Objective—We previously reported that interferons (IFNs) regulate transcription of HIF-1 in human endothelial cells (ECs), linking immunity and hypoxia. Prolyl hydroxylases (PHDs) regulate expression of HIF-1 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 and, to a lesser extent, IFN 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 induces PHD3 through a JAK/STAT1-dependent mechanism in human ECs. Induction is independent of HIF-1 and may contribute to expression of IFN-dependent genes.