title: Conditional deletion of IkappaB-kinase-beta accelerates helicobacter-dependent gastric apoptosis, proliferation, and preneoplasia.
abstract: OBJECTIVE
  The nuclear factor kappaB (NF-kappaB)/IkappaB-kinase-beta (IKKbeta) pathway has been shown to represent a key link between inflammation and cancer, inducing pro-inflammatory cytokines in myeloid cells and anti-apoptotic pathways in epithelial cells. However, the role of NF-kappaB pathway in gastric carcinogenesis and injury has not been well-defined. We derived mice with a conditional knockout of IKKbeta in gastric epithelial cells (GECs) and myeloid cells, and examined responses to ionizing radiation (IR) and Helicobacter felis infection.
  
  
  METHODS
  Ikkbeta(Deltastom) mice were generated by crossing Foxa3-Cre mice to Ikkbeta(F/F) mice. Cellular stress was induced with IR and H felis in Ikkbeta(Deltastom), Ikkbeta(F/F), and cis-NF-kappaB-enhanced green fluorescent protein (GFP) reporter mice. Gastric histopathology, apoptosis, proliferation, necrosis, reactive oxygen species, and expression of cytokines, chemokines, and anti-apoptotic genes were assessed. The role of myeloid IKKbeta in these models was studied by crosses with LysM-Cre mice.
  
  
  RESULTS
  NF-kappaB activity was upregulated in myeloid cells with acute H felis infection, but in GECs by IR or long-term H felis infection during progression to dysplasia. Deletion of IKKbeta in GECs led to increased apoptosis, reactive oxygen species, and cellular necrosis, and resulted in up-regulation of interleukin-1alpha and down-regulation of anti-apoptotic genes. Loss of IKKbeta in GECs resulted in worse inflammation and more rapid progression to gastric preneoplasia, while loss of IKKbeta in myeloid cells inhibited development of gastric atrophy.
  
  
  CONCLUSIONS
  The loss of IKKbeta/NF-kappaB signaling in GECs results in increased apoptosis and necrosis in response to cellular stress, and accelerated development of dysplasia by Helicobacter infection.
authors: Division of Digestive and Liver Disease, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.
authors: Wataru
authors: W
authors: Shibata
authors: Shigeo
authors: S
authors: Takaishi
authors: Sureshkumar
authors: S
authors: Muthupalani
authors: D Mark
authors: DM
authors: Pritchard
authors: Mark T
authors: MT
authors: Whary
authors: Arlin B
authors: AB
authors: Rogers
authors: James G
authors: JG
authors: Fox
authors: Kelly S
authors: KS
authors: Betz
authors: Klaus H
authors: KH
authors: Kaestner
authors: Michael
authors: M
authors: Karin
authors: Timothy C
authors: TC
authors: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001284:Atrophy; D049109:Cell Proliferation / Q000528:radiation effects; D004195:Disease Models, Animal; D018450:Disease Progression; D005753:Gastric Mucosa / Q000201:enzymology* / Q000382:microbiology / Q000473:pathology / Q000528:radiation effects; D017930:Genes, Reporter; D016481:Helicobacter Infections / Q000201:enzymology* / Q000235:genetics / Q000382:microbiology / Q000473:pathology; D044922:Helicobacter felis / Q000472:pathogenicity*; D051543:Hepatocyte Nuclear Factor 3-gamma / Q000235:genetics; D051550:I-kappa B Kinase / Q000172:deficiency* / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism; D019426:Integrases / Q000235:genetics; D053582:Interleukin-1alpha / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000201:enzymology / Q000382:microbiology / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009336:Necrosis; D018384:Oxidative Stress; D011230:Precancerous Conditions / Q000201:enzymology* / Q000235:genetics / Q000382:microbiology / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000382:microbiology / Q000473:pathology; D013997:Time Factors
chemical_list: D051017:Apoptosis Regulatory Proteins; C496506:Foxa3 protein, mouse; D018836:Inflammation Mediators; D053582:Interleukin-1alpha; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D051543:Hepatocyte Nuclear Factor 3-gamma; D051550:I-kappa B Kinase; C045073:Cre recombinase; D019426:Integrases