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

Fitzpatrick, S.F., Tambuwala, Murtaza, Bruning, U. , Schaible, B., Scholz, C.C., Byrne, A., O'Connor, A., Gallagher, W.M., Lenihan, C.R., Garvey, J.F., Howell, K., Fallon, P.G., Cummins, E.P. and Taylor, C.T. (2011) An intact canonical NF-κB pathway is required for inflammatory gene expression in response to hypoxia. Journal of Immunology, 186 (2). pp. 1091-1096. ISSN 15506606

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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 hypoxiainduced 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. Copyright©2011 by The American Association of Immunologists, Inc.

Additional Information:cited By 126
Keywords:cyclooxygenase 2, hypoxia inducible factor 1alpha, immunoglobulin enhancer binding protein, luciferase, protein subunit, small interfering RNA, synaptotagmin I, animal cell, animal cell culture, animal experiment, article, bioaccumulation, controlled study, drug targeting, female, gene expression regulation, heart, human, human cell, hypoxia, in vivo study, inflammation, lung, mouse, nonhuman, priority journal, promoter region, transcription regulation, transgenic mouse, Animals, Anoxia, Caco-2 Cells, Cells, Cultured, Hela Cells, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Inflammation Mediators, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Myocardium, NF-kappa B, Signal Transduction
Subjects:A Medicine and Dentistry > A100 Pre-clinical Medicine
Divisions:College of Science > Lincoln Medical School
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ID Code:51668
Deposited On:15 Sep 2022 13:35

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