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IFN- Induces Transcription of Hypoxia-Inducible Factor-1 to Inhibit Proliferation of Human Endothelial Cells¹

Interdepartmental Program in Vascular Biology and Therapeutics and Department of Immunobiology, School of Medicine, Yale University, New Haven, CT 06509

Expression of hypoxia-inducible factor (HIF)-1, a transcription factor subunit increased by protein stabilization in response to hypoxia, is increased in human endothelial cells (ECs) by IFN- under normoxic conditions. IFN- increases HIF-1 transcript levels within 2 h by up to 50% and doubles HIF-1 protein expression. Based on pharmacological inhibition studies, the increase in HIF-1 mRNA involves new transcription, is independent of new protein synthesis, and requires JAK signaling. Protein knockdown by small interfering RNA confirms the involvement of JAK1 and TYK2, as well of IFN-stimulated gene factor 3 (ISGF3). IFN- does not significantly induce HIF-1 mRNA, but increases the magnitude and duration of the IFN- effect. IFN--induced HIF-1 protein translocates to the nucleus and can bind to hypoxia response elements in DNA. However, IFN- treatment fails to induce transcription of several prototypic HIF-responsive genes (VEGF-A, PPAR, and prostacyclin synthase) due to an insufficient increase in HIF-1 protein levels. Although certain other HIF-responsive genes (PHD3 and VEGF-C) are induced following IFN- and/or IFN- treatment, these responses are not inhibited by siRNA knockdown of HIF-1. Additionally, IFN- induction of ISGF3-dependent genes involved in innate immunity (viperin, OAS2, and CXCL10) are also unaffected by knockdown of HIF-1. Interestingly, knockdown of HIF-1 significantly reduces the capacity of IFN- to inhibit endothelial cell proliferation. We conclude that IFN- induces the transcription of HIF-1 in human endothelial cells though a JAK-ISGF3 pathway under normoxic conditions, and that this response contributes to the antiproliferative activity of this cytokine.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants RO1HL62188, T32-AR07107, and T32-AI007019.

² Address correspondence and reprint requests to Dr. Jordan S. Pober, School of Medicine, Yale University, Room 401D, 10 Amistad Street, P.O. Box 208089, New Haven, CT 06520-8089. E-mail address: Jordan.Pober{at}yale.edu

³ Abbreviations used in this paper: HIF, hypoxia-inducible factor; PHD, prolyl hydroxylase domain; EC, endothelial cell; IRF, IFN-regulatory factor; ISGF, IFN-stimulated gene factor; ISRE, IFN-stimulated response element; HRE, hypoxia-response element; ISG, IFN--stimulated gene; OAS, 2',5'-oligoadenylate synthetase; HDMEC, human dermal microvascular EC; SMC, smooth muscle cell; HCBEC, human cord blood-derived EC; CHX, cycloheximide; DRB, 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole; DFO, desferroxamine; qRT-PCR, quantitative RT-PCR; siRNA, small interfering RNA; siCon, control siRNA; siHIF, siRNA against HIF-1.