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Title: An Intact Canonical NF-kappa B Pathway Is Required for Inflammatory Gene Expression in Response to Hypoxia
Authors: Fitzpatrick, Susan F
Tambuwala, Murtaza M
BRUENING ROSSOW, 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
Taylor, Cormac T # ×
Issue Date: Jan-2011
Publisher: American Association of Immunologists
Series Title: Journal of Immunology vol:186 issue:2 pages:1091-1096
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-kappa B. Recent studies have revealed a high degree of interdependence between HIF and NF-kappa B 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-kappa B to demonstrate that hypoxia activates NF-kappa B in the heart and lungs of mice in vivo. Using small interfering RNA targeted to the p65 subunit of NF-kappa B, we confirm a unidirectional dependence of hypoxic HIF-1 alpha accumulation upon an intact canonical NF-kappa B 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-kappa B dependent, and in mouse embryonic fibroblasts lacking an intact canonical NF-kappa B pathway, there is a loss of hypoxia-induced inflammatory gene expression. Finally, under conditions of hypoxia, HIF-1 alpha and the p65 subunit of NF-kappa B directly bind to the cyclooxygenase-2 promoter. These results implicate an essential role for NF-kappa B signaling in inflammatory gene expression in response to hypoxia both through the regulation of HIF-1 and through direct effects upon target gene expression. The Journal of Immunology, 2011, 186: 1091-1096.
ISSN: 0022-1767
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Non-KU Leuven Association publications
× corresponding author
# (joint) last author

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