A non-hypoxic, ROS-sensitive pathway mediates TNF-alpha-dependent regulation of HIF-1alpha.
A non-hypoxic, reactive oxygen species (ROS)-sensitive pathway mediating tumor necrosis factor-alpha (TNF-alpha)-dependent regulation of hypoxia-inducible factor-1alpha (HIF-alpha) was investigated in vitro. TNF-alpha mediated the translocation of HIF-1alpha, associated with up-regulating its activity under normoxia. Analysis of the mode of action of TNF-alpha revealed the accumulation of hydrogen peroxide (H2O2), superoxide anion (O(2-.)) and hydroxyl radical (.OH). Antioxidants purported as prototypical scavengers of H2O2 and .OH, attenuated TNF-alpha-induced HIF-1alpha activation, and blockading NADPH-oxidase by scavenging O(2-.) reduced the activity of HIF-1alpha. Inhibition of the mitochondrion complex I abrogated TNF-alpha-dependent activation of HIF-1alpha. Interrupting the respiratory chain reversed the excitatory effect of TNF-alpha on HIF-1alpha. These results indicate a non-hypoxic pathway mediating cytokine-dependent regulation of HIF-1alpha in a ROS-sensitive mechanism.
Haddad
J J
JJ
Oxygen Signaling Group, Tayside Institute of Child Health, Faculty of Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, UK. j.j.haddad@dundee.ac.uk
Land
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D000818:Animals; D000838:Anions; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D000860:Hypoxia; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007249:Inflammation; D020128:Inhibitory Concentration 50; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D021381:Protein Transport; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D015854:Up-Regulation
D000838:Anions; D000975:Antioxidants; D004268:DNA-Binding Proteins; C497443:Hif1a protein, mouse; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D004247:DNA; D006861:Hydrogen Peroxide