Hypoxia
NF-
B Links Immunity to the Hypoxic Response
John F. Foley
Science Signaling, AAAS, Washington, DC 20005, USA
Under normal oxygen tension (normoxia), the abundance of mRNA of the 
subunit of hypoxia-inducible transcription factor 1 (HIF-1) is kept low through its degradation by oxygen-dependent enzymes. When oxygen tension is low (hypoxia), HIF-1 mRNA accumulates and its target genes, such as that encoding vascular endothelial growth factor (VEGF), are expressed. HIF-1 also affects the expression of genes encoding inflammatory cytokines, which are activated by nuclear factor 
B (NF-B). Rius et al. investigated the relationship between HIF-1 and NF-B in mice inducibly deficient in the inhibitor of B (IB) kinase β (IKK-β); cells deficient in IKK-β cannot activate NF-B. Reverse transcription polymerase chain reaction (RT-PCR) assays showed that exposing wild-type, but not IKK-β-deficient, macrophages to bacteria resulted in the increased expression of HIF-1 mRNA and that the induction of HIF-1 -target genes in response to bacteria was lower in IKK-β-deficient than in wild-type macrophages. Basal HIF-1 mRNA abundance was also lower in IKK-β-deficient cells. Hypoxic conditions induced the accumulation of HIF-1 in wild-type but not in IKK-β-deficient macrophages, and the induction of HIF-1-responsive genes was almost completely blocked in the IKK-β-deficient cells. Indeed, the basal abundance of HIF-1 mRNA under normoxia was lower in IKK-β-deficient than in wild-type macrophages. Although treatment of a mouse macrophage cell line with bacterial lipopolysaccharide (LPS) induced HIF-1 expression under normoxia, HIF-1 protein accumulated only when LPS treatment occurred under hypoxia. Western blotting of samples from wild-type and IKK-β-deficient mice exposed to hypoxia showed that accumulation of HIF-1 in the liver and brain was dependent on IKK-β, as was the appearance of VEGF mRNA and protein. Together, these data suggest that the basal and hypoxia-induced expression of HIF-1 mRNA requires activated NF-B, which thus acts as a link between innate immunity and the hypoxic response.
J. Rius, M. Guma, C. Schachtrup, K. Akassoglou, A. S. Zinkernagel, V. Nizet, R. S. Johnson, G. G. Haddad, M. Karin, NF-B links innate immunity to the hypoxic response through transcriptional regulation of HIF-1. Nature 453, 807-811 (2008). [PubMed]
