title: 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.affiliation: Laboratory of Gene Regulation and Signal Transduction, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0723, USA.
authors.forename: Jordi
authors.initials: J
authors.lastname: Rius
authors.forename: Monica
authors.initials: M
authors.lastname: Guma
authors.forename: Christian
authors.initials: C
authors.lastname: Schachtrup
authors.forename: Katerina
authors.initials: K
authors.lastname: Akassoglou
authors.forename: Annelies S
authors.initials: AS
authors.lastname: Zinkernagel
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
authors.forename: Randall S
authors.initials: RS
authors.lastname: Johnson
authors.forename: Gabriel G
authors.initials: GG
authors.lastname: Haddad
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D015687:Cell Hypoxia / Q000235:genetics / Q000502:physiology; D005786:Gene Expression Regulation; D000860:Hypoxia / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics* / Q000378:metabolism; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D007113:Immunity, Innate / Q000235:genetics / Q000502:physiology*; D007249:Inflammation; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse