The Interleukin-17 (IL-17) family of proteins are immunoregulatory cytokines that share a conserved cysteine-rich region. IL-17E, which is also known as IL-25, promotes Th2-biased immune responses. This is in contrast to other IL-17 family members which promote Th1- and Th17-biased inflammation. IL-25 is an important mediator of allergic reactions and protection against intestinal parasites (1, 2). Mature human IL-25 shares 80% amino acid sequence identity with mouse and rat IL-25 (3, 4). During helminth infections and allergic reactions, IL-25 is locally up-regulated in intestinal and airway epithelial cells, atopic dermatitis skin lesions, and local Th2 cells, eosinophils, and basophils (4-9). It binds to IL-17 RB but also requires IL-17 RA to exert its activity (3, 8, 10). IL-25 acts on a variety of cell types which respond with increased production of Th2 cytokines ( e.g. IL-4, IL-5, IL-13) and reduced production of Th1 and Th17 cytokines ( e.g. IFN-gamma, IL-12, IL-23, IL-17A, IL-17F) (4-6, 8, 9, 11-15). Airway IL-25 can be activated by MMP-7, a protease that is up-regulated in airway epithelium in response to allergen exposure (16). Cleaved IL-25 shows enhanced binding to IL-17 RB and stronger induction of Th2 cytokines (16). The Th2 cytokines, in turn, trigger expansion of Th2 memory cells and
anti‑inflammatory M2 macrophages, increased eosinophil mobilization and activation, and dendritic cell migration (4, 6, 9, 13). These actions promote protective
anti‑helminth immune responses (4, 5) as well as allergic inflammation and airway hyperreactivity (11). The IL-25 induced suppression of Th1 and Th17 cytokines limits Th17 cell expansion and disease pathology in autoimmunity and colitis [12, 15]. IL-25 also promotes vascular endothelial cell proliferation and assembly into tubular structures (7). It supports the integrity of the blood-brain barrier and limits CD4 ⁺ T cell infiltration into the brain (17).