Interleukin-25 (IL-25) – also known asinterleukin-17E (IL-17E)[5] – is aprotein that in humans is encoded by theIL25gene on chromosome 14.[6][7][8] IL-25 was discovered in 2001 and is made up of 177 amino acids.[6]
IL-25 is acytokine that belongs to theIL-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]
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 induceNF-κB activation, and stimulate the production ofIL-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] andHeligmosomoides 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]
IL-25 induces the production of other cytokines, includingIL-4,IL-5 andIL-13 in multiple tissues, which stimulate the expansion ofeosinophils. This cytokine is an important molecule controllingimmunity of thegut[16] and has been implicated in chronicinflammation associated with thegastrointestinal tract. IL-25 can kill some types of breast cancer cells.[23]
Further, the IL-25gene has been identified in a chromosomal region associated with diseases of the gut such asinflammatory 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 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]
^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.PMID12651226.
^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.PMID23917206.
^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.PMID14641539.
