title: Pharmacologic inhibition of Notch signaling suppresses food antigen-induced mucosal mast cell hyperplasia.
abstract: BACKGROUND
  Mucosal mast cells (MMCs) play a central role in the development of symptoms associated with IgE-mediated food allergy. Recently, Notch2-mediated signaling was shown to be involved in proper MMC distribution in the intestinal tract.
  
  
  OBJECTIVE
  This study aimed to clarify the mechanism by which Notch signaling regulates MMC distribution in the intestinal mucosa. Furthermore, pharmacologic inhibition of Notch signaling was evaluated as a treatment for symptoms associated with experimental food allergy.
  
  
  METHODS
  Bone marrow-derived mast cells generated from mice were cultured with Notch ligands, and then expression of genes associated with MMCs was measured in the cells. In addition, the effect of an inhibitor of Notch signaling on food antigen-induced allergic reactions was examined in a mouse model of food allergy.
  
  
  RESULTS
  Notch signaling induced MMC differentiation through upregulation of expression of genes characteristic of MMCs in the presence of IL-3. Some lamina propria cells isolated from the mouse small intestine expressed Notch ligands and were able to upregulate MMC markers in bone marrow-derived mast cells through Notch signaling. In a mouse model of food allergy, administration of a Notch signaling inhibitor led to suppression of food antigen-induced hyperplasia of intestinal MMCs, resulting in alleviation of allergic diarrhea and systemic anaphylaxis.
  
  
  CONCLUSIONS
  Notch signaling contributes to differentiation and accumulation of MMCs in the intestinal mucosa. Thus inhibition of Notch signaling alleviates symptoms associated with experimental food allergy. These results raise the possibility that Notch signaling in mast cells is a novel target for therapy in patients with food allergy.
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Asuka
authors.initials: A
authors.lastname: Honjo
authors.affiliation: Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan. Electronic address: nbnakano@juntendo.ac.jp.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Nakano
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Yamazaki
authors.affiliation: Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Mutsuko
authors.initials: M
authors.lastname: Hara
authors.affiliation: Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Uchida
authors.affiliation: Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Jiro
authors.initials: J
authors.lastname: Kitaura
authors.affiliation: Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan; Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, Tokyo, Japan.
authors.forename: Chiharu
authors.initials: C
authors.lastname: Nishiyama
authors.affiliation: Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Ohtsuka
authors.affiliation: Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Hideoki
authors.initials: H
authors.lastname: Ogawa
authors.affiliation: Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Ko
authors.initials: K
authors.lastname: Okumura
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Shimizu
mesh_terms: D000485:Allergens / Q000276:immunology; D000818:Animals; D016207:Cytokines / Q000276:immunology; D004151:Dipeptides / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D005512:Food Hypersensitivity / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D006965:Hyperplasia / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D007413:Intestinal Mucosa / Q000276:immunology*; D007421:Intestine, Small / Q000166:cytology; D008407:Mast Cells / Q000276:immunology* / Q000473:pathology; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology; D051880:Receptors, Notch / Q000037:antagonists & inhibitors* / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000485:Allergens; D016207:Cytokines; D004151:Dipeptides; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D051880:Receptors, Notch; D010047:Ovalbumin
keywords: Notch signaling; food allergy; mast cell hyperplasia; mucosal mast cells