27 nM

Hypoxia and inflammation are intimately linked. It is known that nuclear factor kappaB (NF-kappaB) regulates the hypoxia-inducible factor (HIF) system, but little is known about how HIF regulates NF-kappaB. Here, we show that HIF-1alpha represses NF-kappaB-dependent gene expression. HIF-1alpha depletion results in increased NF-kappaB transcriptional activity both in mammalian cells and in the model organism Drosophila melanogaster. HIF-1alpha depletion enhances the NF-kappaB response, and this required not only the TAK-IKK complex, but also CDK6. Loss of HIF-1alpha results in an increased angiogenic response in mammalian cancer cells and increased mortality in Drosophila following infection. These results indicate that HIF-1alpha is required to restrain the NF-kappaB response, and thus prevents excessive and damaging pro-inflammatory responses.