Oxysterols induce interleukin-1beta production in human macrophages.

Abstract

Oxysterols are biologically active molecules generated during the oxidation of low-density lipoprotein or formed enzymatically in vivo. In the atherosclerotic plaque newly recruited macrophages may be exposed to oxysterols present in the plaque. How these oxysterols affect the expression and secretion of inflammatory cytokines such as interleukin-1beta (IL-1beta) in macrophages is not known. Therefore the aim of the present study was to investigate how oxysterols regulate the expression and secretion of IL-1beta in human monocyte-derived macrophages. The IL-1beta messenger RNA (mRNA) expression was analysed by reverse transcription-polymerase chain reaction, and the IL-1beta protein secretion was measured by enzyme-linked immunosorbent assay. A significant, dose-dependent increase in the secretion of IL-1beta was given by 25-hydroxycholesterol without the addition of lipopolysaccharide (LPS). At a concentration of 2.5 microg mL(-1) this increase was similar to that obtained by endotoxin (LPS, 1 microg mL(-1)). A transient increase in IL-1beta mRNA expression was found in macrophages incubated with 25-hydroxycholesterol compared with untreated controls. In addition, 25-hydroxycholesterol dramatically increased the IL-1beta secretion induced by LPS. At a concentration of 5 microg mL(-1) of 25-hydroxycholesterol the LPS-induced IL-1beta secretion was increased by about 25-fold. A similar tendency, but not so consistent, was found for 27-hydroxycholesterol. Our results show that oxysterols, and 25-hydroxycholesterol in particular, may modulate the inflammatory response in human macrophages. Consequently the presence of oxysterols in atherosclerotic tissue may dramatically influence the effect of inflammation.