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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.


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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-{kappa}B). Blocking NF-{kappa}B activation effectively prevented cytokine-induced down-regulation of TM, both in vitro and in a mouse model of TNF-{alpha}-mediated lung injury. Though the TM promoter lacks a classic NF-{kappa}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-{alpha} 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-{kappa}B is a critical mediator of TM repression by cytokines. Further evidence suggests a mechanism involving competition by NF-{kappa}B for limited pools of the transcriptional co-activator p300 necessary for TM gene expression.


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