Interleukin-1β and Tumor Necrosis Factor- Stimulate DNA Binding of Hypoxia-Inducible Factor-1
1999; Elsevier BV; Volume: 94; Issue: 5 Linguagem: Inglês
10.1182/blood.v94.5.1561.417a06_1561_1567
ISSN1528-0020
AutoresThomas Hellwig‐Bürgel, Karen Rutkowski, Eric Metzen, Joachim Fandrey, Wolfgang Jelkmann,
Tópico(s)Erythropoietin and Anemia Treatment
ResumoThe 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 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- (TNF-), while no such effect has been reported with respect to the VEGF gene, we investigated the effects of IL-1β and TNF- on the activation of the HIF-1 DNA-binding complex and the amount of HIF-1 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-1 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- decreased VEGF production. The mRNA levels of HIF-1 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.
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