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-Secretase Inhibitor Reduces Allergic Pulmonary Inflammation by Modulating Th1 and Th2 Responses

¹ Division of Molecular and Life Sciences, College of Science and Technology, Hanyang University, Seoul; ² Genome Research Center for Allergy and Respiratory Diseases, Division of Allergy and Respiratory Medicine, Soonchunhyang University Hospital, Bucheon; and ³ Department of Life Science, Sogang University, Seoul, South Korea

Correspondence and requests for reprints should be addressed to Il Yup Chung, Ph.D., Division of Molecular and Life Sciences, College of Science and Technology, Hanyang University, 1271 Sa-1-dong, Ansan, Gyeonggi-do 426-791, South Korea. E-mail: iychu{at}hanyang.ac.kr

Rationale: -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. In asthma, a subset of CD4⁺ T cells is believed to initiate and perpetuate the disease.

Objectives: The aim of this study was to evaluate the therapeutic potential of GSI against allergic asthma.

Methods: GSI was administered to an ovalbumin-sensitized mouse via an intranasal route at the time of ovalbumin challenge.

Measurements and Main Results: The administration of GSI inhibits asthma phenotypes, including eosinophilic airway inflammation, goblet cell metaplasia, methacholine-induced airway hyperresponsiveness, and serum IgE production. GSI treatment of bronchoalveolar lavage cells stimulated via TCR or non-TCR pathways led to a decrease in Th2 cytokine production with a concomitant increase in Th1 cytokine secretion. Expression of Hes-1, a target of Notch signaling, was down-regulated in conjunction with a reduction of Notch intracellular domain and GATA-3 levels after GSI treatment of bronchoalveolar lavage cells. GSI treatment resulted in an inhibition of NF-B activation, and combined treatment with GSI and an NF-B inhibitor augmented IFN- production in a synergistic manner.

Conclusions: These data suggest that GSI directly regulates Th1 and Th2 responses in allergic pulmonary inflammation through a Notch signaling–dependent pathway and that GSI is of high therapeutic value for treating asthma by inhibiting airway inflammatory responses.

Key Words: asthma • GATA-3 • NF-B • notch • -secretase inhibitor

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject -Secretase inhibitor was initially developed to treat neurological diseases by blocking aberrant cleavage of amyloid precursor protein. Additionally, it has been used to block Notch signaling, which plays a crucial role in T-helper cell differentiation. What This Study Adds to the Field In an experimental model of asthma, -secretase inhibitor directly up-regulated Th1 and down-regulated Th2 cytokines via a Notch signaling–dependent mechanism, suggesting the therapeutic potential of -secretase inhibitors in asthma.