Timely neutrophil apoptosis is an essential part of the resolution phase of acute inflammation. Ceruloplasmin, an acute-phase protein, which is the predominant copper-carrying protein in the blood, has been suggested to have a marked effect on neutrophil life span. The present work is a comparative study on the effects of intact holo-ceruloplasmin, its copper-free (apo-) and partially proteolyzed forms, and synthetic free peptides RPYLKVFNPR (883–892) and RRPYLKVFNPRR (882–893) on polymorphonuclear leukocyte (PMNL, neutrophil) oxidant status and apoptosis. The most pronounced effect on both investigated parameters was found with copper-containing samples, namely, intact and proteolyzed proteins. Both effectively reduced spontaneous and tumor necrosis factor-α (TNF-α)-induced extracellular and intracellular accumulation of superoxide radicals, but induced a sharp increase in the oxidation of intracellular 2′,7′-dichlorofluorescein upon short exposure. Therefore, intact and proteolyzed ceruloplasmin have both anti- and pro-oxidant effects on PMNLs wherein the latter effect is diminished by TNF-α and lactoferrin. Additionally, all compounds investigated were determined to be inhibitors of delayed spontaneous apoptosis. Intact enzyme retained its pro-survival activity, whereas proteolytic degradation converts ceruloplasmin from a mild inhibitor to a potent activator of TNF-α-induced neutrophil apoptosis.
Background:
Nitric Oxide (NO) is a key signalling molecule that has an important role in
inflammation. It can be secreted by endothelial cells, neutrophils, and other cells, and once in circulation,
NO plays important roles in regulating various neutrophil cellular activities and fate.
Objective:
To describe neutrophil cellular responses influenced by NO and its concomitant compound
peroxynitrite and signalling mechanisms for neutrophil apoptosis.
Methods:
Literature was reviewed to assess the effects of NO on neutrophils.
Results:
NO plays an important role in various neutrophil cellular activities and interaction with other
cells. The characteristic cellular activities of neutrophils are adhesion and phagocytosis. NO plays a protective
role in neutrophil-endothelial interaction by preventing neutrophil adhesion and endothelial cell
damage by activated neutrophils. NO suppresses neutrophil phagocytic activity but stimulates longdistance
contact interactions through tubulovesicular extensions or cytonemes. Neutrophils are the main
source of superoxide, but NO flow results in the formation of peroxynitrite, a compound with high biological
activity. Peroxynitrite is involved in the regulation of eicosanoid biosynthesis and inhibits endothelial
prostacyclin synthase. NO and peroxynitrite modulate cellular 5-lipoxygenase activity and leukotriene
synthesis. Long-term exposure of neutrophils to NO results in the activation of cell death mechanisms
and neutrophil apoptosis.
Conclusion:
Nitric oxide and the NO/superoxide interplay fine-tune mechanisms regulating life and
death in neutrophils.
In the present study we have presented data on the regulation of LT (leukotriene) and 5-oxo-ETE (5-oxo-6,8,11,14-eicosatetraenoic acid) syntheses in human neutrophils upon interaction with OZ (opsonized zymosan) or Salmonella typhimurium. Priming of neutrophils with PMA (phorbol 12-myristate 13-acetate) and LPS (lipopolysaccharide) elicits 5-oxo-ETE formation in neutrophils exposed to OZ, and the addition of AA (arachidonic acid) significantly increases 5-oxo-ETE synthesis. We found that NO (nitric oxide)-releasing compounds induce 5-oxo-ETE synthesis in neutrophils treated with OZ or S. typhimurium. Exposure of neutrophils to zymosan or bacteria in the presence of the NO donor DEA NONOate (1,1-diethyl-2-hydroxy-2-nitroso-hydrazine sodium) considerably increased the conversion of endogenously formed 5-HETE (5S-hydroxy-6,8,11,14-eicosatetraenoic acid) to 5-oxo-ETE. To our knowledge, this study is the first to demonstrate that NO is a potent regulator of 5-oxo-ETE synthesis in human polymorphonuclear leucocytes exposed to Salmonella typhimurium and zymosan.
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