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Nonphagocytic oxidase 1 causes death in lung epithelial cells via a TNF-RI-JNK signaling axis

Cristen Pantano1, Vikas Anathy, Priya Ranjan

  • 1Department of Pathology, University of Vermont College of Medicine, 89 Beaumont Avenue, HSRF 216A, Burlington, VT 05405, USA.

American Journal of Respiratory Cell and Molecular Biology
|November 3, 2006
PubMed

Insights

Reactive oxygen species (ROS) produced by lung epithelial cells activate JNK signaling and cause cell death. This occurs through a pathway involving TNF receptor-1 (TNF-RI) and the TRAF2-ASK1 axis.

Area of Science:

  • Cellular Biology
  • Immunology
  • Respiratory Medicine

Background:

  • Airway epithelial cells encounter cytokines and reactive oxygen species (ROS) during inflammation.
  • Previous work showed hydrogen peroxide (H2O2) inhibited TNF-alpha-induced NF-kappaB but enhanced JNK activation via TNF receptor-1 (TNF-RI).

Purpose of the Study:

  • To investigate the effects of endogenously produced ROS on mouse alveolar type II epithelial cells.
  • To elucidate the signaling pathways involved in ROS-induced JNK activation and cell death.

Main Methods:

  • Utilized the nonphagocytic NADPH oxidase (Nox1) to generate endogenous ROS in epithelial cells.
  • Employed dominant-negative TNF-RI constructs and small interfering RNA (siRNA) for apoptosis signal kinase-1 (ASK1).

Main Results:

  • Nox1 expression inhibited TNF-alpha-induced IKK and NF-kappaB activation.
  • Nox1 promoted JNK activation and cell death, which were dependent on TNF-RI.
  • Nox1 signaling involved TNF-receptor-associated factor-2 (TRAF2) and ASK1, as Nox1-induced JNK activation and cell death were attenuated by ASK1 siRNA.

Conclusions:

  • Endogenously produced ROS activate JNK and induce cell death in lung epithelial cells.
  • The mechanism involves TNF-RI and the TRAF2-ASK1 signaling cascade.
  • This pathway highlights a critical role for ROS in inflammatory lung injury.

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