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-α (TNF-α)-dependent regulation of hypoxia-inducible factor-1α (HIF-α) was investigated in vitro. TNF-α mediated the translocation of HIF-1α, associated with up-regulating its activity under normoxia. Analysis of the mode of action of TNF-α revealed the accumulation of hydrogen peroxide (H₂O₂), superoxide anion (O₂^-•) and hydroxyl radical (^•OH). Antioxidants purported as prototypical scavengers of H₂O₂ and ^•OH, attenuated TNF-α-induced HIF-1α activation, and blockading NADPH-oxidase by scavenging O₂^-• reduced the activity of HIF-1α. Inhibition of the mitochondrion complex I abrogated TNF-α-dependent activation of HIF-1α. Interrupting the respiratory chain reversed the excitatory effect of TNF-α on HIF-1α. These results indicate a non-hypoxic pathway mediating cytokine-dependent regulation of HIF-1α in a ROS-sensitive mechanism.