Recombinant human interleukin (IL)-1 beta-mediated regulation of hypoxia-inducible factor-1 alpha (HIF-1 alpha) stabilization, nuclear translocation and activation requires an antioxidant/reactive oxygen species (ROS)-sensitive mechanism

Eur Cytokine Netw. Apr-Jun 2002;13(2):250-60.

Abstract

Cytokine-mediated regulation of hypoxia-inducible factor-1 alpha (HIF-1 alpha) non-hypoxic stabilization, translocation and activation is not well characterized. Furthermore, evidence that reactive oxygen species (ROS) signaling mediates interleukin (IL)-1 beta-dependent regulation of HIF-1 alpha has yet to be ascertained in alveolar epithelial cells. Recombinant human IL-1 beta induced, in a time-dependent manner, the nuclear translocation of HIF-1 alpha, an effect associated with up-regulating the activity of this transcription factor under normoxic conditions. In addition, analysis of the mode of action of IL-1 beta revealed a novel induction of intracellular ROS, including hydrogen peroxide (H(2)O(2)), the superoxide anion (O(2)(-*)) and the hydroxyl radical (*OH). The antioxidants, dimethyl sulfoxide (DMSO) and 1,3-dimethyl-2-thiourea (DMTU), purported to be prototypical scavengers of H2O2 and *OH, attenuated, in a dose-dependent manner, IL-1 beta-induced HIF-1 alpha nuclear translocation and activation. The NADPH-oxidase inhibitor, 4'-hydroxy-3'-methoxy-acetophenone (HMAP), which may affect mitochondrial ROS production, attenuated IL-1 beta-mediated nuclear translocation and activation of HIF-1 alpha. Inhibition of the mitochondrion complex I nicotinamide adenine dinucleotide phosphate-dependent oxidase by diphenylene iodonium (DPI), which blocks the conversion of ubiquinone --> ubiquinol, abrogated IL-1 beta-dependent nuclear translocation and activation of HIF-1 alpha. Similarly, interrupting the respiratory chain with potassium cyanide reversed the excitatory effect of IL-1 beta on HIF-1 alpha nuclear translocation and activation. These results indicate that a non-hypoxic pathway mediates cytokine-dependent regulation of HIF-1 alpha translocation and activation in a ROS-sensitive mechanism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • Antioxidants / metabolism
  • Cells, Cultured
  • Fetus
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Interleukin-1 / pharmacology*
  • Kinetics
  • Pulmonary Alveoli
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism
  • Recombinant Proteins / pharmacology
  • Respiratory Mucosa / drug effects
  • Respiratory Mucosa / physiology*
  • Transcription Factors / metabolism*

Substances

  • Antioxidants
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Interleukin-1
  • Reactive Oxygen Species
  • Recombinant Proteins
  • Transcription Factors