title: Evidence that hypoxia-inducible factor-1 (HIF-1) mediates transcriptional activation of interleukin-1beta (IL-1beta) in astrocyte cultures.
abstract: Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor composed of HIF-1alpha and HIF-1beta subunits and involved in the regulation of gene expression in adaptive response to hypoxia. This study reports that the inflammatory cytokine interleukin-1beta (IL-1beta) shares common features of other known HIF-1alpha-regulated genes. Both human and mouse IL-1beta genes carry multiple HIF-1-binding sites in their promoter regions and are up-regulated by hypoxia and CoCl2 in human and mouse astrocytes in parallel with up-regulation of HIF-1alpha mRNA and protein. Inhibition of HIF-1alpha degradation by proteasome inhibitor, MG-132, potentiated hypoxia-induced IL-1beta release from human astrocytes, and this response was blocked in the presence of CdCl2. Mouse astrocytes with Hif1alpha+/- genotype demonstrated attenuated up-regulation of both HIF-1alpha and IL-1beta by hypoxia and CoCl2. Mutation of HIF-1-binding sites in the IL-1beta promoter abolished hypoxia-induced transactivation of the reporter gene transfected into human astrocytes. Similarly, HIF-1 binding "decoy" oligonuleotide transfected into astrocytes inhibited both hypoxia-induced transactivation of the HIF-1 reporter gene and IL-1beta secretion from transfected astrocytes. Collectively, the evidence suggests that the transcriptional activation of IL-1beta in astrocytes exposed to hypoxia occurs via HIF-1.
authors.affiliation: Cerebrovascular Research Group, Neurobiology Program, Institute for Biological Sciences, National Research Council of Canada, Ottawa, Canada. Wandong.Zhang@nrc-cnrc.gc.ca
authors.forename: Wandong
authors.initials: W
authors.lastname: Zhang
authors.forename: Jelena-Mojsilovic
authors.initials: JM
authors.lastname: Petrovic
authors.forename: Debbie
authors.initials: D
authors.lastname: Callaghan
authors.forename: Aimee
authors.initials: A
authors.lastname: Jones
authors.forename: Hong
authors.initials: H
authors.lastname: Cui
authors.forename: Clare
authors.initials: C
authors.lastname: Howlett
authors.forename: Danica
authors.initials: D
authors.lastname: Stanimirovic
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D016587:Antimutagenic Agents / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D015153:Blotting, Western / Q000379:methods; D015687:Cell Hypoxia / Q000502:physiology; D003035:Cobalt / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005333:Fetus / Q000166:cytology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000502:physiology*; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D016296:Mutagenesis / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013997:Time Factors; D014162:Transfection / Q000379:methods; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D016587:Antimutagenic Agents; D015853:Cysteine Proteinase Inhibitors; D051793:Hypoxia-Inducible Factor 1; D007375:Interleukin-1; D007976:Leupeptins; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D003035:Cobalt; C018021:cobaltous chloride; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde