Previously we have shown that hyperosmolarity increases Na+-myo- inositol cotransporter (SMIT) activity and mRNA levels in cultured endothelial cells. Because hyperosmolarity and cytokines, such as tumor necrosis factor-α (TNF-α), activate similar signal transduction pathways, we examined the effect of TNF-α on SMIT mRNA levels and myo-inositol accumulation. In contrast to the effect of hyperosmolarity, TNF-α caused a time- and concentration-dependent decrease in SMIT mRNA levels and myo- inositol accumulation. The effect of TNF-α on myo-inositol accumulation was found in large-vessel endothelial cells (derived from the aorta and pulmonary artery) and cerebral microvessel endothelial cells. In bovine aorta and bovine pulmonary artery endothelial cells, TNF-α activated nuclear factor (NF)-κB. TNF-α also increased ceramide levels, and C2-ceramide mimicked the effect of TNF-α on SMIT mRNA levels and myo-inositol accumulation in bovine aorta endothelial cells. Pyrrolidinedithiocarbamate, genistein, and 7- amino-1-chloro-3-tosylamido-2-hepatanone, compounds that can inhibit NF-κB activation, partially prevented the TNF-α-induced decrease in myo-inositol accumulation. The effect of TNF-α on myo-inositol accumulation was also partially prevented by the protein kinase C inhibitor calphostin C but not by staurosporine. These studies demonstrate that TNF-α causes a decrease in SMIT mRNA levels and myo-inositol accumulation in cultured endothelial cells, which may be related to the activation of NF-κB.
- Nuclear factor-κB
- Sodium myo-inositol cotransporter
- Tumor necrosis factor-α
ASJC Scopus subject areas
- Cell Biology