gamma-Secretase Inhibitor Reduces Allergic Pulmonary Inflammation by Modulating Th1 and Th2 Responses
- Authors
- Kang, Jin Hyun; Kim, Byung Soo; Uhm, Tae Gi; Lee, Shin-Hwa; Lee, Gap Ryol; Park, Choon-Sik; Chung, Il Yup
- Issue Date
- May-2009
- Publisher
- American Thoracic Society
- Keywords
- asthma; GATA-3; NF-kappa B; notch; gamma-secretase inhibitor
- Citation
- American Journal of Respiratory and Critical Care Medicine, v.179, no.10, pp.875 - 882
- Indexed
- SCIE
SCOPUS
- Journal Title
- American Journal of Respiratory and Critical Care Medicine
- Volume
- 179
- Number
- 10
- Start Page
- 875
- End Page
- 882
- URI
- https://scholarworks.bwise.kr/erica/handle/2021.sw.erica/41202
- DOI
- 10.1164/rccm.200806-893OC
- ISSN
- 1073-449X
- Abstract
- Rationale: gamma-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-kappa B activation, and combined treatment with GSI and an NF-kappa B inhibitor augmented IFN-gamma 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.
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Collections - COLLEGE OF SCIENCE AND CONVERGENCE TECHNOLOGY > ERICA 의약생명과학과 > 1. Journal Articles
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