TNF-alpha preserves lysosomal stability in macrophages: a potential defense against oxidative lung injury.
Iron-catalyzed oxidative damage on the respiratory epithelium is prevented by alveolar macrophages depositing iron inside their lysosomes. Bound in an un-reactive state to various metalloproteins, e.g. ferritin, most lysosomal iron is kept separated from reactive oxygen species (ROS) by intracellular anti-oxidative enzyme systems. Some ROS may, however, escape this protective shield of antioxidants, react with small amounts of free redox-active iron within lysosomes, thereby causing peroxidative damage on lysosomes and possibly also ensuing cell death. Since macrophages, containing large amounts of lysosomal iron, are very resistant to TNF-alpha, we hypothesized that this cell type has developed specific defense mechanisms against TNF-alpha-induced ROS generation. Murine macrophages were exposed (or not) to non-toxic concentrations of TNF-alpha and/or iron and were then challenged with H(2)O(2). Iron-exposed oxidatively stressed cells exhibited extensive lysosomal disruption resulting in pronounced cell death. In contrast, TNF-alpha stabilized lysosomes and protected cells, particularly those iron-exposed, by reducing cellular iron and increasing H-ferritin. Intracellular generation of H(2)O(2) under oxidative stress was kept unchanged by TNF-alpha and/or iron. However, TNF-alpha increased basal levels of glutathione by up-regulating the synthesis of gamma-glutamylcystein synthetase, thereby strengthening the anti-oxidative capacity. TNF-alpha inhibitors would block this novel anti-oxidative defense system, possibly explaining their adverse effects on the lung.
Persson
H Lennart
HL
Division of Pulmonary Medicine, Faculty of Health Sciences, University of Linköping, Linköping, Sweden. Lennart.Persson@lio.se
Vainikka
Linda K
LK
D000818:Animals; D001052:Apoferritins / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D055370:Lung Injury / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D016877:Oxidants / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
D016877:Oxidants; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D001052:Apoferritins; D006861:Hydrogen Peroxide; D007501:Iron; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione