title: Regulation of sterol 27-hydroxylase in human monocyte-derived macrophages: up-regulation by transforming growth factor beta1.
abstract: Regulatory mechanisms for human CYP27A1 enzyme have not yet been fully investigated. Our approach was to add different hormones and cytokines to cultured human monocyte-derived macrophages, and assess the effects on the CYP27A1 by measuring the production of 27-hydroxylated cholesterol in the media. Of the different hormones and cytokines tested, only transforming growth factor beta1 (TGF-beta1) had a clear effect on CYP27A1. Further experiments showed a significant increase in 27-hydroxylated cholesterol products (27-hydroxycholesterol and 3beta-hydroxy-5-cholestenoic acid). A concomitant increase in CYP27A1 mRNA levels was also seen and this positive effect was confirmed using a human CYP27A1 luciferase reporter gene expressed in HepG2 cells. Experiments with progressive deletion/luciferase reporter gene constructs indicated that a TGF-beta1 responsive sequence might be localized in a region about 400 bp upstream of the CYP27A1 translation start. The possibility is discussed that induction of CYP27A1 by TGF-beta1 may be responsible for some of the anti-atherogenic properties of this cytokine.
authors.affiliation: Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska University Hospital at Huddinge, SE-141 86 Stockholm, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Hansson
authors.forename: Kjell
authors.initials: K
authors.lastname: Wikvall
authors.forename: Amir
authors.initials: A
authors.lastname: Babiker
mesh_terms: D002460:Cell Line; D053493:Cholestanetriol 26-Monooxygenase; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D017930:Genes, Reporter; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation
chemical_list: D012333:RNA, Messenger; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D002784:Cholesterol; D013250:Steroid Hydroxylases; C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase