Abstract
Normal spontaneous apoptosis in neutrophils is enhanced by "stress" stimuli such as tumor necrosis factor-alpha, Fas ligand, and oxidants, and this effect is inhibited by anti-apoptotic stimuli including granulocyte-macrophage colony-stimulating factor, lipopolysaccharide, and formylmethionine-leucine-phenylalanine. In this report we demonstrate that anti-apoptotic stimuli protect neutrophils from stress-induced apoptosis via activation of the ERK/MAPK pathway. The protection occurs downstream of mitochondrial alterations assessed as a decrease in membrane potential concomitant with enhanced cytochrome c release. ERK activation was shown to inhibit apoptosis by maintaining levels of XIAP, which is normally decreased in the presence of the pro-apoptotic/stress stimuli. This report also demonstrates that potent intra- and extracellular oxidants inhibit the protective effect of ERK. Oxidant-dependent inhibition of ERK was because of activation of p38 MAPK and activation of the protein phosphatases PP1 and PP2A. Our data suggest that ERK suppresses stress-induced apoptosis downstream of mitochondrial alterations by maintaining XIAP levels and that oxidants block this effect through activation of p38 and protein phosphatases.
Highlights
Apoptosis is an essential process for development, normal growth, and tissue homeostasis
We demonstrated that clustering of the 2 integrin inhibits stress-induced neutrophil apoptosis via the ERK pathway, apparently acting downstream of mitochondrial perturbation [2, 32]
We demonstrate here that stress-induced apoptosis was blocked by a variety of ERK-activating stimuli including growth factors (GM-CSF), ligands for serpentine G-protein-linked receptors, or Toll-like receptors (LPS) in circumstances where mitochondrial damage still occurred (Fig. 1)
Summary
Apoptosis is an essential process for development, normal growth, and tissue homeostasis. The apoptotic process in neutrophils is delayed by at least three major pathways involving 1) PI3K/Akt, 2) the mitogenactivated protein kinase (MAPK) of the extracellular signalregulated kinase (ERK) subgroup [7], and 3) activation of NF-B [8] These pathways block spontaneous apoptosis and prevent apoptosis induced by UV irradiation, TNF␣, or Fas ligation [5, 9]. XIAP is a potent inhibitor of apoptosis that directly binds to and inhibits caspase 3, 7, and 9 and has recently been implicated in protecting T-cells, epithelial cells, and bone marrow macrophages from a variety of pro-apoptotic/stress stimuli including dexamethasone, cisplatin, etoposide, and Fas ligation [13,14,15]. XIAP activity is regulated by the SMAC/DIABLO protein, which binds the baculoviral IAP repeat 3 domain and disassociates XIAP from the caspases [17]
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