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Sci. Signal., 10 June 2008
Vol. 1, Issue 23, p. ec214
[DOI: 10.1126/scisignal.123ec214]


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

Citation: J. F. Foley, NF-{kappa}B Links Immunity to the Hypoxic Response. Sci. Signal. 1, ec214 (2008).

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