Interleukin 25

Interleukin-25 (IL-25) – also known as interleukin-17E (IL-17E)^[5] – is a protein that in humans is encoded by the IL25 gene on chromosome 14.^[6][7][8] IL-25 was discovered in 2001 and is made up of 177 amino acids.^[6]

IL25
Identifiers
Aliases	IL25, IL17E, IL-25, interleukin 25
External IDs	OMIM: 605658 MGI: 2155888 HomoloGene: 15429 GeneCards: IL25
Gene location (Human) Chr. Chromosome 14 (human)^[1] Band 14q11.2 Start 23,372,809 bp^[1] End 23,376,403 bp^[1]
Gene location (Mouse) Chr. Chromosome 14 (mouse)^[2] Band 14|14 C3 Start 55,170,152 bp^[2] End 55,173,294 bp^[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in human musculoskeletal system muscular system gastrocnemius muscle thigh ventricle left ventricle lymph node connective tissue adipose tissue smooth muscle tissue Top expressed in neural tube placenta olfactory bulb diencephalon gland endocrine gland superior frontal gyrus pituitary gland More reference expression data BioGPS More reference expression data
Gene ontology Molecular function interleukin-17E receptor binding cytokine activity Cellular component extracellular region extracellular space Biological process response to fungus interleukin-13 production response to nematode inflammatory response to antigenic stimulus eosinophil differentiation positive regulation of transcription by RNA polymerase II interleukin-5 production inflammatory response regulation of signaling receptor activity biological process interleukin-17-mediated signaling pathway Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 64806 140806 Ensembl ENSG00000166090 ENSMUSG00000040770 UniProt Q9H293 Q8VHH8 RefSeq (mRNA) NM_172314 NM_022789 NM_080729 RefSeq (protein) NP_073626 NP_758525 NP_542767 Location (UCSC) Chr 14: 23.37 – 23.38 Mb Chr 14: 55.17 – 55.17 Mb PubMed search ^[3] ^[4]
Wikidata
View/Edit Human View/Edit Mouse

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.^[9]

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.^[10] 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.^[11][12]

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.^[13][14]

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.^[6]

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.^[7] Evidence is the expression of IL-17RB on Th2 cells, not on Th1 and Th17.^[15] In addition, IL-25 is responsible for the decrease in IFN gamma.^[15][16]

Because IL-25 promotes the development of a Th2 immune response, it acts to protect against several bowel infections caused by helminths.^[16][17] This role of IL-25 has been demonstrated in these intestinal parasites - Nippostrongylus brasiliensis ^[18], Trichuris muris ^[16], Trichinella spiralis ^[19] a Heligmosomoides polygyrus bekeri. ^[17]

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.^[20]

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.^[21][22]

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. ^[23]

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.^[24]

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.^[25]

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^{[clarification needed]} IL-13, cytokines which play important role in allergies.^[7][26]

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.^[18]

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.^[27]

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.^[28]

References

1. GRCh38: Ensembl release 89: ENSG00000166090 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000040770 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Product reference for IL-17E
6. Lee J, Ho WH, Maruoka M, Corpuz RT, Baldwin DT, Foster JS, Goddard AD, Yansura DG, Vandlen RL, Wood WI, Gurney AL (January 2001). "IL-17E, a novel proinflammatory ligand for the IL-17 receptor homolog IL-17Rh1". The Journal of Biological Chemistry. 276 (2): 1660–4. doi:10.1074/jbc.M008289200. PMID 11058597.
7. 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 (December 2001). "IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo". Immunity. 15 (6): 985–95. doi:10.1016/S1074-7613(01)00243-6. PMID 11754819.
8. "Entrez Gene: IL25 interleukin 25".
9. Moseley TA, Haudenschild DR, Rose L, Reddi AH (April 2003). "Interleukin-17 family and IL-17 receptors". Cytokine & Growth Factor Reviews. 14 (2): 155–74. doi:10.1016/S1359-6101(03)00002-9. PMID 12651226.
10. Wilson SC, Caveney NA, Yen M, Pollmann C, Xiang X, Jude KM, et al. (September 2022). "Organizing structural principles of the IL-17 ligand-receptor axis". Nature. 609 (7927): 622–629. Bibcode:2022Natur.609..622W. doi:10.1038/s41586-022-05116-y. PMC 9477748. PMID 35863378.
11. Rickel EA, Siegel LA, Yoon BR, Rottman JB, Kugler DG, Swart DA, et al. (September 2008). "Identification of functional roles for both IL-17RB and IL-17RA in mediating IL-25-induced activities". Journal of Immunology. 181 (6): 4299–4310. doi:10.4049/jimmunol.181.6.4299. PMID 18768888.
12. Reynolds JM, Lee YH, Shi Y, Wang X, Angkasekwinai P, Nallaparaju KC, et al. (April 2015). "Interleukin-17B Antagonizes Interleukin-25-Mediated Mucosal Inflammation". Immunity. 42 (4): 692–703. doi:10.1016/j.immuni.2015.03.008. PMC 5811222. PMID 25888259.
13. Iwakura Y, Ishigame H, Saijo S, Nakae S (February 2011). "Functional specialization of interleukin-17 family members". Immunity. 34 (2): 149–62. doi:10.1016/j.immuni.2011.02.012. PMID 21349428.
14. Song X, Qian Y (December 2013). "IL-17 family cytokines mediated signaling in the pathogenesis of inflammatory diseases". Cellular Signalling. 25 (12): 2335–47. doi:10.1016/j.cellsig.2013.07.021. PMID 23917206.
15. Angkasekwinai P, Park H, Wang YH, Wang YH, Chang SH, Corry DB, Liu YJ, Zhu Z, Dong C (July 2007). "Interleukin 25 promotes the initiation of proallergic type 2 responses". The Journal of Experimental Medicine. 204 (7): 1509–17. doi:10.1084/jem.20061675. PMC 2118650. PMID 17562814.
16. Owyang AM, Zaph C, Wilson EH, Guild KJ, McClanahan T, Miller HR, Cua DJ, Goldschmidt M, Hunter CA, Kastelein RA, Artis D (April 2006). "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. doi:10.1084/jem.20051496. PMC 1800834. PMID 16606667.
17. 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 (December 2016). "Critical Role for Interleukin-25 in Host Protective Th2 Memory Response against Heligmosomoides polygyrus bakeri". Infection and Immunity. 84 (12): 3328–3337. doi:10.1128/IAI.00180-16. PMC 5116711. PMID 27620722.
18. Fallon PG, Ballantyne SJ, Mangan NE, Barlow JL, Dasvarma A, Hewett DR, et al. (April 2006). "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). The Rockefeller University Press: 1105–1116. doi:10.1084/jem.20051615. OCLC 679042420. PMC 2118283. PMID 16606668.
19. Angkasekwinai P, Srimanote P, Wang YH, Pootong A, Sakolvaree Y, Pattanapanyasat K, Chaicumpa W, Chaiyaroj S, Dong C (October 2013). "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. doi:10.1128/IAI.00646-13. PMC 3811766. PMID 23897610.
20. Angkasekwinai P, Chang SH, Thapa M, Watarai H, Dong C (March 2010). "Regulation of IL-9 expression by IL-25 signaling". Nature Immunology. 11 (3): 250–6. doi:10.1038/ni.1846. PMC 2827302. PMID 20154671.
21. 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 (February 2013). "Innate lymphoid cells--a proposal for uniform nomenclature". Nature Reviews. Immunology. 13 (2): 145–9. doi:10.1038/nri3365. PMID 23348417. S2CID 2228459.
22. Neill DR, Wong SH, Bellosi A, Flynn RJ, Daly M, Langford TK, Bucks C, Kane CM, Fallon PG, Pannell R, Jolin HE, McKenzie AN (April 2010). "Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity". Nature. 464 (7293): 1367–70. Bibcode:2010Natur.464.1367N. doi:10.1038/nature08900. PMC 2862165. PMID 20200518.
23. Furuta S, Jeng YM, Zhou L, Huang L, Kuhn I, Bissell MJ, Lee WH (April 2011). "IL-25 causes apoptosis of IL-25R-expressing breast cancer cells without toxicity to nonmalignant cells". Science Translational Medicine. 3 (78): 78ra31. doi:10.1126/scitranslmed.3001374. PMC 3199022. PMID 21490275.
    • Lay summary in: "Researchers Find Healthy Breast Tissue Secretes IL-25 to Kill Tumor Cells". Genetic Engineering & Biotechnology News. April 14, 2011.
24. Büning C, Genschel J, Weltrich R, Lochs H, Schmidt H (October 2003). "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. doi:10.1046/j.1365-2370.2003.00411.x. PMID 14641539.
25. Benatar T, Cao MY, Lee Y, Lightfoot J, Feng N, Gu X, Lee V, Jin H, Wang M, Wright JA, Young AH (June 2010). "IL-17E, a proinflammatory cytokine, has antitumor efficacy against several tumor types in vivo". Cancer Immunology, Immunotherapy. 59 (6): 805–17. doi:10.1007/s00262-009-0802-8. PMC 11030851. PMID 20012860. S2CID 1895002.
26. Yao X, Sun Y, Wang W, Sun Y (May 2016). "Interleukin (IL)-25: Pleiotropic roles in asthma". Respirology. 21 (4): 638–47. doi:10.1111/resp.12707. PMID 26699081.
27. Tang W, Smith SG, Du W, Gugilla A, Du J, Oliveria JP, Howie K, Salter BM, Gauvreau GM, O'Byrne PM, Sehmi R (2018). "Interleukin-25 and eosinophils progenitor cell mobilization in allergic asthma". Clinical and Translational Allergy. 8: 5. doi:10.1186/s13601-018-0190-2. PMC 5809891. PMID 29456832.
28. Khodoun MV, Tomar S, Tocker JE, Wang YH, Finkelman FD (January 2018). "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. doi:10.1016/j.jaci.2017.02.046. PMID 28552763.

Further reading

• Fallon PG, Ballantyne SJ, Mangan NE, Barlow JL, Dasvarma A, Hewett DR, McIlgorm A, Jolin HE, McKenzie AN (April 2006). "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. doi:10.1084/jem.20051615. PMC 2118283. PMID 16606668.
• Pan G, French D, Mao W, Maruoka M, Risser P, Lee J, Foster J, Aggarwal S, Nicholes K, Guillet S, Schow P, Gurney AL (December 2001). "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. doi:10.4049/jimmunol.167.11.6559. PMID 11714825.
• 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 (October 2002). "Transgenic overexpression of human IL-17E results in eosinophilia, B-lymphocyte hyperplasia, and altered antibody production". Blood. 100 (7): 2330–40. doi:10.1182/blood-2002-01-0012. PMID 12239140. S2CID 253678.
• Zhang Z, Henzel WJ (October 2004). "Signal peptide prediction based on analysis of experimentally verified cleavage sites". Protein Science. 13 (10): 2819–24. doi:10.1110/ps.04682504. PMC 2286551. PMID 15340161.
• Létuvé S, Lajoie-Kadoch S, Audusseau S, Rothenberg ME, Fiset PO, Ludwig MS, Hamid Q (March 2006). "IL-17E upregulates the expression of proinflammatory cytokines in lung fibroblasts". The Journal of Allergy and Clinical Immunology. 117 (3): 590–6. doi:10.1016/j.jaci.2005.10.025. PMID 16522458.
• 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 (September 2006). "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. doi:10.1016/j.jaci.2006.04.051. PMID 16950278.
• 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 (August 2007). "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. doi:10.1084/jem.20070406. PMC 2118667. PMID 17635955.