title: Gamma-secretase inhibitor reduces allergic pulmonary inflammation by modulating Th1 and Th2 responses.
abstract: 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.
authors.affiliation: Division of Molecular and Life Sciences, College of Science and Technology, Hanyang University, Seoul, South Korea.
authors.forename: Jin Hyun
authors.initials: JH
authors.lastname: Kang
authors.forename: Byung Soo
authors.initials: BS
authors.lastname: Kim
authors.forename: Tae Gi
authors.initials: TG
authors.lastname: Uhm
authors.forename: Shin-Hwa
authors.initials: SH
authors.lastname: Lee
authors.forename: Gap Ryol
authors.initials: GR
authors.lastname: Lee
authors.forename: Choon-Sik
authors.initials: CS
authors.lastname: Park
authors.forename: Il Yup
authors.initials: IY
authors.lastname: Chung
mesh_terms: 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
chemical_list: 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