[摘要]：The interaction of transcription factors with specific DNA sequences is critical for activation of gene expression programs. In endothelial cells (EC), the transcription factor NF-kappa B is important in the switch from quiescence to activation, and is tightly controlled to avoid excessive inflammation and organ damage. Here we describe a novel mechanism that controls the activation of NF-kappa B in EC. The transcription factor Erg, the most highly expressed ETS member in resting EC, controls quiescence by repressing proinflammatory gene expression. Focusing on intercellular adhesion molecule 1(ICAM)-1 as a model, we identify two ETS binding sites (EBS - 118 and - 181) within the ICAM-1 promoter required for Erg-mediated repression. We show that Erg binds to both EBS - 118 and EBS - 181, the latter located within the NF-kappa B binding site. Interestingly, inhibition of Erg expression in quiescent EC results in increased NF-kappa B-dependent ICAM-1 expression, indicating that Erg represses basal NF-kappa B activity. Erg prevents NF-kappa B p65 from binding to the ICAM-1 promoter, suggesting a direct mechanism of interference. Gene set enrichment analysis of transcriptome profiles of Erg and NF-kappa B-dependent genes, together with chromatin immunoprecipitation (ChIP) studies, reveals that this mechanism is common to other proinflammatory genes, including cIAP-2 and IL-8. These results identify a role for Erg as a gatekeeper controlling vascular inflammation, thus providing an important barrier to protect against inappropriate endothelial activation.
