PMID- 16504308 OWN - NLM STAT- MEDLINE DCOM- 20060706 LR - 20161128 IS - 0165-5728 (Print) IS - 0165-5728 (Linking) VI - 174 IP - 1-2 DP - 2006 May TI - Evidence that hypoxia-inducible factor-1 (HIF-1) mediates transcriptional activation of interleukin-1beta (IL-1beta) in astrocyte cultures. PG - 63-73 AB - 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. FAU - Zhang, Wandong AU - Zhang W AD - Cerebrovascular Research Group, Neurobiology Program, Institute for Biological Sciences, National Research Council of Canada, Ottawa, Canada. Wandong.Zhang@nrc-cnrc.gc.ca FAU - Petrovic, Jelena-Mojsilovic AU - Petrovic JM FAU - Callaghan, Debbie AU - Callaghan D FAU - Jones, Aimee AU - Jones A FAU - Cui, Hong AU - Cui H FAU - Howlett, Clare AU - Howlett C FAU - Stanimirovic, Danica AU - Stanimirovic D LA - eng PT - Comparative Study PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20060228 PL - Netherlands TA - J Neuroimmunol JT - Journal of neuroimmunology JID - 8109498 RN - 0 (Antimutagenic Agents) RN - 0 (Cysteine Proteinase Inhibitors) RN - 0 (Hypoxia-Inducible Factor 1) RN - 0 (Interleukin-1) RN - 0 (Leupeptins) RN - 0 (RNA, Messenger) RN - 0 (Vascular Endothelial Growth Factor A) RN - 3G0H8C9362 (Cobalt) RN - EVS87XF13W (cobaltous chloride) RN - RF1P63GW3K (benzyloxycarbonylleucyl-leucyl-leucine aldehyde) SB - IM MH - Analysis of Variance MH - Animals MH - Antimutagenic Agents/pharmacology MH - Astrocytes/drug effects/*metabolism MH - Blotting, Western/methods MH - Cell Hypoxia/physiology MH - Cobalt/pharmacology MH - Cysteine Proteinase Inhibitors/pharmacology MH - Enzyme Activation/drug effects/physiology MH - Enzyme-Linked Immunosorbent Assay/methods MH - Fetus/cytology MH - Gene Expression Regulation/drug effects/*physiology MH - Humans MH - Hypoxia-Inducible Factor 1/*physiology MH - Interleukin-1/genetics/*metabolism MH - Leupeptins/pharmacology MH - Mice MH - Mice, Transgenic MH - Models, Biological MH - Mutagenesis/physiology MH - RNA, Messenger/metabolism MH - Reverse Transcriptase Polymerase Chain Reaction/methods MH - Time Factors MH - Transfection/methods MH - Vascular Endothelial Growth Factor A/metabolism EDAT- 2006/03/01 09:00 MHDA- 2006/07/11 09:00 CRDT- 2006/03/01 09:00 PHST- 2005/09/02 00:00 [received] PHST- 2006/01/19 00:00 [revised] PHST- 2006/01/20 00:00 [accepted] PHST- 2006/03/01 09:00 [pubmed] PHST- 2006/07/11 09:00 [medline] PHST- 2006/03/01 09:00 [entrez] AID - S0165-5728(06)00016-6 [pii] AID - 10.1016/j.jneuroim.2006.01.014 [doi] PST - ppublish SO - J Neuroimmunol. 2006 May;174(1-2):63-73. doi: 10.1016/j.jneuroim.2006.01.014. Epub 2006 Feb 28.