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.

Increased Intracellular Oxygen Radical Production in Neutrophils During Febrile Episodes of Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis Syndrome

“…Stojanov and colleagues demonstrated that the levels of IL-1␤ mRNA were increased during PFAPA syndrome flares (10). Although this finding was not corroborated by a finding of increased levels of IL-1␤ protein in the serum (9-11), the results of our studies and those of other investigators have suggested that IL-1␤ may regulate apoptosis (48)(49)(50). In a recent study by Blomgran et al, increased IL-1␤ plasma levels were detected in patients with genetic variations in the NALP3 inflammasome, correlating with decreased rates of PMN apoptosis (48).…”

Virus-Infected Alveolar Epithelial Cells Direct Neutrophil Chemotaxis and Inhibit Their Apoptosis

“…Infectious and heat-inactivated RSV directly inhibits PMN apoptosis through activation of PI3Kand NF-kB-dependent prosurvival pathways (28). Furthermore, RSV induces expression of IL-6 by PMNs, which may provide autocrine regulation of PMN survival (28,34,35). In contrast to RSV, influenza A virus enhances PMN apoptosis in vitro (36).…”

“…In addition to CXC chemokines, PMN apoptosis is also inhibited by cytokines, including GM-CSF, G-CSF, IL-1b, IL-6, IFN-g, TNF-a, and IL-15 (35,39,40). In contrast, other proinflammatory cytokines, such as TNF-a and IL-6, significantly induce PMN apoptosis (41)(42)(43).…”

International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the Formyl Peptide Receptor (FPR) Family

“…Neutrophils released to blood circulation have a half-life of 8 to 10 h. If not activated, these cells are destined for apoptosis (Savill, 1997). Stimulation of neutrophils with proinflammatory cytokines such as granulocyte macrophage-colony-stimulating factor, G-CSF, and IL-1␤, but not with fMLF, C5a, or IL-8, prolongs the lifespan of neutrophils (Colotta et al, 1992). Other reports have shown that stimulation of neutrophils with fMLF can induce apoptosis, and this process requires superoxide generation (Kettritz et al, 1997).…”