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Am J Respir Crit Care Med. 2009 May 15;179(10):875-82. doi: 10.1164/rccm.200806-893OC. Epub 2009 Feb 20.

Gamma-secretase inhibitor reduces allergic pulmonary inflammation by modulating Th1 and Th2 responses.

Author information

1
Division of Molecular and Life Sciences, College of Science and Technology, Hanyang University, Seoul, South Korea.

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-kappaB activation, and combined treatment with GSI and an NF-kappaB 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.

PMID:
19234107
DOI:
10.1164/rccm.200806-893OC
[Indexed for MEDLINE]

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