Bacterial lipopolysaccharide and tumor necrosis factor alpha synergistically increase expression of human endothelial adhesion molecules through activation of NF-kappa B and p38 mitogen-activated protein kinase signaling pathways

One of the recognized associations of bacterial infection with cardiovascul ar events is the activation of endothelium and upregulation of adhesion mol ecules. The two major proinflammatory mediators implicated in the causation of cardiovascular events, bacterial lipopolysaccharide (LPS) and tumor nec rosis factor alpha (TNF), were found to cooperate to enhance the adhesive p roperties of endothelial cells. These caused synergistic upregulation of in tercellular adhesion molecule-1, E-selectin, and vascular cell adhesion mol ecule-1 in human umbilical vein endothelial cells as determined by flow cyt ometry analysis and enzyme-linked immunosorbent assay. This synergism was n ot due to TNF causing an upregulation of CD14 expression. Treatment with bo th LPS and TNF resulted in a marked increase in the translocation of NF-KB into the nucleus. The activity of p38 mitogen-activated protein kinase was also synergistically enhanced, while the activity of c-jun N-terminal kinas e was increased in an additive manner. The results demonstrate that LPS and TNF act synergistically to upregulate the expression of endothelial cell a dhesion molecules, possibly by amplification of signaling pathways upstream of transcription. These findings have implications for the understanding o f the acceleration of atherosclerotic events seen in low-grade infections w ith gram-negative organisms.