NF-κB Links Immunity to the Hypoxic Response

Science Signaling  10 Jun 2008:
Vol. 1, Issue 23, pp. ec214
DOI: 10.1126/scisignal.123ec214

Under normal oxygen tension (normoxia), the abundance of mRNA of the α subunit of hypoxia-inducible transcription factor 1 (HIF-1α) is kept low through its degradation by oxygen-dependent enzymes. When oxygen tension is low (hypoxia), HIF-1α mRNA accumulates and its target genes, such as that encoding vascular endothelial growth factor (VEGF), are expressed. HIF-1α also affects the expression of genes encoding inflammatory cytokines, which are activated by nuclear factor κB (NF-κB). Rius et al. investigated the relationship between HIF-1α and NF-κB in mice inducibly deficient in the inhibitor of κB (IκB) kinase β (IKK-β); cells deficient in IKK-β cannot activate NF-κB. 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-1α mRNA and that the induction of HIF-1α -target genes in response to bacteria was lower in IKK-β-deficient than in wild-type macrophages. Basal HIF-1α mRNA abundance was also lower in IKK-β-deficient cells. Hypoxic conditions induced the accumulation of HIF-1α in wild-type but not in IKK-β-deficient macrophages, and the induction of HIF-1α-responsive genes was almost completely blocked in the IKK-β-deficient cells. Indeed, the basal abundance of HIF-1α 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-1α expression under normoxia, HIF-1α 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-1α 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-1α mRNA requires activated NF-κB, 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-κB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α. Nature 453, 807-811 (2008). [PubMed]