The study investigates the relationship between the hypoxic response and the innate immune response, focusing on the transcriptional regulation of HIF-1α by NF-κB. HIF-1α, a key regulator of energy metabolism and angiogenesis, is stabilized under hypoxic conditions through the inhibition of O2-dependent prolyl hydroxylases (PHDs). NF-κB, a central transcription factor in innate immunity, is activated by IκB kinases (IKK), particularly IKKβ. The study uses IKKβ-deficient mice and primary macrophages to demonstrate that NF-κB is a critical activator of HIF-1α in macrophages responding to bacterial infection and in the liver and brain of hypoxic animals. IKKβ deficiency results in defective induction of HIF-1α target genes, including vascular endothelial growth factor (VEGF), and elevated astrogliosis in hypoxic mice. These findings highlight the physiological link between the hypoxic response and innate immunity/inflammation, suggesting that IKKβ provides an important regulatory role in these two ancient stress response systems.The study investigates the relationship between the hypoxic response and the innate immune response, focusing on the transcriptional regulation of HIF-1α by NF-κB. HIF-1α, a key regulator of energy metabolism and angiogenesis, is stabilized under hypoxic conditions through the inhibition of O2-dependent prolyl hydroxylases (PHDs). NF-κB, a central transcription factor in innate immunity, is activated by IκB kinases (IKK), particularly IKKβ. The study uses IKKβ-deficient mice and primary macrophages to demonstrate that NF-κB is a critical activator of HIF-1α in macrophages responding to bacterial infection and in the liver and brain of hypoxic animals. IKKβ deficiency results in defective induction of HIF-1α target genes, including vascular endothelial growth factor (VEGF), and elevated astrogliosis in hypoxic mice. These findings highlight the physiological link between the hypoxic response and innate immunity/inflammation, suggesting that IKKβ provides an important regulatory role in these two ancient stress response systems.