| Adhesion molecules expressed by activated endothelial cells play a key role in regulating leukocyte trafficking to sites of inflammation. Resting endothelial cells normally do not express adhesion molecules, but cytokines activate endothelial cells to express adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1), which mediate leukocyte adherence to endothelial cells. We now show that endothelial cells express the miRNA, miR-126, which inhibits VCAM-1 expression. Transfection of endothelial cells with an oligonucleotide that decreases miR-126 permits an increase in TNF-alpha stimulated VCAM-1 expression. Conversely, over-expression of the precursor to miR-126 increases miR-126 levels and decreases VCAM-1 expression. Additionally, decreasing endogenous miR-126 levels increases leukocyte adherence to endothelial cells. These data suggest that miRNA can regulate adhesion molecule expression and may provide additional control of vascular inflammation. Additionally, we show that the transcription factors Ets-1 and Ets-2 regulate miR-126 expression. Computer analysis identified a potential Ets binding site within the genomic region -71 and -100 bp upstream of the miR-126 transcriptional start site. Mutations within the Ets binding site block transactivation, and Ets-1 and Ets-2 interact with this critical genomic region. Finally, knockdown of endogenous Ets-1 and Ets-2 decreases miR-126 expression. Taken together, these data show that the transcription factors Ets-1 and Ets-2 play a key role in controlling the expression of miR-126. |
