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

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.

• Authors: Susan F Fitzpatrick, Murtaza M 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
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 186 Issue 2 Pg. 1091-6 (Jan 15 2011) ISSN: 1550-6606 [Electronic] United States
• PMID: 21149600 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Inflammation Mediators
• NF-kappa B
• Cyclooxygenase 2
• PTGS2 protein, human

Topics

• Animals
• Caco-2 Cells
• Cells, Cultured
• Cyclooxygenase 2 (biosynthesis, genetics)
• Female
• Gene Expression Regulation (immunology)
• HeLa Cells
• Humans
• Hypoxia (genetics, immunology, pathology)
• Hypoxia-Inducible Factor 1, alpha Subunit (antagonists & inhibitors, biosynthesis)
• Inflammation Mediators (physiology)
• Lung (metabolism, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Myocardium (metabolism, pathology)
• NF-kappa B (antagonists & inhibitors, metabolism, physiology)
• Signal Transduction (genetics, immunology)