Tumor Necrosis Factor-α Up-regulates the Expression of β1,4-Galactosyltransferase I in Primary Human Endothelial Cells by mRNA Stabilization

During the course of an inflammatory response, the pro-inflammatory cytokine tumor necrosis factor-α (TNFα) triggers endothelial cells to increase the expression levels of adhesion molecules that are pivotal for the rolling, adhesion, and transmigration of leukocytes over the endothelial cell wall. Here we show that TNFα, in addition, has a regulatory function in the biosynthesis of proper carbohydrate molecules on endothelial cells that constitute ligands for adhesion molecules on leukocytes. Our data show that TNFα induced an increase in the expression of β1,4-galactosyltransferase-1 (β4GalT-1) in primary human umbilical vein endothelial cells in a time- and concentration-dependent manner. The β4GalT-1 mRNA up-regulation correlated with an increase in the Golgi expression and catalytic activity of the enzyme. Furthermore, an enhanced incorporation of galactose was observed in newly synthesized glycoproteins. Analysis of the molecular mechanism behind the up-regulation of β4GalT-1 showed that the increase in mRNA levels is due to an enhanced stability of the transcripts. These data strongly demonstrate that TNFα modulates the glycosylation of endothelial cells by a mechanism that directly enhances the stability of β4GalT-1 mRNA transcripts.