title: Genetic deletion of Klf4 in the mouse intestinal epithelium ameliorates dextran sodium sulfate-induced colitis by modulating the NF-κB pathway inflammatory response.
abstract: BACKGROUND
  Krüppel-like factor 4 (KLF4) is a zinc finger transcription factor expressed in the differentiated epithelial cells lining of the intestine. Under physiological conditions, KLF4 inhibits cell proliferation. Conversely, KLF4 mediates proinflammatory signaling in macrophages and its overexpression in the esophageal epithelium activates cytokines, leading to inflammation-mediated esophageal squamous cell cancer formation in mice. Here, we tested whether KLF4 has a proinflammatory activity in experimental colitis in mice.
  
  
  METHODS
  Villin-Cre;Klf4 mice with intestine-specific Klf4 deletion (Klf4) and control mice with floxed Klf4 gene (Klf4) were treated or not with 3% dextran sodium sulfate (DSS) for 7 days to induce colitis. Additionally, WT mice were administered or not, nanoparticles loaded with scrambled or Klf4-siRNA, and concomitantly given DSS.
  
  
  RESULTS
  Compared with DSS-treated Klf4 mice, DSS-treated Klf4 mice were significantly less sensitive to DSS-induced colitis. DSS treatment of Klf4 mice induced Klf4 expression in the crypt zone of the colonic epithelium. DSS-treated Klf4 mice had increased proliferation relative to DSS-treated control mice. DSS treatment induced NF-κB signaling pathway in Klf4 mice colon but not Klf4 mice. Additionally, WT mice given DSS and nanoparticle/Klf4-siRNA were less sensitive to colitis and had reduced Klf4 expression and while maintaining the proliferative response in the colonic epithelium.
  
  
  CONCLUSIONS
  Our results indicate that Klf4 is an important mediator of DSS-induced colonic inflammation by modulating NF-κB signaling pathway and could be involved in the pathogenesis and/or propagation of inflammatory bowel disease. Thus, Klf4 may represent a novel therapeutic target in inflammatory bowel disease.
authors.affiliation: *Department of Medicine, Stony Brook University, Stony Brook, New York; †Department of Biology and Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, Georgia; and ‡Veterans Affairs Medical Center, Decatur, GA.
authors.forename: Amr M
authors.initials: AM
authors.lastname: Ghaleb
authors.forename: Hamed
authors.initials: H
authors.lastname: Laroui
authors.forename: Didier
authors.initials: D
authors.lastname: Merlin
authors.forename: Vincent W
authors.initials: VW
authors.lastname: Yang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion; D049109:Cell Proliferation; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D016264:Dextran Sulfate / Q000633:toxicity*; D004195:Disease Models, Animal; D005260:Female; D005455:Fluorescent Antibody Technique; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D019426:Integrases / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000037:antagonists & inhibitors / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000502:physiology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D053758:Nanoparticles / Q000008:administration & dosage; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D008840:Microfilament Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; C026615:villin; D016264:Dextran Sulfate; C045073:Cre recombinase; D019426:Integrases