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High Levels of Catalase and Glutathione Peroxidase Activity Dampen H₂O₂ Signaling in Human Alveolar Macrophages

Department of Medicine and Department of Radiation Oncology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, and Iowa City Veterans Administration Medical Center, Iowa City, Iowa

Address correspondence to: A. Brent Carter, M.D., Division of Pulmonary and Critical Care Medicine, C33 GH, University of Iowa Hospital and Clinics, 200 Hawkins Drive, Iowa City, IA 52242. E-mail: brent-carter{at}uiowa.edu

Results are presented which support the hypothesis that adequate steady-state levels of hydrogen peroxide (H₂O₂) are required to overcome the effects of high catalase and glutathione peroxidase (GPx) expression for p38 mitogen-activated protein (MAP) kinase activation and tumor necrosis factor (TNF)- gene expression in human alveolar macrophages stimulated with asbestos. We found significant differences in the types and amounts of reactive oxygen species generated in human blood monocytes compared with human alveolar macrophages. This difference in reactive oxygen species production is related, in part, to the differences in antioxidant enzyme expression and activity. Most importantly, catalase and GPx activities were significantly increased in alveolar macrophages compared with blood monocytes. Asbestos activated the p38 MAP kinase and induced TNF- gene expression only in blood monocytes. Increasing the steady-state levels of H₂O₂ by using polyethylene glycol superoxide dismutase, an antioxidant that crosses the cell membrane, or aminotriazole, an irreversible inhibitor of catalase, allowed the p38 MAP kinase to be activated in alveolar macrophages. In addition, asbestos-stimulated macrophages cultured with polyethylene glycol superoxide dismutase had a significant increase in gene expression mediated by the TNF- promoter. These results demonstrate that high catalase and GPx activity in human alveolar macrophages limits the effectiveness of H₂O₂ to act as a mediator of inflammatory gene expression.

Abbreviations: aminotriazole, ATZ • 5-(diethoxyphosphoryl)-5-methyl-1-pyrroline N-oxide, DEPMPO • dihydroethidium, DHE • 5,5-dimethyl-1-pyrroline N-oxide, DMPO • enzyme-linked immunosorbent assay, ELISA • electron spin resonance, ESR • glutathione peroxidase, GPx • Hanks' buffered saline solution, HBSS • horseradish peroxidase, HRP • lipopolysaccharide, LPS • mitogen-activated protein, MAP • nitroblue tetrazolium, NBT • superoxide anion, O₂·- • hydroxyl radical, OH· • phosphate-buffered saline, PBS • polyethylene glycol SOD, PEG-SOD • protein tyrosine phosphatase, PTP • reactive oxygen species, ROS • superoxide dismutase, SOD • tumor necrosis factor-, TNF-

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