title: Tumor necrosis factor-alpha-induced iron sequestration and oxidative stress in human endothelial cells.
abstract: OBJECTIVE
  Tumor necrosis factor (TNF)-alpha-induced endothelial injury, which is associated with atherosclerosis, is mediated by intracellular reactive oxygen species. Iron is essential for the amplification of oxidative stress. We tested whether TNF-alpha accelerated iron accumulation in vascular endothelium, favoring synthesis of hydroxyl radical.
  
  
  RESULTS
  Diverse iron transporters, including iron import proteins (transferrin receptor [TfR] and divalent metal transporter 1 [DMT1]) and an iron export protein (ferroportin 1 [FP1]) coexist in human umbilical endothelial cells (HUVECs). TNF-alpha caused upregulation of TfR and DMT1 and downregulation of FP1, which were demonstrated in mRNA as well as protein levels. These changes in iron transporters were accompanied by accumulation of iron that was both transferrin-dependent and transferrin-independent. Modifications of these mRNAs were regulated post-transcriptionally, and were coordinated with activation of binding activity of iron regulatory protein 1 to the iron responsive element on transporter mRNAs. Using a salicylate trap method, we observed that only simultaneous exposure of endothelial cells to iron and TNF-alpha accelerated hydroxyl radical production.
  
  
  CONCLUSIONS
  TNF-alpha could cause intracellular iron sequestration, which may participate importantly in the pathophysiology of atherosclerosis and cardiovascular disease.
authors.affiliation: Division of Kidney and Dialysis, Department of Internal Medicine, Hyogo College of Medicine, Hyogo 663-8501, Japan. m-nanami@hyo-med.ac.jp
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Nanami
authors.forename: Tomomi
authors.initials: T
authors.lastname: Ookawara
authors.forename: Yoshinaga
authors.initials: Y
authors.lastname: Otaki
authors.forename: Katsukiyo
authors.initials: K
authors.lastname: Ito
authors.forename: Rintarou
authors.initials: R
authors.lastname: Moriguchi
authors.forename: Koji
authors.initials: K
authors.lastname: Miyagawa
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Hasuike
authors.forename: Masaaki
authors.initials: M
authors.lastname: Izumi
authors.forename: Hironobu
authors.initials: H
authors.lastname: Eguchi
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Suzuki
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nakanishi
mesh_terms: D000154:Aconitate Hydratase / Q000037:antagonists & inhibitors / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D017665:Hydroxyl Radical / Q000378:metabolism; D007150:Immunohistochemistry; D007501:Iron / Q000378:metabolism*; D007504:Iron Radioisotopes; D035941:Iron Regulatory Protein 1 / Q000378:metabolism; D035925:Iron-Regulatory Proteins / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology; D015854:Up-Regulation; D000098742:Ferroportin; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D000154:Aconitate Hydratase; D027682:Cation Transport Proteins; D017665:Hydroxyl Radical; D007501:Iron; D007504:Iron Radioisotopes; D035941:Iron Regulatory Protein 1; D035925:Iron-Regulatory Proteins; D012333:RNA, Messenger; D011990:Receptors, Transferrin; D014409:Tumor Necrosis Factor-alpha; D000098742:Ferroportin; D000099236:Solute Carrier Family 11, Member 2