title: Nonphagocytic oxidase 1 causes death in lung epithelial cells via a TNF-RI-JNK signaling axis.
abstract: 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 H(2)O(2), TNF-alpha-induced NF-kappaB 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-alpha-induced inhibitor of kappaB kinase (IKK), and NF-kappaB 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.
authors.affiliation: Department of Pathology, University of Vermont College of Medicine, 89 Beaumont Avenue, HSRF 216A, Burlington, VT 05405, USA.
authors.forename: Cristen
authors.initials: C
authors.lastname: Pantano
authors.forename: Vikas
authors.initials: V
authors.lastname: Anathy
authors.forename: Priya
authors.initials: P
authors.lastname: Ranjan
authors.forename: Nicholas H
authors.initials: NH
authors.lastname: Heintz
authors.forename: Yvonne M W
authors.initials: YM
authors.lastname: Janssen-Heininger
mesh_terms: D000818:Animals; D016923:Cell Death; D002460:Cell Line; D008168:Lung / Q000166:cytology / Q000201:enzymology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D051379:Mice; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism* / Q000502:physiology; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases / Q000378:metabolism* / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D020545:Respiratory Mucosa / Q000166:cytology / Q000201:enzymology*; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D017382:Reactive Oxygen Species; D047888:Receptors, Tumor Necrosis Factor, Type I; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; D009247:NADH, NADPH Oxidoreductases; D000074624:NADPH Oxidase 1; D019255:NADPH Oxidases; C402799:NOX1 protein, human; C000614711:NOX1 protein, mouse; D048670:MAP Kinase Kinase 4