Supported by a grant from the National Institutes of Diabetes, Digestive and Kidney Diseases (P01 DK43785).
Role of tumor necrosis factor-α in the extraintestinal thrombosis associated with colonic inflammation†
Version of Record online: 16 DEC 2010
Copyright © 2010 Crohn's & Colitis Foundation of America, Inc.
Inflammatory Bowel Diseases
Volume 17, Issue 11, pages 2217–2223, November 2011
How to Cite
Yoshida, H., Yilmaz, C. E. and Granger, D. N. (2011), Role of tumor necrosis factor-α in the extraintestinal thrombosis associated with colonic inflammation. Inflamm Bowel Dis, 17: 2217–2223. doi: 10.1002/ibd.21593
- Issue online: 10 OCT 2011
- Version of Record online: 16 DEC 2010
- Manuscript Accepted: 2 NOV 2010
- Manuscript Received: 27 OCT 2010
- thrombus formation;
- interleukin-1 beta;
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.
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.
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.
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. (Inflamm Bowel Dis 2010;)