Regulation of Th1 and Th2 phenotypes by γ-secretase inhibitor in an animal model for asthma (79.10)

Abstract

Abstract γ-Secretase inhibitor (GSI) has been used to effectively block Notch signaling, which is implicated in the differentiation and functional regulation of T helper (Th) effector cells. We investigated a therapeutic potential of GSI against development of Th2-mediated inflammatory airway disease and the possible mechanism. Intranasal administration of GSI led to inhibition of asthma phenotypes including airway inflammation, goblet cell metaplasia, and airway hyperresponsiveness. When BAL cells from inflamed airways of mice were stimulated via TCR- or non TCR-pathways in the presence of GSI, Th2 cytokine production was decreased while Th1 cytokine production was increased. Furthermore, GSI treatment of CD4+ T cells that were purified from BAL cells resulted in markedly elevated IFN-g production and declined IL-5 production. However, this analogy was not exactly applied to splenic CD4+ T cells isolated from both naïve and asthma-induced mice: both IL-5 and IFN-g productions were inhibited by GSI, indicating that CD4+ T cells differentially responded to GSI depending on places where they reside. These data suggest that GSI is of therapeutic benefit against asthma by modulating Th effector responses.