| First Author | Fitzpatrick SF | Year | 2011 |
| Journal | J Immunol | Volume | 186 |
| Issue | 2 | Pages | 1091-6 |
| PubMed ID | 21149600 | Mgi Jnum | J:168776 |
| Mgi Id | MGI:4938222 | Doi | 10.4049/jimmunol.1002256 |
| Citation | Fitzpatrick SF, et al. (2011) An intact canonical NF-kappaB pathway is required for inflammatory gene expression in response to hypoxia. J Immunol 186(2):1091-6 |
| abstractText | 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-kappaB. Recent studies have revealed a high degree of interdependence between HIF and NF-kappaB 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-kappaB to demonstrate that hypoxia activates NF-kappaB in the heart and lungs of mice in vivo. Using small interfering RNA targeted to the p65 subunit of NF-kappaB, we confirm a unidirectional dependence of hypoxic HIF-1alpha accumulation upon an intact canonical NF-kappaB 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-kappaB dependent, and in mouse embryonic fibroblasts lacking an intact canonical NF-kappaB pathway, there is a loss of hypoxia-induced inflammatory gene expression. Finally, under conditions of hypoxia, HIF-1alpha and the p65 subunit of NF-kappaB directly bind to the cyclooxygenase-2 promoter. These results implicate an essential role for NF-kappaB signaling in inflammatory gene expression in response to hypoxia both through the regulation of HIF-1 and through direct effects upon target gene expression. |
