Intratracheal administration of OVA-pulsed DCs with IL-33 significantly enhances eosinophil counts and mucous secretion in the lung as compared with OVA-pulsed DCs alone. Taken together, the data indicate that IL-33 affects DC maturation in the lung leading to DC migration to the lymph nodes, where they can thereby contribute to the priming of Th2 cells and the induction of allergic airway inflammation (Figure 1). These findings are remarkable since they demonstrate a new effector cell population that significantly contributes to the IL-33-mediated effects, such as Th2 induction and eosinophil recruitment in the

lung, processes that have not been well understood to date. Consequently, IL-33 may be an alarmin that integrates danger with a I-BET-762 clinical trial Th2-type response, thereby initially controlling the potentially overwhelming immune responses, Afatinib such as those observed in sepsis 14. However, IL-33 may also drive the immune system in the lung towards the development of allergen-specific Th2-type responses. Epidemiological and experimental data suggest a strong link between concomitant infection, in particular with rhinovirus and respiratory syncytial virus in the first year of life that may lead to obstructive bronchitis, and subsequent development of asthma 15. DCs and alternatively activated macrophages are considered to be the key regulators

of the initiation of an immune response and to be modulators of inflammation. Given the assumption that IL-33 is locally released in the lung via exogenous factors such as infections that lead

to cell destruction tuclazepam and inflammation, it is tempting to speculate on the role of IL-33 in the induction of asthma, in particular in the context of virus-induced exacerbations of asthma; however, experimental evidences from models integrating both virus infection and IL-33 are still limited. The IL-33 receptor ST2 was demonstrated to be an orphan receptor over a decade ago and has been linked to allergic diseases 5, 16. It occurs in a membrane-bound form that is responsible for the IL-33-mediated functions, and in a soluble form that is considered to act as a scavenger receptor antagonizing ST2-mediated effects 17. One of the main reasons for the late discovery of IL-33 may be the fact that it is not secreted in a conventional way. In fact, the circumstances of IL-33 release still remain enigmatic since active secretion has not been demonstrated. IL-33 is constitutively expressed in various tissue cells in the lung including smooth muscle cells, fibroblasts, endothelial cells and epithelial cells of mucosal surfaces. In contrast to IL-1β, IL-33 is located in the nucleus in its active form where it is considered to exert repressor activities. The cleavage of IL-33 via caspases 3 and 7 leads to its inactivation 18.