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Abstract
Apoptosis regulation is essential for neutrophil homeostasis. We previously demonstrated that a process involving glycogen synthase kinase (GSK)-3β determines neutrophil apoptosis. As for this apoptotic process, an overdose of propofol (2,6-Diisopropylphenol; 25 μg/ml or 140 μM) also causes GSK-3β-mediated macrophage apoptosis; however, the early deactivation of GSK-3β with low-dose propofol has been shown. Therefore, we hypothesize that low-dose propofol may induce neutrophil survival via GSK-3β inactivation. Following in vitro culture, the therapeutic concentration of propofol (10 μg/ml or 56 μM) treatment decreased constitutive apoptosis in isolated human primary neutrophils and in granulocyte-differentiated HL60 cells after all-trans retinoic acid (1 μM) treatment. The inactivation of phosphatidylinositol 3-kinase (PI3-kinase)/AKT and the activation of GSK-3β results in myeloid cell leukemia 1 (Mcl-1) down-regulation, the loss of the mitochondrial transmembrane potential, and caspase-3 activation in these cells, which is accompanied by apoptosis. Notably, propofol treatment attenuates these effects in a PI3-kinase-regulated manner. We found that propofol initiates PI3-kinase/AKT-mediated GSK-3β inactivation and Mcl-1 stabilization, rescuing the constitutive apoptosis in primary neutrophils and granulocyte-differentiated acute promyelocytic leukemia HL60 cells.
Highlights
Neutrophils, called polymorphonuclear leukocytes (PMNs), are the major population of circulating leukocytes that participate in inflammation as the first line of defense against invading pathogens, exerting their effects through phagocytosis
Isolated human primary PMN cells were purified from the peripheral blood leukocyte (PBL) of whole blood [11] and the purity was confirmed by CD177 staining
These results indicate that propofol sequentially prevents constitutive apoptosis in primary neutrophils
Summary
Neutrophils, called polymorphonuclear leukocytes (PMNs), are the major population of circulating leukocytes that participate in inflammation as the first line of defense against invading pathogens, exerting their effects through phagocytosis. Propofol Inhibits Apoptosis in Neutrophils activation [1,2]. During inflammation and drug treatment, a prolong survival response can be found in neutrophils and its molecular mechanisms underlying cell survival are under investigation [1,2]. The anesthetic propofol (2,6-di(propan-2-yl)phenol), a short-acting and widely used, intravenously administered hypnotic/amnestic agent, has immunomodulating actions by modulating the production of pro-inflammatory mediators and responses in activated neutrophils [3]. A significant increase in the neutrophil count has been reported in patients with propofol sedation during gynecologic laparoscopy [6]. It is worth investigating the effects of propofol on the inflammatory activation and on the cell fate of neutrophils
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