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(Circulation Research. 2005;96:1233.)
© 2005 American Heart Association, Inc.

Molecular Medicine

Procoagulant Soluble Tissue Factor Is Released From Endothelial Cells in Response to Inflammatory Cytokines

Björn Szotowski, Silvio Antoniak, Wolfgang Poller, Heinz-Peter Schultheiss, Ursula Rauch

From the Department of Cardiology and Pneumology (B.S., S.A., W.P., H.-P.S., U.R.), Charité –Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany; and the Institute of Pharmacy (B.S.), Free University of Berlin, Germany.

Correspondence to Dr Ursula Rauch, Medical Clinic II, Charité –Universitätsmedizin Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany. E-mail ursula.rauch{at}charite.de

Inflammatory cytokines alter the hemostatic balance of endothelial cells (ECs). Alternatively spliced human tissue factor (asHTF), a soluble isoform of tissue factor (TF), has recently been detected in ECs, possibly contributing to procoagulability. Agonists regulating asHTF expression and release are yet unknown. This study examines the effect of TNF- and IL-6 on the endothelial expression of both TF variants and delineates the impact of asHTF on the procoagulability of extracellular fluids. asHTF and TF mRNA were assessed by real-time PCR, and asHTF, TF, and tissue factor pathway inhibitor (TFPI) proteins by Western blot and fluorescence microscopy before and after stimulation with TNF- (10 ng/mL) or IL-6 (10 ng/L). The procoagulability of cell supernatant was analyzed by a chromogenic assay with or without phospholipid vesicles. We found asHTF mRNA to be maximally increased 10 minutes after TNF- and 40 minutes after IL-6 treatment (asHTF/GAPDH ratio 0.0223±0.0069 versus 0.0012±0.0006 for control, P<0.001 and 0.0022±0.0004 versus 0.0012±0.0007, P<0.05, respectively). Not only was asHTF increased, but also TFPI decreased after cytokine treatment. asHTF was found in the supernatant as early as 5 hours after TNF- stimulation, supporting factor Xa generation after relipidation (6.55±1.13 U versus 2.99±0.59 U in control supernatant, P<0.00001). Removal of asHTF from supernatants by immunoprecipitation diminished its procoagulability to baseline. The soluble TF isoform expressed and released from ECs in response to inflammatory cytokines becomes procoagulant in the presence of phospholipids. Thus, asHTF released from ECs is a marker for and a contributor to imbalanced hemostasis.

Key Words: tissue factor • procoagulability • cytokines • inflammation • endothelial cells

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