Khodoun MV, Tomar S, Tocker JE, Wang YH, Finkelman FD . Prevention of food allergy development and suppression of established food allergy by neutralization of thymic stromal lymphopoietin, IL-25, and IL-33 . The Journal of Allergy and Clinical Immunology . 141 . 1 . 171–179.e1 . January 2018 . 28552763 . 10.1016/j.jaci.2017.02.046 . free .