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J. Biol. Chem., Vol. 279, Issue 34, 36142-36147, August 20, 2004

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Thrombin and Tumor Necrosis Factor Synergistically Stimulate Tissue Factor Expression in Human Endothelial Cells

REGULATION THROUGH c-Fos AND c-Jun^*

Yuchuan Liu, Katrina Pelekanakis, and Marilyn J. Woolkalis

From the Department of Physiology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

Tissue factor is critically important for initiating the activation of coagulation zymogens leading to the generation of thrombin. Quiescent endothelial cells do not express tissue factor on their surface, but many stimuli including cytokines and coagulation proteases can elicit tissue factor synthesis. We challenged human endothelial cells simultaneously with tumor necrosis factor (TNF) and thrombin because many pathophysiological conditions, such as sepsis, diabetes, and coronary artery disease, result in the concurrent presence of circulating inflammatory mediators and activated thrombin. We observed a remarkable synergy in the expression of tissue factor by thrombin plus TNF. This was due to altered regulation of the transcription factors c-Jun and c-Fos. The activation of c-Jun was greater and more sustained than that obtained with either thrombin or TNF alone. Thrombin-stimulated expression of c-Fos was both enhanced and prolonged by the concurrent presence of TNF. These changes support the increased availability of c-Jun/c-Fos AP-1 complexes for mediating transcription at the tissue factor promoter. Transcription factors downstream of the extracellular signal-regulated kinases as well as changes in NFB regulation were not involved in the synergistic increase in tissue factor expression by thrombin and TNF. Thus, concurrent exposure of vascular endothelial cells to cytokines and procoagulant proteases such as thrombin can result in greatly enhanced tissue factor expression on the endothelium, thereby perpetuating the prothrombotic phenotype of the endothelium.

Received for publication, May 6, 2004

^* This work was supported by a grant from the NHLBI, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom all correspondence should be addressed: Dept. of Physiology, Thomas Jefferson University, 411 Jefferson Alumni Hall, 1020 Locust St., Philadelphia, PA 19107. Tel.: 215-503-6715; Fax: 215-503-2073; E-mail: Marilyn.Woolkalis{at}jefferson.edu.

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