NF kB links innate immunity to the hypoxic response through transcriptional regulation of HIF 1a
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 a subunit is rapidly degraded under normoxia but stabilized when O2 dependent prolyl hydroxylases (PHDs) that target its O2 dependent degradation domain are inhibited. Thus, the amount of HIF 1a, 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 kB plays a central role. NF kB activation is controlled by IkB kinases (IKK) mainly IKK b, needed for phosphorylation induced degradation of IkB inhibitors in response to infection and inflammation. IKK b is modestly activated in hypoxic cell cultures when PHDs that attenuate its activation are inhibited. However, defining the relationship between NF kB and HIF 1a has proven elusive. Using in vitro systems, it was reported that HIF 1a activates NF kB, that NF kB controls HIF 1a transcription and that HIF 1a activation may be concurrent with inhibition of NF kB. Here we show, with the use of mice lacking IKK b in different cell types, that NF kB is a critical transcriptional activator of HIF 1a and that basal NF kB activity is required for HIF 1a protein accumulation under hypoxia in cultured cells and in the liver and brain of hypoxic animals. IKK b deficiency results in defective induction of HIF 1a target genes including vascular endothelial growth factor. IKK b is also essential for HIF 1a accumulation in macrophages experiencing a bacterial infection. Hence, IKK b is an important physiological contributor to the hypoxic response, linking it to innate immunity and inflammation.
Nature