title: Activation of liver X receptor α protects amyloid β1-40induced inflammatory and senescent responses in human retinal pigment epithelial cells.
abstract: OBJECTIVE
  To investigate whether activation of the liver X receptors (LXRs) inhibits amyloid β1-40(Aβ1-40) induced inflammatory and senescent responses in human retinal pigment epithelial (RPE) cells.
  
  
  METHODS
  Confluent cultures of human primary RPE and ARPE-19 cells pretreated with 5 μΜ of TO901317 (TO90), a synthetic agonist of LXR, or vehicle were incubated with 1 μΜ of Aβ1-40or Aβ40-1. The optimum concentrations of Aβ1-40and TO90 were determined by cell viability assay. Pro-inflammatory cytokines IL-6, IL-8, MCP-1 were detected by real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA). Expression and localization of an aging protein p16INK4a (p16) were analyzed by western blotting and immunofluorescence. Expressions of LXRs and one of their target genes ATP-binding cassette transporter A1 (ABCA1) were examined by real-time PCR and western blotting. Phosphorylated transcription inhibition factor-κB-α (p-IκB-α) was assessed by western blotting.
  
  
  RESULTS
  A negative linear relationship between the Aβ1-40concentration and the cell viability was evident, indicating Aβ1-40decreased ARPE-19 cell viability in a dose-dependent manner. Aβ1-40enhanced the expression of IL-6, IL-8, MCP-1 as well as p16 in both RPE cell lines at both mRNA and protein levels, whereas TO90 counteracted the detrimental effects. TO90 upregulated the expression of LXRα and its target gene ABCA1, but it did not affect the expression of LXRβ. Meanwhile, TO90 inhibited the phosphorylation of IκB-α mediated by Aβ1-40stimulation.
  
  
  CONCLUSIONS
  Activation of the LXRα-ABCA1 axis may alleviate Aβ1-40induced inflammatory and senescent responses in RPE cells. The beneficial effect appears associated with the inhibition of the NF-κB signaling pathway.
authors.affiliation: Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Chongqing, 400016, China.
authors.forename: Bingling
authors.initials: B
authors.lastname: Dai
authors.affiliation: Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Chongqing, 400016, China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Lei
authors.affiliation: Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Chongqing, 400016, China.
authors.forename: Ru
authors.initials: R
authors.lastname: Lin
authors.affiliation: Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Chongqing, 400016, China.
authors.forename: Lifei
authors.initials: L
authors.lastname: Tao
authors.affiliation: Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Chongqing, 400016, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Bin
authors.affiliation: Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Chongqing, 400016, China. pengh9@sina.com.
authors.forename: Hui
authors.initials: H
authors.lastname: Peng
authors.affiliation: Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Chongqing, 400016, China. bolei99@126.com.|Henan Provincial People's Hospital, Henan Eye Institute, Henan Eye Hospital, People's Hospital of Zhengzhou University, 7 Weiwu Road, Zhengzhou, 450003, China. bolei99@126.com.
authors.forename: Bo
authors.initials: B
authors.lastname: Lei
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence; D016207:Cytokines / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology*; D007249:Inflammation / Q000378:metabolism; D000071518:Liver X Receptors / Q000819:agonists* / Q000378:metabolism; D008268:Macular Degeneration; D016328:NF-kappa B / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D055213:Retinal Pigment Epithelium / Q000166:cytology*; D013449:Sulfonamides / Q000494:pharmacology*; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D016229:Amyloid beta-Peptides; D016207:Cytokines; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D016328:NF-kappa B; D010446:Peptide Fragments; D013449:Sulfonamides; C000605213:NR1H3 protein, human; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C078592:amyloid beta-protein (1-40)
keywords: ATP-binding cassette transporter A1; Age-related macular degeneration; Amyloidβ; Liver X receptor; P16INK4a; Retinal pigment epithelium