Opposite effects of HIF-1α and HIF-2α on the regulation of IL-8 expression in endothelial cells

Recently we have shown that hypoxia as well as overexpression of the stable form of hypoxia-inducible factor-1 alpha (HIF-1 alpha) diminished the expression of interleukin-8 (IL-8) by inhibition of the Nrf2 transcription factor in HMEC-1 cells. Because HIF isoforms may exert different effects, we aimed to examine the influence of HIF-2 alpha on IL-8 expression in endothelial cells. In contrast to HIF-1 alpha, overexpression of HIF-2 alpha obtained by adenoviral transduction resulted in increased expression of IL-8 in an Nrf2-independent way. Importantly, HIF-2 alpha augmented the activity of SP-1, a transcription factor involved in IL-8 regulation and known coactivator of c-Myc. Additionally, HIF-1 decreased, whereas HIF-2 increased, c-Myc expression, and silencing of Mxi-1, a c-Myc antagonist, restored IL-8 expression downregulated by HIF-1 alpha or hypoxia. Accordingly, binding of c-Myc to the IL-8 promoter was abolished in hypoxia. Importantly, both severe (0.5% O-2) and mild (5% O-2) hypoxia diminished IL-8 expression despite the stabilization of both HIF-1 and HIF-2. This study reveals the opposite roles of HIF-1 alpha and HIF-2 alpha in the regulation of IL-8 expression in endothelial cells. However, despite stabilization of both isoforms in hypoxia the effect of HIF-1 is predominant, and downregulation of IL-8 expression in hypoxia is caused by attenuation of Nrf2 and c-Myc. (C) 2011 Elsevier Inc. All rights reserved.