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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 (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 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 Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 11, 2004 Accepted January 17, 2005 Regulation of endothelial thrombomodulin expression by inflammatory cytokines is mediated via 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* Department of Medicine, Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD, USA Department of Neurosurgery, Johns Hopkins School of Medicine, Baltimore, MD, USA Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, Bethesda, MD, USA * Corresponding author; email: jjrade{at}jhmi.edu. Inflammation and thrombosis are increasingly recognized as inter-related biological 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 TNF--mediated lung injury. Though 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. Though cytokine exposure did not alter Ets factor binding, it did reduce binding of p300, a co-activator required by Ets for full transcriptional activity. Over-expression 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 co-activator 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: T. Hiroi, C. B. Deming, H. Zhao, B. S. Hansen, E. K. Arkenbout, T. J. Myers, M. A. McDevitt, and J. J. Rade Proteasome Inhibitors Enhance Endothelial Thrombomodulin Expression via Induction of Kruppel-Like Transcription Factors Arterioscler Thromb Vasc Biol, October 1, 2009; 29(10): 1587 - 1593. [Abstract] [Full Text] [PDF] D. Song, X. Ye, H. Xu, and S. F. Liu Activation of endothelial intrinsic NF-{kappa}B pathway impairs protein C anticoagulation mechanism and promotes coagulation in endotoxemic mice Blood, September 17, 2009; 114(12): 2521 - 2529. [Abstract] [Full Text] [PDF] B.-S. Ding, N. Hong, M. Christofidou-Solomidou, C. Gottstein, S. M. Albelda, D. B. Cines, A. B. Fisher, and V. R. Muzykantov Anchoring Fusion Thrombomodulin to the Endothelial Lumen Protects against Injury-induced Lung Thrombosis and Inflammation Am. J. Respir. Crit. Care Med., August 1, 2009; 180(3): 247 - 256. [Abstract] [Full Text] [PDF] I.-C. Lo, T.-M. Lin, L.-H. Chou, S.-L. Liu, L.-W. Wu, G.-Y. Shi, H.-L. Wu, and M. J. Jiang Ets-1 mediates platelet-derived growth factor-BB-induced thrombomodulin expression in human vascular smooth muscle cells Cardiovasc Res, March 1, 2009; 81(4): 771 - 779. [Abstract] [Full Text] [PDF] D. C. Johnson, S. Corthals, C. Ramos, A. Hoering, K. Cocks, N. J. Dickens, J. Haessler, H. Goldschmidt, J. A. Child, S. E. Bell, et al. Genetic associations with thalidomide mediated venous thrombotic events in myeloma identified using targeted genotyping Blood, December 15, 2008; 112(13): 4924 - 4934. [Abstract] [Full Text] [PDF] A. M. Gannon and B. T. Kinsella Regulation of the human thromboxane A2 receptor gene by Sp1, Egr1, NF-E2, GATA-1, and Ets-1 in megakaryocytes J. Lipid Res., December 1, 2008; 49(12): 2590 - 2604. [Abstract] [Full Text] [PDF] 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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