title: p38 Mitogen-activated protein kinase and phosphatidylinositol 3-kinase activities have opposite effects on human neutrophil apoptosis.
abstract: Neutrophil apoptosis is essential for resolution of inflammatory reactions. Here, we studied the role of two apoptosis/survival-associated protein kinases in this process. We discovered a previously undetected early and transient inhibition of the activity of p38 mitogen-activated protein kinase (p38 MAPK) during both spontaneous and Fas-induced apoptosis. Pharmacological inhibition of this enzyme augmented the activation of caspases and the apoptotic response, which suggests that the p38 MAPK signals survival in neutrophils. Our finding that caspase-3 activity was initiated during the transient inhibition of p38 MAPK suggests that apoptosis is initiated during this inhibition. Furthermore, such transient inhibition was counteracted by granulocyte-macrophage colony-stimulating factor, which elicits survival. We also found that neither this inhibition of p38 MAPK nor the spontaneous apoptotic response depended on Fas. Instead, the early inhibition of p38 MAPK concurred with a Fas-induced activation of phosphatidylinositol 3-kinase, inhibition of which reduced apoptosis. Thus, the Fas-induced augmentation of spontaneous apoptosis can be explained by its activation of phosphatidylinositol 3-kinase. We conclude that p38 MAPK activity represents a survival signal 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.
authors.affiliation: Experimental Pathology, Department of Laboratory Medicine, Lund University, U-MAS, S-205 02 Malmö, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Alvarado-Kristensson
authors.forename: M Isabella
authors.initials: MI
authors.lastname: Porn-Ares
authors.forename: Simone
authors.initials: S
authors.lastname: Grethe
authors.forename: David
authors.initials: D
authors.lastname: Smith
authors.forename: Limin
authors.initials: L
authors.lastname: Zheng
authors.forename: Tommy
authors.initials: T
authors.lastname: Andersson
mesh_terms: D000906:Antibodies / Q000494:pharmacology; D017209:Apoptosis; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D002470:Cell Survival; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007700:Kinetics; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D008954:Models, Biological; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D009842:Oligopeptides / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines / Q000494:pharmacology; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D000906:Antibodies; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D004791:Enzyme Inhibitors; D007093:Imidazoles; D020928:Mitogen-Activated Protein Kinases; D009842:Oligopeptides; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines; D019014:fas Receptor; D048051:p38 Mitogen-Activated Protein Kinases; C425644:isoleucyl-glutamyl-threonyl-aspartic acid fluoromethyl ketone; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; C093642:SB 203580