Differential susceptibility to nitric oxide-evoked apoptosis in human inflammatory cells.
Apoptosis of neutrophils and their subsequent phagocytosis is critical to the successful resolution of inflammation. During inflammation, activated inflammatory cells generate reactive oxygen and nitrogen species, including nitric oxide (NO) and superoxide anion (O(2)(•-)), which rapidly combine to generate peroxynitrite (ONOO(-)). NO and ONOO(-) are proapoptotic in human neutrophils. This study examines the effects of NO and ONOO(-) on caspase activation and mitochondrial permeability in human neutrophils and determines the ability of these species to evoke apoptosis in human monocyte-derived macrophages (MDMs). NO or ONOO(-) release from donor compounds was characterized by electrochemistry and electron paramagnetic resonance. Neutrophils and MDMs isolated from the peripheral blood of healthy volunteers were exposed to NO or ONOO(-) before analysis of apoptosis by caspase activation, mitochondrial permeability, and annexin V binding. Both NO and ONOO(-) induced apoptosis via rapid activation of caspases 2 and 3 in neutrophils. In contrast, only ONOO(-) promoted apoptosis in MDMs, whereas a variety of NO donors were ineffective at inducing apoptosis in this cell type. We propose that human macrophages are refractory to NO-stimulated apoptosis in order that they persist long enough within the inflammatory focus to phagocytose apoptotic neutrophils, thereby ensuring successful resolution of inflammation.
Shaw
Catherine A
CA
Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh EH16 4TJ, UK. catherine.shaw@ed.ac.uka
Taylor
Emma L
EL
Fox
Sarah
S
Megson
Ian L
IL
Rossi
Adriano G
AG
D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D004351:Drug Resistance / Q000276:immunology / Q000502:physiology; D004563:Electrochemistry; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010539:Permeability / Q000187:drug effects; D030421:Peroxynitrous Acid / Q000494:pharmacology
D020030:Nitric Oxide Donors; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D020169:Caspases