Takao Hamakubo

Function of GATA Transcription Factors in Induction of Endothelial Vascular Cell Adhesion Molecule-1 by Tumor Necrosis Factor-α

Abstract—Endothelial vascular cell adhesion molecule-1 (VCAM-1) is expressed in response to cytokine stimulation and plays a critical role in inflammatory reactions. Previously, we developed a novel VCAM-1 inhibitor that acts through a mechanism independent of nuclear factor-&kgr;B activity. It suppresses the binding activity of GATA proteins in cytokine-stimulated endothelial cells, which may be related to the anti–VCAM-1 induction effect of this drug. In this study, we investigated the role of GATA proteins in the induction of VCAM-1 by tumor necrosis factor-&agr; (TNF-&agr;) in human endothelial cells. The mRNA expression of GATA-6 was increased, whereas GATA-3 mRNA was decreased by TNF-&agr; stimulation. Electrophoretic mobility shift assay showed that TNF-&agr; stimulation increased the DNA binding of GATA-6 but decreased 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 able to suppress TNF-&agr;–induced VCAM-1 expression. Our results provide evidence of the importance of GATA proteins in the induction of VCAM-1 by TNF-&agr; in vascular endothelial cells. The switch from GATA-3 to GATA-6 is taken to be an important transcriptional control event in TNF-&agr; induction of VCAM-1.