Role of oxidants in NF-kappa B activation and TNF-alpha gene transcription induced by hypoxia and endotoxin

  • Chandel N
  • Trzyna W
  • McClintock D
 et al. 
  • 68

    Readers

    Mendeley users who have this article in their library.
  • N/A

    Citations

    Citations of this article.

Abstract

The transcription factor NF-kappa B stimulates the transcription of proinflammatory cytokines including TNF-alpha, LPS (endotoxin) and hypoxia both induce NF-kappa B activation and TNF-alpha gene transcription. Furthermore, hypoxia augments LPS induction of TNF-alpha mRNA. Previous reports have indicated that antioxidants abolish NF-kappa B activation in response to LPS or hypoxia, which suggests that reactive oxygen species (ROS) are involved in NF-kappa B activation. This study tested whether mitochondrial ROS are required for both NF-kappa B activation and the increase in TNF-alpha mRNA levels during hypoxia and LPS, Our results indicate that hypoxia (1.5% O-2) stimulates NF-kappa B and TNF-alpha gene transcription and increases ROS generation as measured by the oxidant sensitive dye 2',7'-dichlorofluorescein diacetate in murine macrophage J774.1 cells. The antioxidants N-acetylcysteine and pyrrolidinedithiocarbamic acid abolished the hypoxic activation of NF-kappa B, TNF-alpha gene transcription, and increases in ROS levels. Rotenone, an inhibitor of mitochondrial complex I, abolished the increase in ROS signal, the activation of NF-kappa B, and TNF-alpha gene transcription during hypoxia. LPS stimulated NF-kappa B and TNF-alpha gene transcription but not ROS generation in J774.1 cells. Rotenone, pyrrolidinedithiocarbamic acid, and N-acetylcysteine had no effect on the LPS stimulation of NF-kappa B and TNF-alpha gene transcription, indicating that LPS activates NF-kappa B and TNF-alpha gene transcription through a ROS-independent mechanism. These results indicate that mitochondrial ROS are required for the hypoxic activation of NF-kappa B and TNF-LU gene transcription, but not for the LPS activation of NF-kappa B.

Author-supplied keywords

  • antioxidant treatment
  • binding-protein
  • expression
  • human septic shock
  • hydrogen-peroxide
  • intact-cells
  • lipopolysaccharide
  • organ failure
  • oxidative stress
  • tumor-necrosis-factor

Get free article suggestions today

Mendeley saves you time finding and organizing research

Sign up here
Already have an account ?Sign in

Find this document

Authors

  • N S Chandel

  • W C Trzyna

  • D S McClintock

  • P T Schumacker

Cite this document

Choose a citation style from the tabs below

Save time finding and organizing research with Mendeley

Sign up for free