A non-hypoxic, ROS-sensitive pathway mediates TNF-α-dependent regulation of HIF-1α

A non-hypoxic, reactive oxygen species (ROS)sensitive pathway mediating tumor necrosis factor-alpha (TNF-alpha )dependent regulation of hypoxia-inducible factor-1 alpha (HIF-alpha) was investigated in vitro. TNF-alpha mediated the translocation of HIF-1 alpha, associated with up-regulating its activity under normoxia. Analysis of the mode of action of TNF-alpha revealed the accumulation of hydrogen peroxide (H2O2), superoxide anion (O-2(-.)) and hydroxyl radical ((OH)-O-.). Antioxidants purported as prototypical scavengers of H2O2 and (OH)-O-., attenuated TNF-alpha -induced HIF-1 alpha activation, and blockading NADPH-oxidase by scavenging O-2(.) reduced the activity of HIF-1 alpha. Inhibition of the mitochondrion complex I abrogated TNF-alpha -dependent activation of HIF-1 alpha. Interrupting the respiratory chain reversed the excitatory effect of TNF-alpha on HIF-1 alpha. These results indicate a non-hypoxic pathway mediating cytokine-dependent regulation of HIF-1 alpha in a ROS-sensitive mechanism. (C) 2001 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.