Interferon-Gamma Induces Prolyl Hydroxylase (PHD)3 Through a STAT1-Dependent Mechanism in Human Endothelial Cells

Objective-We previously reported that interferons (IFNs) regulate transcription of HIF-1 alpha in human endothelial cells (ECs), linking immunity and hypoxia. Prolyl hydroxylases (PHDs) regulate expression of HIF-1 alpha in response to hypoxia. We examined whether IFNs affect PHD expression and whether PHDs regulate the EC response to IFNs. Methods and Results-Human cell cultures were treated with various cytokines, and PHD expression was examined using qRT-PCR and immunoblotting. IFN gamma and, to a lesser extent, IFN alpha significantly induced PHD3, but not PHD1 or 2, mRNA, and protein expression selectively in ECs directly via a JAK/STAT1 pathway as demonstrated by pharmacological inhibition, siRNA knockdown, and chromatin immunoprecipitation. Inhibition of PHD activity with dimethyloxallyl glycine or desferroxamine reduced IFNg-dependent responses in these same cells. Conclusions-IFN gamma induces PHD3 through a JAK/STAT1-dependent mechanism in human ECs. Induction is independent of HIF-1 alpha and may contribute to expression of IFN gamma-dependent genes. (Arterioscler Thromb Vasc Biol. 2009;29:1363-1369.)