Abstract
Hypoxia and inflammation are intimately linked. It is known that nuclear factor κB (NF-κB) regulates the hypoxia-inducible factor (HIF) system, but little is known about how HIF regulates NF-κB. Here, we show that HIF-1α represses NF-κB-dependent gene expression. HIF-1α depletion results in increased NF-κB transcriptional activity both in mammalian cells and in the model organism Drosophila melanogaster. HIF-1α depletion enhances the NF-κB response, and this required not only the TAK-IKK complex, but also CDK6. Loss of HIF-1α results in an increased angiogenic response in mammalian cancer cells and increased mortality in Drosophila following infection. These results indicate that HIF-1α is required to restrain the NF-κB response, and thus prevents excessive and damaging pro-inflammatory responses.
Keywords:
Drosophila; HIF-1; Hypoxia; IKK; Inflammation; NF-κB.
© 2015. Published by The Company of Biologists Ltd.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line
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Cyclin-Dependent Kinase 6 / metabolism
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DNA-Binding Proteins / metabolism
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Drosophila Proteins / metabolism
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Drosophila melanogaster / genetics*
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Drosophila melanogaster / immunology*
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Drosophila melanogaster / microbiology
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Escherichia coli Infections / genetics
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Escherichia coli Infections / pathology
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Gene Expression Regulation*
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Gene Knockdown Techniques
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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I-kappa B Kinase / metabolism
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Immunity, Innate / genetics*
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MAP Kinase Kinase Kinases / metabolism
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Mammals / metabolism
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NF-kappa B / metabolism*
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Neovascularization, Physiologic
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Signal Transduction / genetics*
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Survival Analysis
Substances
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DNA-Binding Proteins
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Drosophila Proteins
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Hypoxia-Inducible Factor 1, alpha Subunit
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NF-kappa B
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Sima protein, Drosophila
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I-kappa B Kinase
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Cyclin-Dependent Kinase 6
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MAP Kinase Kinase Kinases
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MAP kinase kinase kinase 7