Oxysterols suppress inducible nitric oxide synthase expression in lipopolysaccharide-stimulated astrocytes through liver X receptor.
Cholesterols are enriched in the brain and can be oxidized to oxysterols by several 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, we treated lipopolysaccharide-stimulated rat brain astrocytes with two oxysterols, 7-ketocholesterol and 22(R)-hydroxycholesterol. Both oxysterols suppressed inducible nitric oxide synthase expression and nitric oxide release as well as upstream signaling molecules including interferon-beta, phosphorylated signal transducer and activator of transcription 1/3, and interferon regulatory factor-1. Oxysterols are known as liver X receptor agonists, and inhibitory effects were also observed with synthetic agonists of liver X receptor and retinoid X receptor. Thus, we conclude that it is most likely mediated by liver X receptor/retinoid X receptor heterodimers.
Lee
Chang Seok
CS
Department of Pharmacology, Ajou University School of Medicine, Suwon, Korea.
Joe
Eun-hye
EH
Jou
Ilo
I
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D001565:Benzoates / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D015153:Blotting, Western / Q000379:methods; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000502:physiology*; D003897:Desmosterol / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006845:Hydrocarbons, Fluorinated; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism; D016899:Interferon-beta / Q000378:metabolism; D007653:Ketocholesterols / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D000071518:Liver X Receptors; D008954:Models, Biological; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013449:Sulfonamides / Q000494:pharmacology; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D001565:Benzoates; D001596:Benzylamines; D002784:Cholesterol; D004268:DNA-Binding Proteins; D003897:Desmosterol; D004791:Enzyme Inhibitors; D006845:Hydrocarbons, Fluorinated; D050856:Interferon Regulatory Factor-1; D016899:Interferon-beta; D007653:Ketocholesterols; D008070:Lipopolysaccharides; D000071518:Liver X Receptors; D052247:Nitric Oxide Synthase Type II; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; C473027:GW 3965; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C022238:22(R)-hydroxydesmosterol; C003001:7-ketocholesterol