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.
Highlights
In response to a drop in oxygen, the cell orchestrates a variety of coordinated responses in order to restore oxygen homeostasis
hypoxia-inducible factor (HIF)-1α depletion enhances the nuclear factor κB (NF-κB) response and this requires the involvement of other factors, including the TAK-IKK complex and cyclindependent kinase 6 (CDK6)
Implications and future directions These results indicate that HIF-1α is required to restrain the NF-κB response and, it is important to prevent excessive and damaging pro-inflammatory responses during infection and inflammation
Summary
In response to a drop in oxygen (hypoxia), the cell orchestrates a variety of coordinated responses in order to restore oxygen homeostasis. The physiological responses to hypoxia are well established, the molecular processes activated within the cells are not completely understood. HIF was first identified in 1995 together with the hypoxia response element (HRE, 5′-RCGTG-3′) of the erythropoietin gene (EPO) (Wang and Semenza, 1995). Further studies revealed that HIF is a heterodimeric complex composed of an α and a β subunit, which exist as a series of isoforms: 1α, 2α and 3α (Rocha, 2007). Even though the expression of the HIF-1β gene and protein is not dependent upon oxygen changes, HIF-α subunits are extremely labile at normal oxygen levels (Kenneth and Rocha, 2008)
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