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

FEBS Letters

Land, Stephen C¹  Haddad, John J¹ 

[1] Oxygen Signaling Group, Tayside Institute of Child Health, Faculty of Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK

关键词: Antioxidant;    Hypoxia-inducible factor-1α;    Mitochondrion;    Oxygen sensing;    Reactive oxygen species;    Tumor necrosis factor-α;   

DOI  :  10.1016/S0014-5793(01)02833-2

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

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.

【 授权许可】

Unknown