TNF-alpha preserves lysosomal stability in macrophages: A potential defense against oxidative lung injury
2010 (English)In: TOXICOLOGY LETTERS, ISSN 0378-4274, Vol. 192, no 2, 261-267 p.Article in journal (Refereed) Published
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 H2O2. 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 H2O2 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.
Place, publisher, year, edition, pages
2010. Vol. 192, no 2, 261-267 p.
Apoptosis, Ferritin, Inflammation, Lysosomes, Oxidative stress
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-54247DOI: 10.1016/j.toxlet.2009.10.031ISI: 000274743300025OAI: oai:DiVA.org:liu-54247DiVA: diva2:302304