Sustained nitric oxide delivery delays nitric oxide-dependent apoptosis in macrophages: contribution to the physiological function of activated macrophages.
Treatment of the macrophage cell line RAW 264.7 with the short-lived NO donor S-nitrosoglutathione triggers apoptosis through the release of mitochondrial mediators. However, continuous supply of NO by long-lived NO donors protected cells from apoptosis through mechanisms that involved the maintenance or an increase in the levels of the inhibitor of apoptosis proteins (IAPs) cIAP-1, cIAP-2, and xIAP and decreases in the accumulation of p53 and in the levels and targeting of Bax to the mitochondria. As a result of these changes, the activation of caspases 9 and 3 was notably delayed, expanding the time of viability of the macrophages. Moreover, inhibition of NO synthase 2 activity after 8 h of stimulation of RAW 264.7 cells with LPS and IFN-gamma accelerated apoptosis via an increase in the processing and activation of caspases. These data suggest that NO exerts an important role in the autoregulation of apoptosis in macrophages.
Hortelano
Sonsoles
S
Instituto de Bioquímica (Centro Mixto Consejo Superior de Investigaciones Científicas-Universidad Complutense) and Centro Nacional de Investigaciones Cardiovasculares, Facultad de Farmacia, Universidad Complutense, Madrid, Spain.
Través
Paqui G
PG
Zeini
Miriam
M
Alvarez
Alberto M
AM
Boscá
Lisardo
L
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D004789:Enzyme Activation / Q000502:physiology; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000502:physiology*; D051379:Mice; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D026422:S-Nitrosoglutathione / Q000494:pharmacology; D013997:Time Factors; D014226:Triazenes / Q000494:pharmacology
C105351:1-hydroxy-2-oxo-3,3-bis(2-aminoethyl)-1-triazene; D008070:Lipopolysaccharides; D020030:Nitric Oxide Donors; D014226:Triazenes; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; D007371:Interferon-gamma; C506434:Casp9 protein, mouse; D053453:Caspase 9; D020169:Caspases