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Inflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin-1 (IL-1), trigger the activation of transcription factor NF-κB that induces the expression of a variety of genes, including intercellular adhesion molecule (ICAM)-1. Odoroside A [3β-O-(β-D-diginosyl)-14-hydroxy-5β,14β-card-20(22)-enolide] was found to inhibit the cell-surface expression of ICAM-1 induced by TNF-α and IL-1 at comparable concentrations in human lung carcinoma A549 cells. In this study, the molecular mechanism underlying the inhibition of TNF-α-induced cell-surface ICAM-1 expression by odoroside A together with the specific Na+/K+-ATPase inhibitor ouabain was further investigated. Odoroside A and ouabain neither prevented IκBα degradation nor NF-κB translocation to the nucleus upon TNF-α stimulation. While odoroside A and ouabain had no inhibitory effect on the induction of ICAM-1 mRNA, they inhibited the TNF-α-induced ICAM-1 expression at the protein level. Consistent with these results, odoroside A and ouabain potently reduced de novo protein synthesis, largely due to its ability to block Na+-dependent transport of amino acids across the plasma membrane, but not to interfering with the translation machinery. As a direct molecular target, odoroside A was found to inhibit the ATP-hydrolyzing activity of Na+/K+-ATPase as potently as ouabain. These results clearly demonstrate that odoroside A and ouabain prevent NF-κB-inducible protein expression by blocking the Na+-dependent amino acid transport.