p38 mitogen-activated protein kinase and phosphatidylinositol 3-kinase activities have opposite effects on human neutrophil apoptosis

Citation
M. Alvarado-kristensson et al., p38 mitogen-activated protein kinase and phosphatidylinositol 3-kinase activities have opposite effects on human neutrophil apoptosis, FASEB J, 15(13), 2001, pp. NIL_95-NIL_116
Citations number
42
Categorie Soggetti
Experimental Biology
Journal title
FASEB JOURNAL
ISSN journal
08926638 → ACNP
Volume
15
Issue
13
Year of publication
2001
Pages
NIL_95 - NIL_116
Database
ISI
SICI code
0892-6638(200111)15:13<NIL_95:PMPKAP>2.0.ZU;2-V
Abstract
Neutrophil apoptosis is essential for resolution of inflammatory reactions. Here, we studied the role of two apoptosis/survival-associated protein kin ases in this process. We discovered a previously undetected early and trans ient inhibition of the activity of p38 mitogen-activated protein kinase (p3 8 MAPK) during both spontaneous and Fas-induced apoptosis. Pharmacological inhibition of this enzyme augmented the activation of caspases and the apop totic response, which suggests that the p38 MAPK signals survival in neutro phils. Our finding that caspase-3 activity was initiated during the transie nt inhibition of p38 MAPK suggests that apoptosis is initiated during this inhibition. Furthermore, such transient inhibition was counteracted by gran ulocyte-macrophage colony-stimulating factor, which elicits survival. We al so found that neither this inhibition of p38 MAPK nor the spontaneous apopt otic response depended on Fas. Instead, the early inhibition of p38 MAPK co ncurred with a Fas-induced activation of phosphatidylinositol 3-kinase, inh ibition of which reduced apoptosis. Thus, the Fas-induced augmentation of s pontaneous apoptosis can be explained by its activation of phosphatidylinos itol 3-kinase. We conclude that p38 MAPK activity represents a survival sig nal that is inactivated transiently during both spontaneous and Fas-induced apoptosis, whereas Fas-induced phosphatidylinositol 3-kinase activity is a proapoptotic signal in isolated human neutrophils.