Regulation of endothelial thrombomodulin expression by inflammatory cytokines is mediated by activation of nuclear factor-kappa B.
Blood
; 105(10): 3910-7, 2005 May 15.
Article
in En
| MEDLINE
| ID: mdl-15677570
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-kappaB). Blocking NF-kappaB activation effectively prevented cytokine-induced down-regulation of TM, both in vitro and in a mouse model of tumor necrosis factor-alpha (TNF-alpha)-mediated lung injury. Although the TM promoter lacks a classic NF-kappaB 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. 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-kappaB is a critical mediator of TM repression by cytokines. Further evidence suggests a mechanism involving competition by NF-kappaB for limited pools of the transcriptional coactivator p300 necessary for TM gene expression.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Gene Expression Regulation
/
NF-kappa B
/
Interleukin-1
/
Tumor Necrosis Factor-alpha
/
Thrombomodulin
/
Inflammation Mediators
/
Endothelial Cells
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
Blood
Year:
2005
Type:
Article
Affiliation country:
United States