Interferon-gamma induces prolyl hydroxylase (PHD)3 through a STAT1-dependent mechanism in human endothelial cells

Abstract

OBJECTIVE-: We previously reported that interferons (IFNs) regulate transcription of HIF-1α in human endothelial cells (ECs), linking immunity and hypoxia. Prolyl hydroxylases (PHDs) regulate expression of HIF-1α 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. IFNγ and, to a lesser extent, IFNα 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-: IFNγ induces PHD3 through a JAK/STAT1-dependent mechanism in human ECs. Induction is independent of HIF-1α and may contribute to expression of IFNγ-dependent genes. © 2009 American Heart Association, Inc.