Publication Date:
2008-04-25
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2669289/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2669289/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rius, Jordi -- Guma, Monica -- Schachtrup, Christian -- Akassoglou, Katerina -- Zinkernagel, Annelies S -- Nizet, Victor -- Johnson, Randall S -- Haddad, Gabriel G -- Karin, Michael -- P41 RR004050/RR/NCRR NIH HHS/ -- P41 RR004050-208577/RR/NCRR NIH HHS/ -- R01 AI043477/AI/NIAID NIH HHS/ -- R01 AI043477-12/AI/NIAID NIH HHS/ -- R01 CA118165/CA/NCI NIH HHS/ -- England -- Nature. 2008 Jun 5;453(7196):807-11. doi: 10.1038/nature06905. Epub 2008 Apr 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Gene Regulation and Signal Transduction, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0723, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18432192" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Anoxia/*genetics/immunology/*metabolism
;
Brain/metabolism
;
Cell Hypoxia/genetics/physiology
;
*Gene Expression Regulation
;
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
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
Permalink