期刊
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
卷 179, 期 10, 页码 875-882出版社
AMER THORACIC SOC
DOI: 10.1164/rccm.200806-893OC
关键词
asthma; GATA-3; NF-kappa B; notch; gamma-secretase inhibitor
资金
- Korea Research Foundation [2007-521-E00052]
- BK21
- Korea Research Foundation
- National Research Foundation of Korea [2007-521-E00052, 과C6A2605] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据