Modulation of granulocyte survival and programmed cell death by cytokines and bacterial products

Abstract

Mature circulating polymorphonuclear cells (PMN) have the shortest half- life among leukocytes and undergo rapid programmed cell death in vitro. In this study, we have examined the possibility that inflammatory signals (cytokines and bacterial products) can regulate PMN survival. PMN in culture were found to rapidly die, with percentages of survival at 24, 48, 72, and 96 hours of 97.3% +/- 1.9%, 36.8% +/- 5.3%, 14.5% +/- 3.1%, and 4.2% +/- 2.9%, respectively (mean +/- SE of 20 different donors). PMN incubated with interleukin-1 beta (IL-1 beta), tumor necrosis factor, granulocyte-macrophage colony-stimulating factor (CSF), granulocyte-CSF, and interferon-gamma (IFN-gamma), but not with prototypic chemoattractants (fMLP, recombinant C5a, and IL-8), showed a marked increase in survival, with values ranging at 72 hours of incubation from 89.5% +/- 5.8% for IL-1 beta to 47.6% +/- 6.4% for IFN- gamma. The calculated half-life was 35 hours for untreated and 115 hours for IL-1-treated PMN. PMN activated with lipopolysaccharide (LPS) or inactivated streptococci also showed a longer survival compared with untreated cells (94.4% +/- 3.2% and 95.5% +/- 2.4%, respectively, at 72 hours). PMN surviving in response to LPS or IL-1 beta retained the capacity to produce superoxide anion when treated with phorbol esters or fMLP. All inducers of PMN survival protect these cells from programmed cell death because they reduced cells with morphologic features of apoptosis and the fragmentation of DNA in multiples of 180 bp. Thus, certain cytokines and bacterial products can prolong PMN survival by interfering with the physiologic process of apoptosis. Prolongation of survival may be important for the regulation of host resistance and inflammation, and may represent a crucial permissive step for certain cytokines and microbial products that activate gene expression and function in PMN.

Human Mesenchymal Stem Cells Inhibit Neutrophil Apoptosis: A Model for Neutrophil Preservation in the Bone Marrow Niche

“…The antiapopotic effects of MSC were of similar magnitude and duration as those reported by other investigators upon neutrophil incubation with various cytokines, including IL‐1β, TNF, IL‐6, interferon‐γ, granulocyte colony‐stimulating factor, and granulocyte macrophage–colony‐stimulating factor [49, 50]. In analogy to our findings, cytokine‐driven rescue of neutrophils from apoptosis occurred through rapid modulation of Bax and MCL‐1 [47].…”

Storage of G–CSF‐mobilized granulocyte concentrates

“…Other studies have shown that when granulocytes are stored in solutions containing G–CSF or dexamethasone, apoptosis is delayed, and cell viability and function can be maintained for more than 48 hours 11,12 . These studies differed from the current study in several ways: donors were not given G–CSF or dexamethasone, but these agents were added to the granulocytes during storage; granulocytes were separated from RBCs, platelets, and lymphocytes; and granulocytes were stored in culture media at a much lower cell concentration.…”

“…When granulocytes are incubated with G–CSF or dexamethasone, apoptosis is delayed and in vitro survival prolonged 11,12 . When granulocyte donors are given G–CSF plus dexamethosone, in vivo granulocyte survival is prolonged 13 .…”

“…However, these studies tested granulocytes under conditions that differ markedly from the storage conditions of granulocyte concentrates. Such studies assessed the effects of G–CSF on granulocyte apoptosis using isolated cells at concentrations of approximately 5 to 10 × 10 9 cells per L 11,12 . However, granulocyte concentrates collected from donors given G–CSF plus dexamethasone can contain as many as 10.0 × 10 10 WBCs in 0.2 to 0.3 L of plasma, and cell concentrations may be as high as 300 to 500 × 10 9 cells per L. In addition, granulocyte concentrates contain approximately 30 mL of RBCs and approximately 4.0 × 10 11 platelets.…”

Managing passively acquired autoimmune neonatal neutropenia: a case study

“…This resulted in the desired correction of both parameters. A possible explanation is that recommencing G‐CSF increased the number of circulating neutrophils (Demetri & Griffin, 1991) and delayed neutrophil apoptosis (Colotta et al ., 1992) thereby allowing the maternal antibody to be mopped up.…”