Fine Regulation of Neutrophil Oxidative Status and Apoptosis by Ceruloplasmin and Its Derivatives

• Published in: Cells (Basel, Switzerland) Vol. 7; no. 1; p. 8
• Main Authors: Golenkina, Ekaterina A, Viryasova, Galina M, Galkina, Svetlana I, Gaponova, Tatjana V, Sud'ina, Galina F, Sokolov, Alexey V
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 12.01.2018; MDPI
• Subjects: Acute phase proteins; Apoptosis; Ceruloplasmin; Copper; Intracellular; Lactoferrin; neutrophil; Neutrophils; Oxidation; Proteolysis; reactive oxygen species; Superoxide; Tumor necrosis factor-TNF; Tumor necrosis factor-α; ceruloplasmin; apoptosis; superoxide; neutrophil; reactive oxygen species
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells7010008

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.