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

The hypoxic response is an ancient stress response triggered by low ambient oxygen ( O(2)) ( ref. 1) and controlled by hypoxia-inducible transcription factor- 1 ( HIF- 1), whose a subunit is rapidly degraded under normoxia but stabilized when O(2)- dependent prolyl hydroxylases ( PHDs) that target its O(2)- dependent degradation domain are inhibited(2-4). Thus, the amount of HIF-1 alpha, 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-kappa B plays a central role(5,6). NF-kappa B activation is controlled by I kappa B kinases ( IKK), mainly IKK-beta, needed for phosphorylation- induced degradation of I kappa B inhibitors in response to infection and inflammation(7). IKK-beta is modestly activated in hypoxic cell cultures when PHDs that attenuate its activation are inhibited(8). However, defining the relationship between NF-kappa B and HIF-1 alpha has proven elusive. Using in vitro systems, it was reported that HIF-1 alpha activates NF- kappa B(9), that NF-kappa B controls HIF-1 alpha transcription(10) and that HIF-1 alpha activation may be concurrent with inhibition of NF-kappa B(11). Here we show, with the use of mice lacking IKK-beta in different cell types, that NF-kappa B is a critical transcriptional activator of HIF-1 alpha and that basal NF-kappa B activity is required for HIF-1 alpha protein accumulation under hypoxia in cultured cells and in the liver and brain of hypoxic animals. IKK-beta deficiency results in defective induction of HIF-1 alpha target genes including vascular endothelial growth factor. IKK-beta is also essential for HIF-1 alpha accumulation in macrophages experiencing a bacterial infection. Hence, IKK-beta is an important physiological contributor to the hypoxic response, linking it to innate immunity and inflammation.