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

ABSTRACT: We previously reported that interferons (IFNs) regulate transcription of HIF-1alpha in human endothelial cells (ECs), linking immunity and hypoxia. Prolyl hydroxylases (PHDs) regulate expression of HIF-1alpha in response to hypoxia. We examined whether IFNs affect PHD expression and whether PHDs regulate the EC response to IFNs.Human cell cultures were treated with various cytokines, and PHD expression was examined using qRT-PCR and immunoblotting. IFNgamma and, to a lesser extent, IFNalpha 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.IFNgamma induces PHD3 through a JAK/STAT1-dependent mechanism in human ECs. Induction is independent of HIF-1alpha and may contribute to expression of IFNgamma-dependent genes.

SUBMITTER: Gerber SA

PROVIDER: S-EPMC2757736 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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

Gerber Scott A SA Yatsula Bogdan B Maier Cheryl L CL Sadler Timothy J TJ Whittaker Laurence W LW Pober Jordan S JS

Arteriosclerosis, thrombosis, and vascular biology 20090702 9

<h4>Objective</h4>We previously reported that interferons (IFNs) regulate transcription of HIF-1alpha in human endothelial cells (ECs), linking immunity and hypoxia. Prolyl hydroxylases (PHDs) regulate expression of HIF-1alpha in response to hypoxia. We examined whether IFNs affect PHD expression and whether PHDs regulate the EC response to IFNs.<h4>Methods and results</h4>Human cell cultures were treated with various cytokines, and PHD expression was examined using qRT-PCR and immunoblotting. I ...[more]

PMID: 19574556

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Project description:As an economically and ecologically important freshwater fish, silver carp (Hypophthalmichthys molitrix) is sensitive to low oxygen tension. Prolyl hydroxylase domain (PHD) proteins are critical regulators of adaptive responses to hypoxia for their function of regulating the hypoxia inducible factor-1 alpha subunit (HIF-1α) stability via hydroxylation reaction. In the present study, three PHD genes were cloned from H. molitrix by rapid amplification of cDNA ends (RACE). The total length of HmPHD1, HmPHD2, and HmPHD3 were 2981, 1954, and 1847 base pair (bp), and contained 1449, 1080, and 738 bp open reading frames (ORFs) that encoded 482, 359, and 245 amino acids (aa), respectively. Amino acid sequence analysis showed that HmPHD1, HmPHD2, and HmPHD3 had the conserved prolyl 4-hydroxylase alpha subunit homolog domains at their C-termini. Meanwhile, the evaluation of phylogeny revealed PHD2 and PHD3 of H. molitrix were more closely related as they belonged to sister clades, whereas the clade of PHD1 was relatively distant from these two. The transcripts of PHD genes are ubiquitously distributed in H. molitrix tissues, with the highest expressional level of HmPHD1 and HmPHD3 in liver, and HmPHD2 in muscle. After acute hypoxic treatment for 0.5 h, PHD genes of H. molitrix were induced mainly in liver and brain, and different from HmPHD1 and HmPHD2, the expression of HmPHD3 showed no overt tissue specificity. Furthermore, under continued hypoxic condition, PHD genes exhibited an obviously rapid but gradually attenuated response from 3 h to 24 h, and upon reoxygenation, the transcriptional expression of PHD genes showed a decreasing trend in most of the tissues. These results indicate that the PHD genes of H. molitrix are involved in the early response to hypoxic stress, and they show tissue-specific transcript expression when performing physiological regulation functions. This study is of great relevance for advancing our understanding of how PHD genes are regulated when addressing the hypoxic challenge and provides a reference for the subsequent research of the molecular mechanisms underlying hypoxia adaptation in silver carp.

Dataset Information

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

Publications

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

Similar Datasets

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