Transcription of Interleukin-25 and Extracellular Release of the Protein Is Regulated by Allergen Proteases in Airway Epithelial CELLS

Abstract

Epithelial cells at mucosal surfaces are integral components of innate and adaptive immunity. IL-25 is reportedly produced by epithelial cells and likely plays vital roles in regulating type-2 immune responses. However, little is known regarding the mechanisms that control production and extracellular releases of IL-25. We hypothesized that proteases from the multiple allergens may induce IL-25 production in airway epithelial cells. In this study, we found that IL-25 is constitutively produced and detectable in cytoplasm of resting normal human bronchial epithelial (NHBE) cells. When exposed to airborne allergens such as house dust mite (HDM), stored IL-25 was released rapidly to the extracellular space. IL-25 release was not accompanied by cell death, suggesting involvement of active secretory mechanism(s). HDM also enhanced IL-25 mRNA transcription, which was dependent on their protease activities. Furthermore, activation of NHBE cells with authentic proteases, such as trypsin and papain, or with a peptide agonist for protease-activated receptor 2 was sufficient to enhance IL-25 mRNA transcription and protein. Protease-driven increase in mRNA transcription and allergen-driven extracellular release of IL-25 protein was also observed in primary nasal epithelial cells from healthy individuals. These findings suggest that IL-25 production by airway epithelial cells is regulated by the transcription and protein release levels and that allergen proteases likely play pivotal roles in both biological processes.Keywords: airway epithelial cells; allergen; PAR-2; protease; In addition to being a physical barrier between the airway and the immune system, epithelial cells are now thought to play vital roles in innate and adaptive immune responses (1). Epithelial cells produce chemokines and cytokines that recruit and enhance survival of dendritic cells and interact directly with dendritic cells through membrane-associated chemokines (2-4). Epithelial cells also express soluble and cell-surface molecules that regulate recruitment, differentiation, proliferation, and function of T and B cells (2, 5). In particular, newly discovered epithelial-derived cytokines, such as thymic stromal lymphopoietin, IL-25, and IL-33, may play key roles in the development and regulation of T helper 2 (Th2) cytokine-dependent immune responses (6).There is increasing evidence to suggest the roles for IL-25 in the type-2 immune response and in the pathogenesis of asthma and allergic diseases. IL-25 (also known as IL-17E) is a member of a family of six structurally related but functionally distinct proteins. IL-17A and IL-17F appear to play important roles in neutrophilic inflammation and autoimmunity. In contrast, IL-25 is exceptional in promoting eosinophilic inflammation and a type-2 immune response (7). This has been well demonstrated in mouse models: exogenous administration of IL-25 (8, 9) or transgenic expression (10, 11) induces Th2-type inflammation. IL-25 is increased in animal bronchial challenge models (12), and its inhibition reduce...

Keratinocyte-Derived IL-17E Contributes to Inflammation in Psoriasis

“…Epithelial cells in general and keratinocytes in particular up-regulate the production of IL-17E in response to a variety of stimuli including allergens, fungal antigens, and TLR ligands Kouzaki et al, 2013;Peterson and Artis, 2014). In the context of psoriasis, physical/biochemical stimuli in early disease or the marked inflammatory environment in later disease stages may represent the driving force for IL-17E over-production.…”

IL-33 and Thymic Stromal Lymphopoietin in mast cell functions

“…However, the other epithelial derived cytokine IL-25 is equally important in allergic diseases since it is also expressed in different immune cells such as eosinophil, MCs and T cells (Corrigan et al, 2011). Unlikely to IL-33, and similar to TSLP, IL-25 release is independent of cell necrosis and it could be actively and rapidly released without mechanical stress or cell injury (Kouzaki et al, 2013). SNPs in the gene regions of IL25 and its association with several allergic disorders have not yet been explored and further research are required in this direction.…”

Spectrum of allergens for Japanese cedar pollinosis and impact of component-resolved diagnosis on allergen-specific immunotherapy

“…18 Protease-stimulated epithelial cells also secrete alarmins with or without the induction of necrosis. 19,20 IL-25, IL-33, and TSLP can activate innate immune cells in a process orchestrated by other cytokines in different manners; IL-25 alone induces inflammatory group 2 innate lymphoid cells (iILC2), while natural helper (NH) cells are strongly activated by a combination of IL-25 and IL-2. A combination of IL-25 and IL-33 induces and activates group 2 innate lymphoid cells (ILC2), while IL-33 alone increases NH cell numbers.…”