HIF-1α restricts NF-κB dependent gene expression to control innate immunity signals

Abstract Hypoxia and inflammation are intimately linked. It is known that NF-κB regulates the 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 enhanced 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.