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Blood, 15 May 2005, Vol. 105, No. 10, pp. 3910-3917. Prepublished online as a Blood First Edition Paper on January 27, 2005; DOI 10.1182/blood-2004-03-0928. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-03-0928v1 105/10/3910    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Sohn, R. H. Articles by Rade, J. J. Search for Related Content PubMed PubMed Citation Articles by Sohn, R. H. Articles by Rade, J. J. Related Collections Gene Expression Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Regulation of endothelial thrombomodulin expression by inflammatory cytokines is mediated by activation of nuclear factor-kappa B Richard H. Sohn, Clayton B. Deming, David C. Johns, Hunter C. Champion, Ce Bian, Kevin Gardner, and Jeffrey J. Rade From the Department of Medicine, Division of Cardiology, Johns Hopkins School of Medicine, Baltimore MD; the Department of Neurosurgery, Johns Hopkins School of Medicine, Baltimore MD; and the Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, Bethesda, MD. Inflammation and thrombosis are increasingly recognized as interrelated biologic processes. Endothelial cell expression of thrombomodulin (TM), a key component of the anticoagulant protein C pathway, is potently inhibited by inflammatory cytokines. Because the mechanism underlying this effect is largely unknown, we investigated a potential role for the inflammatory transcription factor nuclear factor-kappa B (NF-B). Blocking NF-B activation effectively prevented cytokine-induced down-regulation of TM, both in vitro and in a mouse model of tumor necrosis factor- (TNF-)–mediated lung injury. Although the TM promoter lacks a classic NF-B consensus site, it does contain tandem Ets transcription factor binding sites previously shown to be important for both constitutive TM gene expression and cytokine-induced repression. Using electrophoretic mobility shift assay and chromatin immunoprecipitation, we found that multiple Ets species bind to the TNF- response element within the TM promoter. Although cytokine exposure did not alter Ets factor binding, it did reduce binding of p300, a coactivator required by Ets for full transcriptional activity. Overexpression of p300 also prevented TM repression by cytokines. We conclude that NF-B is a critical mediator of TM repression by cytokines. Further evidence suggests a mechanism involving competition by NF-B for limited pools of the transcriptional coactivator p300 necessary for TM gene expression. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. F. Liu and A. B. Malik NF-{kappa}B activation as a pathological mechanism of septic shock and inflammation Am J Physiol Lung Cell Mol Physiol, April 1, 2006; 290(4): L622 - L645. [Abstract] [Full Text] [PDF]

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