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

J Rius, M Guma, C Schachtrup, K Akassoglou… - Nature, 2008 - nature.com
J Rius, M Guma, C Schachtrup, K Akassoglou, AS Zinkernagel, V Nizet, RS Johnson
Nature, 2008nature.com
The hypoxic response is an ancient stress response triggered by low ambient oxygen
(O2)(ref.) 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 inhibited,,. 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 …
Abstract
The hypoxic response is an ancient stress response triggered by low ambient oxygen (O2) (ref. ) 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 inhibited,,. 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 role,. 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 inflammation. IKK-β is modestly activated in hypoxic cell cultures when PHDs that attenuate its activation are inhibited. 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-κB, that NF-κB controls HIF-1α transcription and that HIF-1α activation may be concurrent with inhibition of NF-κB. 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.
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