Granulocyte-Macrophage Colony-Stimulating Factor Delays Neutrophil Constitutive Apoptosis Through Phosphoinositide 3-Kinase and Extracellular Signal-Regulated Kinase Pathways

Abstract

Activated neutrophils play an important role in the pathogenesis of sepsis, glomerulonephritis, acute renal failure, and other inflammatory processes. The resolution of neutrophil-induced inflammation relies, in large part, on removal of apoptotic neutrophils. Neutrophils are constitutively committed to apoptosis, but inflammatory mediators, such as GM-CSF, slow neutrophil apoptosis by incompletely understood mechanisms. We addressed the hypothesis that GM-CSF delays neutrophil apoptosis by activation of extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI 3-kinase) pathways. GM-CSF (20 ng/ml) significantly inhibited neutrophil apoptosis (GM-CSF, 32 vs 65% of cells p < 0.0001). GM-CSF activated the PI 3-kinase/Akt pathway as determined by phosphorylation of Akt and BAD. GM-CSF-dependent Akt and BAD phosphorylation was blocked by the PI 3-kinase inhibitor LY294002. A role for the PI 3-kinase/Akt pathway in GM-CSF-stimulated delay of apoptosis was indicated by the ability of LY294002 to attenuate apoptosis delay. GM-CSF-dependent inhibition of apoptosis was significantly attenuated by PD98059, an ERK pathway inhibitor. LY294002 and PD98059 did not produce additive inhibition of apoptosis delay. To determine whether PI 3-kinase and ERK are used by other ligands that delay neutrophil apoptosis, we examined the role of these pathways in IL-8-induced apoptosis delay. LY294002 blocked IL-8-dependent Akt phosphorylation. PD98059 and LY294002 significantly attenuated IL-8 delay of apoptosis. These results indicate IL-8 and GM-CSF act, in part, to delay neutrophil apoptosis by stimulating PI 3-kinase and ERK-dependent pathways.

Aspirin-Triggered Lipoxins Override the Apoptosis-Delaying Action of Serum Amyloid A in Human Neutrophils: A Novel Mechanism for Resolution of Inflammation

“…Neutrophil apoptosis is controlled by a complex network of signaling pathways, including the ERK, Akt, and p38 MAPK pathways (30,32,35,38). The present study provides evidence that SAA also uses these pathways.…”

“…However, the combination of PD98059 with wortmannin did not produce an additive inhibition, indicating that ERK1/2 and Akt work in concert to delay PMN apoptosis. Transient activation of PI3K without ERK activation may not be sufficient to delay apoptosis (38). The role of p38 MAPK in the regulation of PMN apoptosis has been a matter of controversy, for both proapoptosis (30,32,39) and antiapoptosis actions (40) have been reported.…”

Angiotensin II in apoptotic lung injury: potential role in meconium aspiration syndrome

“…11 This accumulation is due in part to delayed neutrophil apoptosis,; in addition, apoptosis of epithelial cells is enhanced at the same site. [12][13][14] BAL fluids from patients with ARDS had elevated levels of granulocyte/macrophage colony-stimulating factor that inhibits neutophil apoptosis through phosphoinositide 3-kinase and ERK pathway 15,16 and stabilizes the factor Mcl-1 that is crucial for the delay of apoptosis initiated by antiapoptotic factors. 17,18 BAL fluids from patients with ARDS was also cytotoxic to lung microvascular endothelial cells due to the presence of TNF-a and angiostatin, an inhibitor of angiogenesis in vivo.…”

High insulin enhances neutrophil transendothelial migration through increasing surface expression of platelet endothelial cell adhesion molecule-1 via activation of mitogen activated protein kinase

“…The PMN transendothelial migration enhanced by high insulin might account for the high incidence of atherosclerotic diseases such as AMI and stroke in patients with diabetes, because PMN transendothelial migration seems to contribute to the formation of atherosclerotic plaques and their disruption [4,13]. There is growing evidence supporting a close relation between atherosclerosis and PMN activation and migration [11,12,22,23,24,25,26,27]. Firstly, atherosclerosis has been reported to be characterized by monocyte infiltration which can be mediated by the neutrophil-induced release of endothelial monocyte-chemoattractant protein-1 [22].…”

“…Cells were treated without (control) or with anisomycin at doses ranging from 0.01 to 10 µmol/l for 3 h. Values are expressed as means ± SEM. **p<0.01, ***p<0.001 compared to respective control gration seems to be crucial for the progression of atherosclerotic plaques because their delayed apoptosis after migration results in the maintenance of oxygen radicals and chemoattractant release leading to enhanced cytotoxicity and subsequent tissue damage, that predispose to cause plaque disruption [25,26,27].…”