NF-κB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α

Abstract

Several lines of evidence have hinted at a possible connection between two evolutionarily ancient cellular defence mechanisms — innate immunity and the hypoxic response. Now that link has been clearly demonstrated with the discovery that a single protein is essential to both responses. The cellular response to hypoxia is triggered by low oxygen levels and controlled by hypoxia-inducible factor-1α (HIF-1α). The new work shows that HIF-1α transcription is regulated by the transcription factor NF-κB — more usually encountered as the master regulator of the innate immune response. The cellular response to hypoxia is regulated by the hypoxia-inducible factor (HIF) pathway. This paper shows that HIF-1α transcription is regulated by basal IKK-β-dependent NF-κB signalling, thus linking the hypoxic response to innate immunity and inflammation. The hypoxic response is an ancient stress response triggered by low ambient oxygen (O2) (ref. 1) and controlled by hypoxia-inducible transcription factor-1 (HIF-1), whose α subunit is rapidly degraded under normoxia but stabilized when O2-dependent prolyl hydroxylases (PHDs) that target its O2-dependent degradation domain are inhibited2,3,4. Thus, the amount of HIF-1α, which controls genes involved in energy metabolism and angiogenesis, is regulated post-translationally. Another ancient stress response is the innate immune response, regulated by several transcription factors, among which NF-κB plays a central role5,6. NF-κB activation is controlled by IκB kinases (IKK), mainly IKK-β, needed for phosphorylation-induced degradation of IκB inhibitors in response to infection and inflammation7. IKK-β is modestly activated in hypoxic cell cultures when PHDs that attenuate its activation are inhibited8. However, defining the relationship between NF-κB and HIF-1α has proven elusive. Using in vitro systems, it was reported that HIF-1α activates NF-κB9, that NF-κB controls HIF-1α transcription10 and that HIF-1α activation may be concurrent with inhibition of NF-κB11. Here we show, with the use of mice lacking IKK-β in different cell types, that NF-κB is a critical transcriptional activator of HIF-1α and that basal NF-κB activity is required for HIF-1α protein accumulation under hypoxia in cultured cells and in the liver and brain of hypoxic animals. IKK-β deficiency results in defective induction of HIF-1α target genes including vascular endothelial growth factor. IKK-β is also essential for HIF-1α accumulation in macrophages experiencing a bacterial infection. Hence, IKK-β is an important physiological contributor to the hypoxic response, linking it to innate immunity and inflammation.