title: Anti-inflammatory activity of bone morphogenetic protein signaling pathways in stomachs of mice.
abstract: OBJECTIVE
  Bone morphogenetic protein (BMP)4 is a mesenchymal peptide that regulates cells of the gastric epithelium. We investigated whether BMP signaling pathways affect gastric inflammation after bacterial infection of mice.
  
  
  METHODS
  We studied transgenic mice that express either the BMP inhibitor noggin or the β- galactosidase gene under the control of a BMP-responsive element and BMP4(βgal/+) mice. Gastric inflammation was induced by infection of mice with either Helicobacter pylori or Helicobacter felis. Eight to 12 weeks after inoculation, gastric tissue samples were collected and immunohistochemical, quantitative, reverse-transcription polymerase chain reaction and immunoblot analyses were performed. We used enzyme-linked immunosorbent assays to measure cytokine levels in supernatants from cultures of mouse splenocytes and dendritic cells, as well as from human gastric epithelial cells (AGS cell line). We also measured the effects of BMP-2, BMP-4, BMP-7, and the BMP inhibitor LDN-193189 on the expression of interleukin (IL)8 messenger RNA by AGS cells and primary cultures of canine parietal and mucus cells. The effect of BMP-4 on NFkB activation in parietal and AGS cells was examined by immunoblot and luciferase assays.
  
  
  RESULTS
  Transgenic expression of noggin in mice increased H pylori- or H felis-induced inflammation and epithelial cell proliferation, accelerated the development of dysplasia, and increased expression of the signal transducer and activator of transcription 3 and activation-induced cytidine deaminase. BMP-4 was expressed in mesenchymal cells that expressed α-smooth muscle actin and activated BMP signaling pathways in the gastric epithelium. Neither BMP-4 expression nor BMP signaling were detected in immune cells of C57BL/6, BRE-β-galactosidase, or BMP-4(βgal/+) mice. Incubation of dendritic cells or splenocytes with BMP-4 did not affect lipopolysaccharide-stimulated production of cytokines. BMP-4, BMP-2, and BMP-7 inhibited basal and tumor necrosis factor α-stimulated expression of IL8 in canine gastric epithelial cells. LDN-193189 prevented BMP4-mediated inhibition of basal and tumor necrosis factor α-stimulated expression of IL8 in AGS cells. BMP-4 had no effect on TNFα-stimulated phosphorylation and degradation of IκBα, or on TNFα induction of a NFκβ reporter gene.
  
  
  CONCLUSIONS
  BMP signaling reduces inflammation and inhibits dysplastic changes in the gastric mucosa after infection of mice with H pylori or H felis.
authors.affiliation: Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Takabayashi
authors.affiliation: Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Shinohara
authors.affiliation: Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Maria
authors.initials: M
authors.lastname: Mao
authors.affiliation: Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Piangwarin
authors.initials: P
authors.lastname: Phaosawasdi
authors.affiliation: Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Mohamad
authors.initials: M
authors.lastname: El-Zaatari
authors.affiliation: Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Tuo
authors.initials: T
authors.lastname: Ji
authors.affiliation: Laboratory Animal Medicine Unit, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Eaton
authors.affiliation: Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: Duyen
authors.initials: D
authors.lastname: Dang
authors.affiliation: Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan.
authors.forename: John
authors.initials: J
authors.lastname: Kao
authors.affiliation: Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan. Electronic address: atodisco@umich.edu.
authors.forename: Andrea
authors.initials: A
authors.lastname: Todisco
mesh_terms: D000818:Animals; D001665:Binding Sites; D055415:Bone Morphogenetic Protein 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism*; D005756:Gastritis / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D044922:Helicobacter felis / Q000472:pathogenicity; D016480:Helicobacter pylori / Q000472:pathogenicity; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013270:Stomach / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D013997:Time Factors; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism; D000099176:Noggin Protein
chemical_list: D055415:Bone Morphogenetic Protein 4; D002352:Carrier Proteins; D016207:Cytokines; D018836:Inflammation Mediators; D012333:RNA, Messenger; D001616:beta-Galactosidase; D000099176:Noggin Protein; C525810:Bmp4 protein, mouse
keywords: BRE; Differentiation; Immune Regulation; STAT3
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