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

Fitzpatrick, Susan F, Tambuwala, Murtaza, Bruning, Ulrike, Schaible, Bettina, Scholz, Carsten C, Byrne, Annette, O'Connor, Aisling, Gallagher, William M, Lenihan, Colin R, Garvey, John F, Howell, Katherine, Fallon, Padraic G, Cummins, Eoin P and Taylor, Cormac T (2010) An intact canonical NF-κB pathway is required for inflammatory gene expression in response to hypoxia. J Immunol, 186 (2). pp. 1091-1096. [Journal article]

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URL: http://www.jimmunol.org/content/186/2/1091.long

DOI: 10.4049/jimmunol.1002256

Abstract

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.

Item Type:Journal article
Faculties and Schools:Faculty of Life and Health Sciences > School of Pharmacy and Pharmaceutical Science
Faculty of Life and Health Sciences
Research Institutes and Groups:Biomedical Sciences Research Institute
Biomedical Sciences Research Institute > Pharmacy & Pharmaceutical Sciences
ID Code:26695
Deposited By: Dr Murtaza Tambuwala
Deposited On:21 Aug 2013 13:49
Last Modified:05 Apr 2017 10:23

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