An intact canonical NF-κB pathway is required for inflammatory gene expression in response to hypoxia.

Susan F Fitzpatrick, Murtaza Tambuwala, Ulrike Bruning, Bettina Schaible, Carsten C Scholz, Annette Byrne, Aisling O'Connor, William M Gallagher, Colin R Lenihan, John F Garvey, Katherine Howell, Padraic G Fallon, Eoin P Cummins, Cormac T Taylor

    Research output: Contribution to journalArticlepeer-review

    137 Citations (Scopus)


    Hypoxia is a feature of the microenvironment in a number of chronic inflammatory conditions due to increased metabolic activity and disrupted perfusion at the inflamed site. Hypoxia contributes to inflammation through the regulation of gene expression via key oxygen-sensitive transcriptional regulators including the hypoxia-inducible factor (HIF) and NF-κB. Recent studies have revealed a high degree of interdependence between HIF and NF-κB signaling; however, the relative contribution of each to hypoxia-induced inflammatory gene expression remains unclear. In this study, we use transgenic mice expressing luciferase under the control of NF-κB to demonstrate that hypoxia activates NF-κB in the heart and lungs of mice in vivo. Using small interfering RNA targeted to the p65 subunit of NF-κB, we confirm a unidirectional dependence of hypoxic HIF-1α accumulation upon an intact canonical NF-κB pathway in cultured cells. Cyclooxygenase-2 and other key proinflammatory genes are transcriptionally induced by hypoxia in a manner that is both HIF-1 and NF-κB dependent, and in mouse embryonic fibroblasts lacking an intact canonical NF-κB pathway, there is a loss of hypoxia-induced inflammatory gene expression. Finally, under conditions of hypoxia, HIF-1α and the p65 subunit of NF-κB directly bind to the cyclooxygenase-2 promoter. These results implicate an essential role for NF-κB signaling in inflammatory gene expression in response to hypoxia both through the regulation of HIF-1 and through direct effects upon target gene expression.
    Original languageEnglish
    Pages (from-to)1091-1096
    JournalJ Immunol
    Issue number2
    Publication statusPublished (in print/issue) - 13 Dec 2010


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