Function of GATA transcription factors in induction of endothelial vascular cell adhesion molecule-1 by tumor necrosis factor-alpha

Endothelial vascular cell adhesion molecule-1 (VCAM-1) is expressed in resp onse to cytokine stimulation and plays a critical role in inflammatory reac tions. Previously, we developed a novel VCAM-1 inhibitor that acts through a mechanism independent of nuclear factor-kappaB activity. It suppresses th e binding activity of GATA proteins in cytokine-stimulated endothelial cell s, which may be related to the anti-VCAM-1 induction effect of this drug. I n this study, we investigated the role of GATA proteins in the induction of VCAM-1 by tumor necrosis factor-alpha (TNF-alpha) in human endothelial cel ls. The mRNA expression of GATA-6 was increased, whereas GATA-3 mRNA was de creased by TNF-alpha stimulation. Electrophoretic mobility shift assay show ed that TNF-alpha stimulation increased the DNA binding of GATA-6 but decre ased that of GATA-3. Experiments using protein overexpression or antisense oligonucleotides revealed that GATA-6 potently acts as a positive regulator of VCAM-1 gene transcription. In contrast. overexpression of GATA-3 was ab le to suppress TNF-alpha -induced VCAM-1 expression. Our results provide ev idence of the importance of GATA proteins in the induction of VCAM-1 by TNF -alpha in vascular endothelial cells. The switch from GATA-3 to GATA-6 is t aken to be an important transcriptional control event in TNF-alpha inductio n of VCAM-1.