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The transcription factor Erg inhibits vascular inflammation by repressing NF-kappaB activation and proinflammatory gene expression in endothelial cells.
- Source :
-
Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2011 Jan; Vol. 31 (1), pp. 142-50. Date of Electronic Publication: 2010 Oct 21. - Publication Year :
- 2011
-
Abstract
- Objective: To test whether ETS-related gene (Erg) inhibits tumor necrosis factor (TNF)-α-dependent endothelial activation and inflammation.<br />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-α-induced expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule (VCAM), and interleukin 8 (IL-8). Erg inhibited TNF-α-dependent activation of the ICAM-1 promoter, nuclear factor (NF)-κB activity, and NF-κB p65 phosphorylation. Basal NF-κB 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-α-dependent acute inflammation. The injection of AdErg into the paw decreased TNF-α-induced inflammation compared with control. Finally, staining of human coronary plaques showed loss of Erg expression from the endothelium overlaying active plaque shoulders.<br />Conclusions: We have identified a novel physiological anti-inflammatory pathway under the control of the transcription factor Erg; this pathway inhibits NF-κB-dependent transcription and TNF-α-induced inflammation in vivo. These results suggest a novel approach to anti-inflammatory therapies.
- Subjects :
- Animals
Base Sequence
Binding Sites
Cells, Cultured
Coronary Artery Disease metabolism
Disease Models, Animal
Down-Regulation
Humans
Inflammation genetics
Inflammation immunology
Intercellular Adhesion Molecule-1 genetics
Intercellular Adhesion Molecule-1 metabolism
Interleukin-8 genetics
Interleukin-8 metabolism
Mice
Mice, Inbred C57BL
Molecular Sequence Data
Phosphorylation
Promoter Regions, Genetic
RNA Interference
Time Factors
Trans-Activators genetics
Transcription Factor RelA metabolism
Transcriptional Regulator ERG
Transfection
Tumor Necrosis Factor-alpha metabolism
Vascular Cell Adhesion Molecule-1 genetics
Vascular Cell Adhesion Molecule-1 metabolism
Endothelial Cells immunology
Inflammation prevention & control
Inflammation Mediators metabolism
NF-kappa B metabolism
Trans-Activators metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4636
- Volume :
- 31
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Arteriosclerosis, thrombosis, and vascular biology
- Publication Type :
- Academic Journal
- Accession number :
- 20966395
- Full Text :
- https://doi.org/10.1161/ATVBAHA.110.216473