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, Jeffrey J. Rade

Research output: Contribution to journalArticlepeer-review

Abstract

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-κB). Blocking NF-κB activation effectively prevented cytokine-induced down-regulation of TM, both in vitro and in a mouse model of tumor necrosis factor-α (TNF-α)-mediated lung injury. Although the TM promoter lacks a classic NF-κB 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-α 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-κB is a critical mediator of TM repression by cytokines. Further evidence suggests a mechanism involving competition by NF-κB for limited pools of the transcriptional coactivator p300 necessary for TM gene expression.

Original languageEnglish (US)
Pages (from-to)3910-3917
Number of pages8
JournalBlood
Volume105
Issue number10
DOIs
StatePublished - May 15 2005

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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