The transcription factor Erg inhibits vascular inflammation by repressing NF-kappaB activation and proinflammatory gene expression in endothelial cells.
OBJECTIVE
To test whether ETS-related gene (Erg) inhibits tumor necrosis factor (TNF)-α-dependent endothelial activation and inflammation.


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.


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.
Sperone
Andrea
A
Imperial College London, Hammersmith Hospital, London W12 0NN, England.
Dryden
Nicola H
NH
Birdsey
Graeme M
GM
Madden
Leigh
L
Johns
Mike
M
Evans
Paul C
PC
Mason
Justin C
JC
Haskard
Dorian O
DO
Boyle
Joseph J
JJ
Paleolog
Ewa M
EM
Randi
Anna M
AM
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D042783:Endothelial Cells / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism; D000071230:Transcriptional Regulator ERG; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
C508606:CXCL8 protein, human; C072312:ERG protein, human; D018836:Inflammation Mediators; D016209:Interleukin-8; D016328:NF-kappa B; C498143:RELA protein, human; D015534:Trans-Activators; D051996:Transcription Factor RelA; D000071230:Transcriptional Regulator ERG; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1