25-hydroxycholesterol induces lipopolysaccharide-tolerance and decreases a lipopolysaccharide-induced TNF-α secretion in macrophages

Several different oxysterols are formed when LDL is oxidized. The role of oxysterols in the inflammatory process in the atherosclerotic plaque is not totally elucidated. In this study we have investigated the effect of four different oxysterols on an LPS-induced TNF-alpha secretion in human macrophages. Cultured human macrophages were incubated with 7-keto-, 7 beta -hydroxy-, 27-hydroxy- and 25-hydroxycholesterol for 24 h before exposure to endotoxin (LPS) for 3 h. All oxysterols, except 7-ketocholesterol, significantly decreased an LPS-induced TNF-alpha secretion. The most pronounced effect was obtained with 25-hydroxycholesterol, where the TNF-alpha secretion was reduced to 8%. This decreased effect was also found on the TNF-alpha mRNA level. The decreased LPS-induced TNF-alpha secretion coincided with an increased binding of the transcription factors Sp1 and Sp3 to the TNF-alpha promoter. In vitro studies of the TNF-alpha promoter suggests possible interactions between Sp1 and Sp3 and the NF-kappaB transcription factor complex that might affect the transcriptional initiation. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.