title: ZBP-89 regulates expression of tryptophan hydroxylase I and mucosal defense against Salmonella typhimurium in mice.
abstract: OBJECTIVE
  ZBP-89 (also ZNF148 or Zfp148) is a butyrate-inducible zinc finger transcription factor that binds to GC-rich DNA elements. Deletion of the N-terminal domain is sufficient to increase mucosal susceptibility to chemical injury and inflammation. We investigated whether conditional deletion of ZBP-89 from the intestinal and colonic epithelium of mice increases their susceptibility to pathogens such as Salmonella typhimurium.
  
  
  METHODS
  We generated mice with a conditional null allele of Zfp148 (ZBP-89(FL/FL)) using homologous recombination to flank Zfp148 with LoxP sites (ZBP-89(FL/FL)), and then bred the resulting mice with those that express VillinCre. We used microarray analysis to compare gene expression patterns in colonic mucosa between ZBP-89(ΔInt) and C57BL/6 wild-type mice (controls). Mice were gavaged with 2 isogenic strains of S. typhimurium after administration of streptomycin.
  
  
  RESULTS
  Microarray analysis revealed that the colonic mucosa of ZBP-89(ΔInt) mice had reduced levels of tryptophan hydroxylase 1 (Tph1) messenger RNA, encoding the rate-limiting enzyme in enterochromaffin cell serotonin (5-hydroxytryptamine [5HT]) biosynthesis. DNA affinity precipitation demonstrated direct binding of ZBP-89 to the mouse Tph1 promoter, which was required for its basal and butyrate-inducible expression. ZBP-89(ΔInt) mice did not increase mucosal levels of 5HT in response to S. typhimurium infection, and succumbed to the infection 2 days before control mice. The ΔhilA isogenic mutant of S. typhimurium lacks this butyrate-regulated locus and stimulated, rather than suppressed, expression of Tph1 approximately 50-fold in control, but not ZBP-89(ΔInt), mice, correlating with fecal levels of butyrate.
  
  
  CONCLUSIONS
  ZBP-89 is required for butyrate-induced expression of the Tph1 gene and subsequent production of 5HT in response to bacterial infection in mice. Reductions in epithelial ZBP-89 increase susceptibility to colitis and sepsis after infection with S. typhimurium, partly because of reduced induction of 5HT production in response to butyrate and decreased secretion of antimicrobial peptides.
authors: Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan 48109-2200, USA.
authors: Bryan E
authors: BE
authors: Essien
authors: Helmut
authors: H
authors: Grasberger
authors: Rachael D
authors: RD
authors: Romain
authors: David J
authors: DJ
authors: Law
authors: Natalia A
authors: NA
authors: Veniaminova
authors: Milena
authors: M
authors: Saqui-Salces
authors: Mohamad
authors: M
authors: El-Zaatari
authors: Arthur
authors: A
authors: Tessier
authors: Michael M
authors: MM
authors: Hayes
authors: Alexander C
authors: AC
authors: Yang
authors: Juanita L
authors: JL
authors: Merchant
mesh_terms: D000818:Animals; D002087:Butyrates / Q000276:immunology; D003092:Colitis / Q000276:immunology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004759:Enterochromaffin Cells / Q000276:immunology; D007413:Intestinal Mucosa / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis*; D012480:Salmonella Infections / Q000276:immunology*; D012486:Salmonella typhimurium; D012701:Serotonin / Q000096:biosynthesis* / Q000276:immunology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014365:Tryptophan Hydroxylase / Q000502:physiology*
chemical_list: D002087:Butyrates; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; C491741:Zfp148 protein, mouse; D012701:Serotonin; C487801:Tph1 protein, mouse; D014365:Tryptophan Hydroxylase
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