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Molecular Medicine

, Volume 17, Issue 9–10, pp 1119–1126 | Cite as

Tissue Factor-Dependent Chemokine Production Aggravates Experimental Colitis

  • Karla C. S. Queiroz
  • Cornelis van’t Veer
  • Yascha van den Berg
  • JanWillem Duitman
  • Henri H. Versteeg
  • Hella L. Aberson
  • Angelique P. Groot
  • Marleen I. Verstege
  • Joris J. T. H. Roelofs
  • Anje A. te Velde
  • C. Arnold Spek
Research Article

Abstract

Tissue factor (TF) is traditionally known as the initiator of blood coagulation, but TF also plays an Important role In inflammatory processes. Considering the pivotal role of coagulation in inflammatory bowel disease, we assessed whether genetic ablation of TF limits experimental colitis. To this end, wild-type and TF-deficient (TFlow) mice were treated with 1.5% dextran sulfate sodium (DSS) for 7 d, and effects on disease severity, cytokine production and leukocyte recruitment were examined. Clinical and histological parameters showed that the severity of colitis was reduced in both heterozygous and homozygous TFlow mice compared with controls. Most notably, edema, granulocyte numbers at the site of inflammation and cytokine levels were reduced in TFlow mice. Although anticoagulant treatment with dalteparin of wild-type mice reduced local fibrin production and cytokine levels to a similar extent as in TFlow mice, it did not affect clinical and histological parameters of experimental colitis. Mechanistic studies revealed that TF expression did not influence the intrinsic capacity of granulocytes to migrate. Instead, TF enhanced granulocyte migration into the colon by inducing high levels of the granulocyte chemoattractant keratinocyte-derived chemokine (KC). Taken together, our data indicate that TF plays a detrimental role in experimental colitis by signal transduction-dependent KC production in colon epithelial cells, thereby provoking granulocyte influx with subsequent inflammation and organ damage.

Notes

Acknowledgments

We would like to thank Joost Daalhuisen, Marieke ten Brink and Danielle Kruijswijk for expert technical assistance. This work is supported by grant WO 06-02 of the Dutch Digestive Diseases Foundation (Maag Lever Darm Stichting [MLDS]).

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Copyright information

© The Feinstein Institute for Medical Research 2011
www.feinsteininstitute.org

Authors and Affiliations

  • Karla C. S. Queiroz
    • 1
  • Cornelis van’t Veer
    • 1
  • Yascha van den Berg
    • 2
  • JanWillem Duitman
    • 1
  • Henri H. Versteeg
    • 2
  • Hella L. Aberson
    • 1
  • Angelique P. Groot
    • 1
  • Marleen I. Verstege
    • 3
  • Joris J. T. H. Roelofs
    • 4
  • Anje A. te Velde
    • 3
  • C. Arnold Spek
    • 1
  1. 1.Center for Experimental and Molecular MedicineAcademic Medical CenterAmsterdamThe Netherlands
  2. 2.Einthoven Laboratory for Experimental Vascular MedicineLeiden University Medical CenterLeidenThe Netherlands
  3. 3.Tytgat Institute for Liver and Intestinal Research, Academic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands
  4. 4.Department of Pathology, Academic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands

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