HIF-1 induction attenuates Nrf2-dependent IL-8 expression in human endothelial cells.
Through hypoxia-inducible factor 1 (HIF-1), hypoxia regulates the expression of numerous genes and is a potent inducer of angiogenesis. However, interleukin-8 (IL-8), an important angiogenic mediator, has been reported to be downregulated by HIF-1, although the mechanisms have not been elucidated. HIF-1 was induced in human endothelial cells by hypoxia and dimethyloxaloylglycine (DMOG). Interestingly, both hypoxia and DMOG attenuated IL-8 expression, and a similar effect has been obtained by adenoviral overexpression of the stable form of HIF-1alpha. Heme oxygenase-1 (HO-1) expression was also downregulated by HIF-1 induction. This suggests similar mechanisms of regulation of IL-8 and HO-1, indicating the involvement of Nrf2, a transcription factor previously linked to hypoxia-mediated inhibition of HO-1. Indeed, HIF-1-mediated downregulation of both IL-8 and HO-1 was associated with both lowered Nrf2 expression and induction of Bach1, a repressor of Nrf2 transcriptional activity. Accordingly, overexpression of Nrf2 reversed the inhibitory effect of HIF-1 on IL-8 and HO-1 expression. However, neither overexpression of HO-1 nor HO-1 inhibition affected IL-8 synthesis. The data indicate that HIF-1-dependent inhibition of IL-8 expression is caused by downregulation of Nrf2. However, expression of IL-8 is independent of HO-1. Cross-talk between HIF-1 and Nrf2 may influence the outcome of anti-angiogenic therapies aimed at targeting HIF-1. Antioxid.
Loboda
Agnieszka
A
Department of Medical Biotechnology, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
Stachurska
Anna
A
Florczyk
Urszula
U
Rudnicka
Dominika
D
Jazwa
Agnieszka
A
Wegrzyn
Joanna
J
Kozakowska
Magdalena
M
Stalinska
Krystyna
K
Poellinger
Lorenz
L
Levonen
Anna-Liisa
AL
Yla-Herttuala
Seppo
S
Jozkowicz
Alicja
A
Dulak
Jozef
J
D000818:Animals; D001483:Base Sequence; D050976:Basic-Leucine Zipper Transcription Factors / Q000096:biosynthesis; D002478:Cells, Cultured; D017931:DNA Primers; D024202:Electrophoretic Mobility Shift Assay; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D051856:Fanconi Anemia Complementation Group Proteins / Q000096:biosynthesis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis* / Q000235:genetics; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018808:Transcription Factor AP-1 / Q000378:metabolism
C102108:BACH1 protein, human; D050976:Basic-Leucine Zipper Transcription Factors; D017931:DNA Primers; D051856:Fanconi Anemia Complementation Group Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016209:Interleukin-8; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495635:NFE2L2 protein, human; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1