title: Regulation of anergy-related ubiquitin E3 ligase, GRAIL, in murine models of colitis and patients with Crohn's disease.
abstract: BACKGROUND
  Abrogating tolerance is a critical step in the pathogenesis of Crohn's disease (CD). T cell-anergy is one of the main mechanisms of tolerance and is regulated by the gene related to anergy in lymphocytes (GRAIL). This study investigated the expressions and regulation of GRAIL in CD and murine colitis models.
  
  
  METHODS
  Expressions of GRAIL mRNA and protein in CD4+ T cells were investigated in the peripheral blood and mucosal tissues of patients with CD, mice with dextran sodium salt (DSS)-induced colitis, and Il-10-deficient mice. MicroRNAs responsible for the regulation of GRAIL were examined by miRNA microarray. GRAIL-overexpressing T cells were intravenously injected in mice with DSS-induced colitis.
  
  
  RESULTS
  The GRAIL expression was higher in the lamina propria (LP) CD4+ T cells of CD patients than of the control subjects, while it was lower in the peripheral blood CD4+ T cells of the CD patients than of the control subjects. The GRAIL mRNA expression was lower, but the GRAIL protein expression was higher in the LP of colitic mice than that of non-colitic mice. The miRNA microarray identified miR-290-5p as an miRNA that inhibits expression of the GRAIL protein and that is highly expressed in the LP of non-colitic mice. GRAIL-expressing T cells expressed regulatory T cell markers and showed suppressive effects in murine DSS-induced colitis.
  
  
  CONCLUSIONS
  Our results show that expression of GRAIL is uniquely regulated by the specific miRNA in the intestinal mucosa, and suggest that GRAIL may associate with the pathophysiology of CD.
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 K1 Yamadaoka, Suita, Osaka, 565-0871, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Mukai
authors.forename: Hideki
authors.initials: H
authors.lastname: Iijima
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hiyama
authors.forename: Hironobu
authors.initials: H
authors.lastname: Fujii
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Shinzaki
authors.forename: Takahiro
authors.initials: T
authors.lastname: Inoue
authors.forename: Eri
authors.initials: E
authors.lastname: Shiraishi
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Kawai
authors.forename: Manabu
authors.initials: M
authors.lastname: Araki
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Jumpei
authors.initials: J
authors.lastname: Kondo
authors.forename: Tsunekazu
authors.initials: T
authors.lastname: Mizushima
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kanto
authors.forename: Satoshi
authors.initials: S
authors.lastname: Egawa
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nishida
authors.forename: Masahiko
authors.initials: M
authors.lastname: Tsujii
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Takehara
mesh_terms: D000328:Adult; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016022:Case-Control Studies; D003092:Colitis / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D006801:Humans; D007108:Immune Tolerance; D016753:Interleukin-10 / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger; D016753:Interleukin-10; D016264:Dextran Sulfate; C520250:RNF128 protein, human; D044767:Ubiquitin-Protein Ligases