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...

Interleukin 17 Family Cytokines: Signaling Mechanisms, Biological Activities, and Therapeutic Implications

“…In addition, tissue stromal cells can express IL-17E. Human lung epithelial cells and murine primary type II alveolar epithelial cells express IL-17E following challenge with Aspergillus oryzae , ragweed allergens, and allergen proteases [41, 42]. Concordantly, IL-17E was detected at higher levels via immunohistochemistry (IHC) in the bronchial mucosa of asthmatics [43].…”

Recent advances in epithelium-derived cytokines (IL-33, IL-25, and thymic stromal lymphopoietin) and allergic inflammation

“…Unlike IL-33, which is stored in the nucleus, IL-25 is stored in and released from extra-nuclear cellular compartments. Kouzaki et al have reported that IL-25 is constitutively expressed in epithelial cells and is released upon exposure to proteases, such as trypsin, papain or in a more clinically relevant context, allergen proteases present in house dust mite (HDM) extract [21]. Given the immunological effects of IL-25, release of this cytokine by environmental proteases could have important implications in allergic disease.…”

New Insights into Cockroach Allergens

“…Effects of cockroach extracts on human airway epithelial cells have been described, that include the induction of cytokines and chemokines (IL-8, IL-25, IL-33, CCL20 and GM-CSF) [42–44]. Some effects are mediated by proteases acting on protease-activated receptors (PAR-2) (see also Group 10 section) [45,46].…”