Anti-Inflammatory Mechanism By Oxysterols In Cultured Rat Brain Astrocytes

Abstract

"Cholesterols are enriched in the brain and can be oxidized to oxysterols by spontaneous or enzyme-mediated processes. Oxysterols are transport forms of cholesterols across cell membranes and the blood-brain barrier. Here, to elucidate the roles of oxysterols in brain inflammation, I treated lipopolysaccharides(LPS)- or interferon gamma(IFN-stimulated rat brain astrocytes with two oxysterols, 7-ketocholesterol and 22(R)-hydroxycholesterol. In LPS-stimulated astrocytes, both oxysterols suppressed inducible nitric oxide synthase expression and nitric oxide release as well as upstream signaling molecules including interferon-, phosphorylated signal transducer and activator of transcription 1/3, and interferon regulatory factor-1. And oxysterols also inhibited interleukin-6 and tumor necrosis factor  transcripts, and monocyte chemoattractant protein-1 release. Oxysterols are known as nuclear receptor liver X receptor agonists, and these inhibitory effects were observed with synthetic agonists of liver X receptor and retinoid X receptor in a similar manner. In addition, ATP-binding cassette transporter a1 transcription, LXR-induced target gene, was increased by addition of either oxysterol or LXR agonist. Thus, I conclude that these effects are mediated by LXR/RXR heterodimers. Next, these inhibitory effects of oxysterols also appeared and were potentiated by RXR agonist in IFN-stimulated astrocytes. Furthermore, iNOS expression was inhibited by oxysterols and synthetic LXR ligands in LPS-stimulated primary microglia as well as in LPS- or IFN-stimulated primary astrocytes. I conclude that oxysterols suppress inflammatory gene expression through LXR/RXR activation in activated rat brain glial cells and these results provide new insights into the roles of oxysterols in brain inflammation."