T. Hellwig-burgel et al., Interleukin-1 beta and tumor necrosis factor-alpha stimulate DNA binding of hypoxia-inducible factor-1, BLOOD, 94(5), 1999, pp. 1561-1567
The rate of transcription of several genes encoding proteins involved in O-
2 and energy homeostasis is controlled by hypoxia-inducible factor-1 (HIF-1
), a heterodimeric DNA binding complex composed of alpha and beta subunits.
HIF-1 is considered the primary trans-acting factor for the erythropoietin
(EPO) and vascular endothelial growth factor (VEGF) genes. Since EPO gene
expression is inhibited by the proinflammatory cytokines interleukin-1 beta
(IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha), while no such eff
ect has been reported with respect to the VEGF gene, we investigated the ef
fects of IL-1 beta and TNF-alpha on the activation of the HIF-1 DNA-binding
complex and the amount of HIF-1 alpha protein in human hepatoma cells in c
ulture. Under normoxic conditions, both cytokines caused a moderate activat
ion of HIF-1 DNA binding. In hypoxia, cytokines strongly increased HIF-1 ac
tivity compared with the effect of hypoxia alone, Only IL-1 beta increased
HIF-1 alpha. protein levels. In transient transfection experiments, HIF-1-d
riven reporter gene expression was augmented by cytokines only under hypoxi
c conditions. In contrast to their effect on EPO synthesis, neither IL-1 be
ta nor TNF-alpha decreased VEGF production. The mRNA levels of HIF-1 alpha
and VEGF were unaffected. Thus, cytokine-induced inhibition of EPO producti
on is not mediated by impairment of HIF-1 function. We propose that HIF-1 m
ay be involved in modulating gene expression during inflammation. (C) 1999
by The American Society of Hematology.