title: Role of tumor necrosis factor-α in the extraintestinal thrombosis associated with colonic inflammation.
abstract: BACKGROUND
  Inflammatory bowel diseases (IBDs) are associated with a hypercoagulable state and an increased risk of thromboembolism, with accelerated thrombus formation occurring both within the inflamed bowel and in distant tissues. While the IBD-associated prothrombogenic state has been linked to the inflammatory response, the mediators that link inflammation and thrombosis remain poorly defined. The objective of this study was to assess the role of tumor necrosis factor alpha (TNF-α) in the enhanced extraintestinal microvascular thrombosis that accompanies colonic inflammation.
  
  
  METHODS
  TNF-α concentration was measured in plasma, colon, and skeletal muscle of control mice and in mice with dextran sodium sulfate (DSS)-induced colitis. A light/dye injury method was used to induce microvascular thrombosis in cremaster microvessels. The effects of exogenous TNF-α on thrombus formation were determined in control mice. DSS-enhanced thrombus formation was evaluated in wildtype (WT) mice treated with an anti-TNF-α antibody (±an anti-IL-1β antibody) and in TNF-α receptor-deficient (TNFr(-/-) ) mice.
  
  
  RESULTS
  DSS colitis enhanced thrombus formation in cremaster arterioles. A similar response was produced by TNF-α administration in control mice. TNF-α concentration was elevated in plasma, colon, and skeletal muscle. Immunoblockade of TNF-α or genetic deficiency of the TNF-α receptor blunted the thrombotic response of arterioles to DSS colitis. Additional protection was noted in mice receiving antibodies to both TNF-α and IL-1β.
  
  
  CONCLUSIONS
  Our findings implicate TNF-α in the enhanced microvascular thrombosis that occurs in extraintestinal tissue during colonic inflammation, and suggests that the combined actions of TNF-α and IL-1β accounts for most of the colitis-enhanced thrombotic response.
authors: Eiju General Hospital, Taito-ku, Tokyo, Japan.
authors: Hideo
authors: H
authors: Yoshida
authors: Cigdem Erkuran
authors: CE
authors: Yilmaz
authors: D Neil
authors: DN
authors: Granger
mesh_terms: D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000150:complications* / Q000276:immunology*; D003106:Colon / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity; D007249:Inflammation / Q000139:chemically induced / Q000150:complications* / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism; D013927:Thrombosis / Q000209:etiology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D016264:Dextran Sulfate