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


OBJECTIVE
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.


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.
Kang
Jin Hyun
JH
Division of Molecular and Life Sciences, College of Science and Technology, Hanyang University, Seoul, South Korea.
Kim
Byung Soo
BS
Uhm
Tae Gi
TG
Lee
Shin-Hwa
SH
Lee
Gap Ryol
GR
Park
Choon-Sik
CS
Chung
Il Yup
IY
D000281:Administration, Intranasal; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000276:immunology; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004357:Drug Synergism; D004802:Eosinophilia / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology; D050990:GATA3 Transcription Factor / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000276:immunology; D009842:Oligopeptides / Q000494:pharmacology*; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D011014:Pneumonia / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D051880:Receptors, Notch / Q000378:metabolism; D012130:Respiratory Hypersensitivity / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects; D018417:Th1 Cells / Q000187:drug effects* / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects* / Q000276:immunology
D016207:Cytokines; D050990:GATA3 Transcription Factor; D016328:NF-kappa B; D009842:Oligopeptides; D051880:Receptors, Notch; C523462:benzyloxycarbonyl-leucyl-leucyl-norleucinal; D010047:Ovalbumin; D053829:Amyloid Precursor Protein Secretases