title: Interferon-gamma induces prolyl hydroxylase (PHD)3 through a STAT1-dependent mechanism in human endothelial cells.
abstract: OBJECTIVE
  We previously reported that interferons (IFNs) regulate transcription of HIF-1alpha in human endothelial cells (ECs), linking immunity and hypoxia. Prolyl hydroxylases (PHDs) regulate expression of HIF-1alpha in response to hypoxia. We examined whether IFNs affect PHD expression and whether PHDs regulate the EC response to IFNs.
  
  
  RESULTS
  Human cell cultures were treated with various cytokines, and PHD expression was examined using qRT-PCR and immunoblotting. IFNgamma and, to a lesser extent, IFNalpha significantly induced PHD3, but not PHD1 or 2, mRNA, and protein expression selectively in ECs directly via a JAK/STAT1 pathway as demonstrated by pharmacological inhibition, siRNA knockdown, and chromatin immunoprecipitation. Inhibition of PHD activity with dimethyloxallyl glycine or desferroxamine reduced IFNg-dependent responses in these same cells.
  
  
  CONCLUSIONS
  IFNgamma induces PHD3 through a JAK/STAT1-dependent mechanism in human ECs. Induction is independent of HIF-1alpha and may contribute to expression of IFNgamma-dependent genes.
authors: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520-8089 , USA.
authors: Scott A
authors: SA
authors: Gerber
authors: Bogdan
authors: B
authors: Yatsula
authors: Cheryl L
authors: CL
authors: Maier
authors: Timothy J
authors: TJ
authors: Sadler
authors: Laurence W
authors: LW
authors: Whittaker
authors: Jordan S
authors: JS
authors: Pober
mesh_terms: D000600:Amino Acids, Dicarboxylic / Q000494:pharmacology; D015687:Cell Hypoxia; D002478:Cells, Cultured; D003676:Deferoxamine / Q000494:pharmacology; D049308:Dioxygenases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017781:Genes, Immediate-Early; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D016898:Interferon-alpha / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism*; D053612:Janus Kinases / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic
chemical_list: D000600:Amino Acids, Dicarboxylic; D004791:Enzyme Inhibitors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016898:Interferon-alpha; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D007371:Interferon-gamma; D049308:Dioxygenases; C488894:EGLN3 protein, human; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D053612:Janus Kinases; D003676:Deferoxamine; C040947:oxalylglycine