Role of the transcription factor Erg in inflammation

Pro-inflammatory and atherogenic stimuli up-regulate the expression of endothelial adhesion molecules which support the extravasation of leukocytes into the sub-endothelial space. This process drives plaque progression and contributes to its complications. Erg is an ETS transcription factor constitutively expressed in EC which regulates angiogenesis and endothelial homeostasis. Recently, Erg was shown to inhibit endothelial expression of the chemokine IL-8. In EC, Erg expression is down-regulated by the pro-inflammatory cytokine TNF-alpha, through a mechanism which appears to involve Erg protein degradation. These data suggest that Erg may be involved in inflammation. To test this hypothesis, I modulated Erg expression in HUVEC by inhibition with antisense or over-expression using adenovirus encoding for Erg (AdErg). Basal ICAM-1 expression was up-regulated following Erg inhibition, and down-regulated by Erg over-expression. Both of these effects were transcriptional, as shown by a luciferase reporter assay. Over-expression of Erg could inhibit TNF-dependent up-regulation of ICAM-1 and ICAM-1 promoter activity. Thus Erg acts as a transcriptional repressor of ICAM-1 expression in resting and activated EC. This pathway involves NF-kB, since both basal and TNF-α-induced NF-kB activity was repressed by AdErg, and Erg over-expression inhibited the TNF-α induction of NF-kB p65 phosphorylation. In vitro, Erg over-expression led to decreased adhesion of leukocytes to TNF-stimulated HUVEC. In vivo, local injection of AdErg in the mouse paw resulted in reduction of TNF-α-induced inflammation. Interestingly, staining of human coronary artery plaques showed that Erg is absent from activated endothelium over the vulnerable region of the plaque. In conclusion, I propose that Erg exerts a protective role in the endothelium by repressing pro- inflammatory signaling and gene expression. These results suggest a novel approach to anti-inflammatory therapies.EThOS - Electronic Theses Online ServiceGBUnited Kingdo