title: Expression of heme oxygenase-1 is repressed by interferon-gamma and induced by hypoxia in human retinal pigment epithelial cells.
abstract: The retinal pigment epithelium (RPE) is essential for maintenance of photoreceptors and normally functions under conditions enriched with reactive oxygen species. RPE therefore expresses various defense enzymes against oxidative stress, including heme oxygenase-1 (HO-1). HO-1 catalyzes heme breakdown to release iron, carbon monoxide, and biliverdin, which is reduced to bilirubin, a potent radical scavenger. HO-1 expression is induced by various environmental factors, which has been established as a defense mechanism. To explore the hypothesis that the expression level of HO-1 is reduced in those RPE cells under certain conditions, we analyzed the effects of interferon-gamma and hypoxia, each of which represses the expression of HO-1 mRNA in other types of human cells. Expression levels of HO-1 mRNA were reduced by interferon-gamma in two human RPE cell lines, D407 and ARPE-19, which was consistently associated with the induction of mRNA for Bach1, a transcriptional repressor for the HO-1 gene. On the other hand, HO-1 and Bach1 mRNAs were induced by hypoxia in D407 cells but remained unchanged in ARPE-19 cells, suggesting that Bach1 is not a sole regulator for HO-1 expression. The hypoxia-mediated induction of HO-1 mRNA in D407 cells depends on gene transcription and protein synthesis, as judged by the effects of their inhibitors. The half-life of HO-1 mRNA did not change during hypoxia. Thus, hypoxia may increase transcription of the HO-1 gene through a certain protein factor in RPE cells. These results indicate that RPE cells maintain retinal homeostasis by repressing or inducing the expression of HO-1, depending on the microenvironment.
authors.affiliation: Department of Molecular Biology and Applied Physiology, Tohoku University School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Udono-Fujimori
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Takahashi
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Takeda
authors.forename: Kazumichi
authors.initials: K
authors.lastname: Furuyama
authors.forename: Kiriko
authors.initials: K
authors.lastname: Kaneko
authors.forename: Shigeru
authors.initials: S
authors.lastname: Takahashi
authors.forename: Makoto
authors.initials: M
authors.lastname: Tamai
authors.forename: Shigeki
authors.initials: S
authors.lastname: Shibahara
mesh_terms: D050976:Basic-Leucine Zipper Transcription Factors; D015687:Cell Hypoxia; D002460:Cell Line; D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003609:Dactinomycin / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051856:Fanconi Anemia Complementation Group Proteins; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D016350:Leucine Zippers; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; D018384:Oxidative Stress; D010857:Pigment Epithelium of Eye / Q000166:cytology*; D011401:Promoter Regions, Genetic; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C102108:BACH1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D051856:Fanconi Anemia Complementation Group Proteins; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors; D003609:Dactinomycin; D007371:Interferon-gamma; D003513:Cycloheximide; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1