The Transcription Factor Erg Inhibits Vascular Inflammation by Repressing NF-kappa B Activation and Proinflammatory Gene Expression in Endothelial Cells

Objective-To test whether ETS-related gene (Erg) inhibits tumor necrosis factor (TNF)-alpha-dependent endothelial activation and inflammation. Methods and Results-Endothelial activation underlies many vascular diseases, including atherosclerosis. Endothelial activation by proinflammatory cytokines decreases expression of the ETS transcription factor Erg. By using human umbilical vein endothelial cells (HUVECs), we showed that Erg overexpression by adenovirus (AdErg) repressed basal and TNF-alpha-induced expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule (VCAM), and interleukin 8 (IL-8). Erg inhibited TNF-alpha-dependent activation of the ICAM-1 promoter, nuclear factor (NF)-kappa B activity, and NF-kappa B p65 phosphorylation. Basal NF-kappa B activity was also inhibited by Erg overexpression. Chromatin immunoprecipitation showed that Erg binds to the ICAM-1 proximal promoter region, which contains 7 putative ETS binding sites. To test the anti-inflammatory role of Erg in vivo, we used a murine model of TNF-alpha-dependent acute inflammation. The injection of AdErg into the paw decreased TNF-alpha-induced inflammation compared with control. Finally, staining of human coronary plaques showed loss of Erg expression from the endothelium overlaying active plaque shoulders. Conclusion-We have identified a novel physiological anti-inflammatory pathway under the control of the transcription factor Erg; this pathway inhibits NF-kappa B-dependent transcription and TNF-alpha-induced inflammation in vivo. These results suggest a novel approach to anti-inflammatory therapies. (Arterioscler Thromb Vasc Biol. 2011;31:142-150.)