title: Gastric mucosal hyperplasia via upregulation of gastrin induced by persistent activation of gastric innate immunity in major histocompatibility complex class II deficient mice.
abstract: OBJECTIVE
  Major histocompatibility complex class II deficient (Aalpha0/0) mice have decreased CD4+ T cells, making them immunologically similar to patients with acquired immunodeficiency syndrome (AIDS). Both patients with AIDS and Aalpha0/0 mice have hypertrophic gastric folds. To clarify the mechanism of gastric mucosal hyperplasia, we investigated the pathophysiology and the role of the innate immunity in the stomach of Aalpha0/0 mice.
  
  
  METHODS
  Stomachs from 1-6 month old Aalpha0/0 mice, kept under specific pathogen free conditions, were examined at 1 month intervals histologically and immunohistochemically. Gene expression of proinflammatory cytokines, Toll-like receptors (TLRs), cyclooxygenase (COX)-2, and myeloperoxidase (MPO) activity in the gastric mucosa was investigated. Serum gastrin levels and gastric acidity were measured. Bacterial culture of the stomach was performed. To clarify the roles of hypergastrinaemia in the gastric mucosa, a gastrin receptor antagonist (AG041R) was administered.
  
  
  RESULTS
  Aalpha0/0 mice had a diffusely thick corpus mucosa with infiltration of CD11b+ granulocytes and macrophages. Anti-Ki67 staining demonstrated expansion of the proliferating neck zone. Gene expression of interleukin 1beta, interferon gamma, TLR-2, TLR-4, and COX-2 were upregulated, and MPO activity was increased. Only a small amount of non-pathogenic bacteria was detected in the stomach. Serum gastrin levels and Reg-Ialpha positive cells in the gastric mucosa increased, despite normal gastric acidity. After treatment with AG041R, gastric mucosal thickness was significantly reduced.
  
  
  CONCLUSIONS
  Persistent activation of innate immunity in the stomach induced gastric mucosal hyperplasia through upregulation of gastrin synthesis in Aalpha0/0 mice, suggesting a pathophysiology similar to the gastric changes in patients with AIDS.
authors.affiliation: Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Fukui
authors.forename: A
authors.initials: A
authors.lastname: Nishio
authors.forename: K
authors.initials: K
authors.lastname: Okazaki
authors.forename: N
authors.initials: N
authors.lastname: Uza
authors.forename: S
authors.initials: S
authors.lastname: Ueno
authors.forename: M
authors.initials: M
authors.lastname: Kido
authors.forename: S
authors.initials: S
authors.lastname: Inoue
authors.forename: H
authors.initials: H
authors.lastname: Kitamura
authors.forename: K
authors.initials: K
authors.lastname: Kiriya
authors.forename: S
authors.initials: S
authors.lastname: Ohashi
authors.forename: M
authors.initials: M
authors.lastname: Asada
authors.forename: H
authors.initials: H
authors.lastname: Tamaki
authors.forename: M
authors.initials: M
authors.lastname: Matsuura
authors.forename: K
authors.initials: K
authors.lastname: Kawasaki
authors.forename: K
authors.initials: K
authors.lastname: Suzuki
authors.forename: K
authors.initials: K
authors.lastname: Uchida
authors.forename: H
authors.initials: H
authors.lastname: Fukui
authors.forename: H
authors.initials: H
authors.lastname: Nakase
authors.forename: N
authors.initials: N
authors.lastname: Watanabe
authors.forename: T
authors.initials: T
authors.lastname: Chiba
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology; D000818:Animals; D016207:Cytokines / Q000276:immunology; D005753:Gastric Mucosa / Q000276:immunology* / Q000473:pathology*; D005755:Gastrins / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D005802:Genes, MHC Class II; D006863:Hydrogen-Ion Concentration; D006965:Hyperplasia; D007113:Immunity, Innate; D007150:Immunohistochemistry / Q000379:methods; D016130:Immunophenotyping; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000276:immunology; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D005755:Gastrins; D012333:RNA, Messenger