NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha.

Abstract

The hypoxic response is an ancient stress response triggered by low ambient oxygen (O2) (ref. 1) and controlled by hypoxia-inducible transcription factor-1 (HIF-1), whose alpha 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-1alpha, 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-kappaB plays a central role. NF-kappaB activation is controlled by IkappaB kinases (IKK), mainly IKK-beta, needed for phosphorylation-induced degradation of IkappaB inhibitors in response to infection and inflammation. IKK-beta is modestly activated in hypoxic cell cultures when PHDs that attenuate its activation are inhibited. However, defining the relationship between NF-kappaB and HIF-1alpha has proven elusive. Using in vitro systems, it was reported that HIF-1alpha activates NF-kappaB, that NF-kappaB controls HIF-1alpha transcription and that HIF-1alpha activation may be concurrent with inhibition of NF-kappaB. Here we show, with the use of mice lacking IKK-beta in different cell types, that NF-kappaB is a critical transcriptional activator of HIF-1alpha and that basal NF-kappaB activity is required for HIF-1alpha protein accumulation under hypoxia in cultured cells and in the liver and brain of hypoxic animals. IKK-beta deficiency results in defective induction of HIF-1alpha target genes including vascular endothelial growth factor. IKK-beta is also essential for HIF-1alpha accumulation in macrophages experiencing a bacterial infection. Hence, IKK-beta is an important physiological contributor to the hypoxic response, linking it to innate immunity and inflammation.

• Authors: Jordi Rius, Monica Guma, Christian Schachtrup, Katerina Akassoglou, Annelies S Zinkernagel, Victor Nizet, Randall S Johnson, Gabriel G Haddad, Michael Karin
• Journal: Nature (Nature) Vol. 453 Issue 7196 Pg. 807-11 (Jun 05 2008) ISSN: 1476-4687 [Electronic] England
• PMID: 18432192 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1, alpha Subunit
• NF-kappa B
• I-kappa B Kinase
• Ikbkb protein, mouse

Topics

• Animals
• Brain (metabolism)
• Cell Hypoxia (genetics, physiology)
• Gene Expression Regulation
• Hypoxia (genetics, immunology, metabolism)
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• I-kappa B Kinase (genetics, metabolism)
• Immunity, Innate (genetics, physiology)
• Inflammation
• Liver (metabolism)
• Macrophages (metabolism, microbiology)
• Mice
• NF-kappa B (metabolism)
• Transcription, Genetic