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.
The authors declare no competing or financial interests.
D.B., J.B., S.M., H.A.M. and S.R. performed experiments. D.B., H.A.M. and S.R. designed, interpreted the experiments and wrote the manuscript.
D.B. holds a PhD studentship from the Portuguese Science Foundation and Graduate Program in Areas of Basic and Applied Biology (GABBA); J.B. is a Cancer Research UK clinical fellow; H.A.M. is supported by Medical Research Council project grants (MR/K018531/1 and G0901020); the S.R. lab is funded by a Cancer Research UK Senior Research Fellowship (C99667/A12918); this work was also supported by a Wellcome Trust Strategic Award (097945/B/11/Z).
Supplementary material available online at http://dmm.biologists.org/lookup/suppl/doi:10.1242/dmm.017285/-/DC1
- Received June 20, 2014.
- Accepted December 11, 2014.
- © 2015. Published by The Company of Biologists Ltd
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