Role of Phosphoinositide 3-Kinase and Extracellular Signal-Regulated Kinase Pathways in Granulocyte Macrophage-Colony-Stimulating Factor Failure to Delay Fas-Induced Neutrophil Apoptosis in Elderly Humans

Abstract

Fas-stimulated neutrophils from elderly individuals show impaired granulocyte macrophage-colony-stimulating factor (GM-CSF)-induced apoptosis cell rescue. Herein, this defect was found to be associated with a significant reduction in GM-CSF-mediated Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. Using Akt and ERK1/2 inhibitors, we demonstrated that both kinases were critical for GM-CSF antiapoptotic effects. Whereas Akt inhibition also affected GM-CSF-dependent ERK1/2 phosphorylation, ERK1/2 inhibition did not affect GM-CSF-induced Akt phosphorylation, suggesting that phosphoinositide 3-kinase (PI3-K)/Akt and ERK1/2 are activated in series and that PI3-K is located upstream of ERK1/2 along the GM-CSF-dependent signaling pathway. No age-associated changes in GM-CSF receptor expression were observed. Interestingly, both suppressors of cytokine signaling (SOCS)1 and SOCS3 proteins were significantly higher in unstimulated neutrophils from elderly individuals and, unlike in young individuals, did not further increase following GM-CSF cell triggering. These results indicate that defective PI3-K/Akt/ERK1/2 activation, likely dependent on elevated SOCS1 and SOCS3 levels, may affect the GM-CSF capacity to delay neutrophil apoptosis in elderly persons.

Nutrition, diet and immunosenescence

“…Chemotaxis (Fortin et al, 2006;Fulop et al, 2004) and phagocytosis (Butcher et al, 2001;Wenisch et al, 2000) is decreased in healthy aged individuals and in advanced age there is delayed cellular apoptosis during inflammatory responses (Fortin et al, 2007;Fulop et al, 1997;Tortorella et al, 2001;Tortorella et al, 2006). Studies of ROS production by neutrophils in the elderly have produced conflicting findings with some showing an increased production (De la Fuente, 2008;Ogawa et al, 2008) whereas others have reported decreased production of superoxide and hydrogen peroxide (Di Lorenzo et al, 1999;Fulop et al, 1985;Nagel et al, 1982).…”

“…The use of different stimuli and bacterial strains in the different studies may explain these conflicting results. Age-related changes in intracellular signalling pathways have also been described including reduced phosphorylation of extracellular receptor-activated kinase (ERK) and mitogenactivated protein (MAP) (Fulop et al, 2004;Larbi et al, 2005), signal tyrosine phosphatase-1 (SHT-1), and suppressor of cytokine signalling (SOCS) (Tortorella et al, 2006).…”

Melatonin is able to delay endoplasmic reticulum stress-induced apoptosis in leukocytes from elderly humans

“…On the contrary, the age-related failure to rescue neutrophils from apoptotic cell death induced by pro-inflammatory mediators, such as GM-CSF, seems to be strictly related to an impairment of GM-CSF-dependent PI3-K/Akt and ERK1/2 activation (Tortorella et al 2006). In fact, we showed that melatonin is able to reverse the loss of mitochondrial membrane potential, as well as the subsequent caspase activation, evoked by intracellular calcium overload.…”

“…Despite the strict analogies between these alterations and the impaired functional capacities displayed by apoptotic neutrophils (Whyte et al 1993), some studies have recently reported that advanced age does not affect either spontaneous or Fas-induced apoptotic events (Larbi et al 2005;Tortorella et al 1998). Nevertheless, neutrophils from aged individuals show a diminished rescue capacity when challenged with pro-inflammatory stimuli, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), lipopolysaccharides (LPS), or interleukin-2 (IL-2) (Tortorella et al 1998(Tortorella et al , 2006.…”

Innate Immune Responses in the Geriatric Population

“…Data remain conflicting in the literature concerning their number and phagocytic functions. One suggested alteration is their propensity to undergo apoptosis because of augmented cell oxidative load and perturbation of anti-apoptotic/proapoptotic mechanisms (Tortorella et al, 2006). Several reports indicate reduced chemotaxis (Fulop et al, 2004), phagocytosis and production of superoxide anion.…”