To know if thioredoxin reductase 1 (TrxR1) plays a role in antioxidant defense mechanisms against atherosclerosis, effect of TrxR1 on expression/release of monocyte chemoattractant protein (MCP-1) was investigated in activated human endothelial-like EAhy926 cells. The MCP-1 release and expression, cellular generation of reactive oxygen species (ROS), nuclear translocation and DNA-binding activity of NF-kappa B subunit p65 were assayed in cells either overexpressing recombinant TrxR1 or having their endogenous TrxR1 knocked down. It was found that overexpression of TrxR1 enhanced, while knockdown of TrxR1 reduced MCP-1 release and expression. Upregulation of MCP-1 by TrxR1 was associated with increasing generation of intracellular ROS generation, enhanced nuclear translocation and DNA-binding activity of NF-kappa B. Assay using NF-kappa B reporter revealed that TrxR1 upregulated transcriptional activity of NF-kappa B. This Study suggests that TrxR1 enhances ROS generation, NF-kappa B activity and subsequent MCP-1 expression in endothelial cells. and may promote rather than prevent vascular endothelium from forming atherosclerotic plaque. (C) 2009 Elsevier Inc. All rights reserved.