Interleukin-1β and Tumor Necrosis Factor-α Stimulate DNA Binding of Hypoxia-Inducible Factor-1

• Published in: Blood Vol. 94; no. 5; pp. 1561 - 1567
• Main Authors: Hellwig-Bürgel, Thomas, Rutkowski, Karen, Metzen, Eric, Fandrey, Joachim, Jelkmann, Wolfgang
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 01.09.1999; The Americain Society of Hematology
• Subjects: Biological and medical sciences; Fundamental and applied biological sciences. Psychology; Inflammation; Molecular and cellular biology; Human; Oxygen; Erythropoietin; Cytokine; Interleukin 1β; Inflammation; Glycoprotein hormone; Gene expression; In vitro; Biological activity; Signal transduction; Vascular endothelium growth factor; Gene; Established cell line; Hypoxia; Transcription factor HIF1; Transcription factor; Tumor necrosis factor α
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V94.5.1561

The rate of transcription of several genes encoding proteins involved in O2 and energy homeostasis is controlled by hypoxia-inducible factor-1 (HIF-1), a heterodimeric DNA binding complex composed of α and β subunits. HIF-1 is considered the primarytrans-acting factor for the erythropoietin (EPO) and vascular endothelial growth factor (VEGF) genes. Since EPO gene expression is inhibited by the proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), while no such effect has been reported with respect to the VEGF gene, we investigated the effects of IL-1β and TNF-α on the activation of the HIF-1 DNA-binding complex and the amount of HIF-1α protein in human hepatoma cells in culture. Under normoxic conditions, both cytokines caused a moderate activation of HIF-1 DNA binding. In hypoxia, cytokines strongly increased HIF-1 activity compared with the effect of hypoxia alone. Only IL-1β increased HIF-1α protein levels. In transient transfection experiments, HIF-1–driven reporter gene expression was augmented by cytokines only under hypoxic conditions. In contrast to their effect on EPO synthesis, neither IL-1β nor TNF-α decreased VEGF production. The mRNA levels of HIF-1α and VEGF were unaffected. Thus, cytokine-induced inhibition of EPO production is not mediated by impairment of HIF-1 function. We propose that HIF-1 may be involved in modulating gene expression during inflammation.