title: Enhanced intestinal inflammation induced by dextran sulfate sodium in tumor necrosis factor-alpha deficient mice.
abstract: OBJECTIVE
  Tumor necrosis factor-alpha (TNF-alpha) is a potent pro-inflammatory cytokine thought to be involved in the pathogenesis of inflammatory bowel disease. To further define the role of TNF-alpha in intestinal inflammation, we studied the effects of dextran sulfate sodium (DSS) administration in mice with targeted deletions of TNF-alpha gene.
  
  
  METHODS
  Acute colitis was induced in female TNF-alpha-/- and TNF-alpha+/+ mice by administering 4.5% DSS orally in drinking water for seven days. The colonic mucosal injury and inflammation was evaluated based on body weight changes, total colon length, luminal hemoglobin, and histological findings. Colonic mRNA expression for inducible nitric oxide synthase (iNOS), TNF-alpha, interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) were measured by reverse transcription polymerase chain reaction (RT-PCR), and nuclear factor kappaB (NF-kappaB) activation was evaluated by electrophoretic mobility shift assay.
  
  
  RESULTS
  In each assessment, colonic injury was significantly aggravated in DSS-treated TNF-alpha-/- mice compared with DSS-treated TNF-alpha+/+ mice. The survival rate of TNF-alpha-/- mice on day seven was 40%; in contrast, all TNF-alpha+/+ mice were alive. Histological study also showed an enhanced infiltration of inflammatory cells, especially neutrophils, and mucosal cell disruption in DSS-treated TNF-alpha-/- mice compared with DSS-treated TNF-alpha+/+ mice. On day seven, mRNA levels of IFN-gamma and IL-4 in the colons of TNF-alpha-/- mice were faint or not detected; in contrast, those of TNF-alpha+/+ mice were detected. Although the expression of iNOS mRNA and luminal nitrite levels were similarly increased in both mice on day seven, this induction was delayed in TNF-alpha-/- mice during the early phase. The degree of NF-kappaB binding activity seemed to be similar between the two types of mice on day seven.
  
  
  CONCLUSIONS
  DSS-induced inflammation is significantly enhanced in TNF-alpha-/- mice compared to TNF-alpha+/+ mice. These data suggest that persistent and marked blockage of TNF-alpha bioactivity may provide a detrimental effect on acute intestinal inflammation.
authors.affiliation: First Department of Medicine, Kyoto Prefectural University of Medicine, Kamigyo-Ku, Kyoto, Japan. ynaito@koto.kpu-m.ac.jp
authors.forename: Yuji
authors.initials: Y
authors.lastname: Naito
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Takagi
authors.forename: Osamu
authors.initials: O
authors.lastname: Handa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Shuji
authors.initials: S
authors.lastname: Nakagawa
authors.forename: Taiji
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Norimasa
authors.initials: N
authors.lastname: Yoshida
authors.forename: Masato
authors.initials: M
authors.lastname: Minami
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kita
authors.forename: Jiro
authors.initials: J
authors.lastname: Imanishi
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Yoshikawa
mesh_terms: D000208:Acute Disease; D000818:Animals; D003092:Colitis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity*; D005260:Female; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000502:physiology*
chemical_list: D016207:Cytokines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016264:Dextran Sulfate; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse