title: Blockade of Notch Signalling by γ-Secretase Inhibitor in Lung T Cells of Asthmatic Mice Affects T Cell Differentiation and Pulmonary Inflammation.
abstract: Notch is a single-pass transmembrane receptor protein expressed by T cells, which contributes to the pathogenesis of asthma through regulation of the development and differentiation of T cells. γ-Secretase inhibitor (GSI) acts as an effective blocker of Notch signalling. The present study aimed to investigate the role of GSI MW167 in T cell differentiation and antigen-induced airway inflammation. An OVA-induced airway inflammation mouse model was established. Blockade of Notch signalling was achieved using MW167. The expression of IL-4, IL-5, IFN-γ, Notch1 signalling and pro-inflammatory transcription factors in activated lung T cells was evaluated. Finally, the therapeutic effect of MW167 was investigated by haematoxylin and eosin staining, real-time PCR and ELISA. The expression of IL-4 and IL-5 decreased and that of IFN-γ increased significantly, and the protein expression levels of pro-inflammatory transcription factors reduced in active lung T cells after administration of MW167, compared to the control group. MW167 treatment prevented OVA-induced airway inflammation and histological changes. The serum and bronchoalveolar lavage fluid (BALF) levels of IL-4 and IL-5 in MW167-treated mice decreased significantly, whereas those of IFN-γ increased, relative to the levels in OVA-challenged animals treated with PBS. Our findings indicate that Notch signalling plays an important role in the pathogenesis of asthma and that MW167 may be a potential therapeutic target for allergen-induced airway inflammation.
authors.affiliation: Department of Respiratory Medicine, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhou
authors.forename: Zhi-lei
authors.initials: ZL
authors.lastname: Cui
authors.forename: Xue-jun
authors.initials: XJ
authors.lastname: Guo
authors.forename: Lian-pin
authors.initials: LP
authors.lastname: Ren
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.forename: Zhi-wen
authors.initials: ZW
authors.lastname: Fan
authors.forename: Rui-chao
authors.initials: RC
authors.lastname: Han
authors.forename: Wei-guo
authors.initials: WG
authors.lastname: Xu
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D050990:GATA3 Transcription Factor / Q000096:biosynthesis; D007073:Immunoglobulin E / Q000097:blood; D007371:Interferon-gamma / Q000096:biosynthesis / Q000097:blood; D015847:Interleukin-4 / Q000096:biosynthesis / Q000097:blood; D015848:Interleukin-5 / Q000096:biosynthesis / Q000097:blood; D008168:Lung / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin; D010455:Peptides / Q000494:pharmacology*; D011014:Pneumonia / Q000188:drug therapy* / Q000276:immunology; D051881:Receptor, Notch1 / Q000096:biosynthesis / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D020825:T-Box Domain Proteins / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D058408:Th1-Th2 Balance / Q000187:drug effects; D000098815:T-bet Transcription Factor
chemical_list: D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D015848:Interleukin-5; C432344:MW167; C497762:Notch1 protein, mouse; D010455:Peptides; D051881:Receptor, Notch1; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D015847:Interleukin-4; D007073:Immunoglobulin E; D007371:Interferon-gamma; D010047:Ovalbumin; D053829:Amyloid Precursor Protein Secretases