title: Tissue factor-dependent chemokine production aggravates experimental colitis.
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.
authors: Center for Experimental and Molecular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
authors: Karla C S
authors: KC
authors: Queiroz
authors: Cornelis
authors: C
authors: Van 't Veer
authors: Yascha
authors: Y
authors: Van Den Berg
authors: Janwillem
authors: J
authors: Duitman
authors: Henri H
authors: HH
authors: Versteeg
authors: Hella L
authors: HL
authors: Aberson
authors: Angelique P
authors: AP
authors: Groot
authors: Marleen I
authors: MI
authors: Verstege
authors: Joris J T H
authors: JJ
authors: Roelofs
authors: Anje A
authors: AA
authors: Te Velde
authors: C Arnold
authors: CA
authors: Spek
mesh_terms: D000818:Animals; D002465:Cell Movement; D018925:Chemokines / Q000378:metabolism*; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D003106:Colon / Q000378:metabolism* / Q000473:pathology; D016264:Dextran Sulfate; D004487:Edema / Q000378:metabolism / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006098:Granulocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012720:Severity of Illness Index; D013925:Thromboplastin / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D046509:Tissue Culture Techniques
chemical_list: D018925:Chemokines; D018836:Inflammation Mediators; C074302:keratinocyte-derived chemokines; D013925:Thromboplastin; D016264:Dextran Sulfate