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-?B. Recent studies have revealed a high degree of interdependence between HIF and NF-?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-?B to demonstrate that hypoxia activates NF-?B in the heart and lungs of mice in vivo. Using small interfering RNA targeted to the p65 subunit of NF-?B, we confirm a unidirectional dependence of hypoxic HIF-1a accumulation upon an intact canonical NF-?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-?B dependent, and in mouse embryonic fibroblasts lacking an intact canonical NF-?B pathway, there is a loss of hypoxia-induced inflammatory gene expression. Finally, under conditions of hypoxia, HIF-1a and the p65 subunit of NF-?B directly bind to the cyclooxygenase-2 promoter. These results implicate an essential role for NF-?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.

View details for DOI 10.4049/jimmunol.1002256

View details for Web of Science ID 000285917700048

View details for PubMedID 21149600