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Nonphagocytic Oxidase 1 Causes Death in Lung Epithelial Cells via a TNF-RI–JNK Signaling Axis

Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont

Correspondence and requests for reprints should be addressed to Yvonne Janssen-Heininger, Ph.D., Department of Pathology, University of Vermont College of Medicine, 89 Beaumont Avenue, HSRF 216A, Burlington, VT 05405. E-mail: yvonne.janssen{at}uvm.edu

Airway epithelial cells are simultaneously exposed to and produce cytokines and reactive oxygen species (ROS) in inflammatory settings. The signaling events and the physiologic outcomes of exposure to these inflammatory mediators remain to be elucidated. Previously we demonstrated that in cultured mouse lung epithelial cells exposed to bolus administration of H₂O₂, TNF-–induced NF-B activity was inhibited, whereas c-Jun-N-terminal kinase (JNK) activation was enhanced via a mechanism involving TNF receptor-1 (TNF-RI). In this study we used the nonphagocytic NADPH oxidase (Nox1) to study the effects of endogenously produced ROS on a line of mouse alveolar type II epithelial cells. Nox1 expression and activation inhibited TNF-–induced inhibitor of B kinase (IKK), and NF-B while promoting JNK activation and cell death. Nox1-induced JNK activation and cell death were attenuated through expression of a dominant-negative TNF-RI construct, implicating a role for TNF-RI in Nox1 signaling. Furthermore, Nox1 used the TNF-RI adaptor protein TNF-receptor–associated factor-2 (TRAF2), and the redox-regulated JNK MAP3K, apoptosis signal kinase-1 (ASK1), to activate JNK. In addition, ASK1 siRNA attenuated both Nox1-induced JNK activity and cell death. Collectively, these studies suggest a mechanism by which ROS produced in lung epithelial cells activate JNK and cause cell death using TNF-RI and the TRAF2–ASK1 signaling axis.

Key Words: Nox1 • c-Jun-N-terminal kinase • hydrogen peroxide • cell death • TNF-RI

CLINICAL RELEVANCE JNK and NF-B pathways are plausible candidates for therapeutic intervention to control inflammation and epithelial cell death in patients with acute lung injury associated with enhanced oxidant production.

 

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