title: Opposite effects of HIF-1α and HIF-2α on the regulation of IL-8 expression in endothelial cells.
abstract: Recently we have shown that hypoxia as well as overexpression of the stable form of hypoxia-inducible factor-1α (HIF-1α) 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-2α on IL-8 expression in endothelial cells. In contrast to HIF-1α, overexpression of HIF-2α obtained by adenoviral transduction resulted in increased expression of IL-8 in an Nrf2-independent way. Importantly, HIF-2α 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-1α 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-1α and HIF-2α 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.
authors.affiliation: Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland.
authors.forename: Urszula
authors.initials: U
authors.lastname: Florczyk
authors.forename: Szymon
authors.initials: S
authors.lastname: Czauderna
authors.forename: Anna
authors.initials: A
authors.lastname: Stachurska
authors.forename: Magdalena
authors.initials: M
authors.lastname: Tertil
authors.forename: Witold
authors.initials: W
authors.lastname: Nowak
authors.forename: Magdalena
authors.initials: M
authors.lastname: Kozakowska
authors.forename: Lorenz
authors.initials: L
authors.lastname: Poellinger
authors.forename: Alicja
authors.initials: A
authors.lastname: Jozkowicz
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Loboda
authors.forename: Jozef
authors.initials: J
authors.lastname: Dulak
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000187:drug effects; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D019076:Transgenes / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016209:Interleukin-8; D051267:NF-E2-Related Factor 2; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D016329:Sp1 Transcription Factor; D025521:Tumor Suppressor Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C079440:MXI1 protein, human