Augmented intracellular glutathione inhibits Fas-triggered apoptosis of activated human neutrophils.
Agonist signals delivered through cell surface Fas induce apoptosis. However, the apoptotic program can be modulated by signals from the environment, and in particular, by signals delivered through adhesion molecules. Because neutrophil functional activity in inflammation is contingent on cell survival, and because circulating neutrophils normally die rapidly through a constitutively expressed apoptotic program, we evaluated Fas-mediated apoptosis in resting and inflammatory human neutrophils. We show that normal neutrophils respond to Fas engagement with accelerated rates of apoptosis, but cross-linking of beta2 integrins or priming with bacterial lipopolysaccharide (LPS) prevents this increase. Adhesion molecule cross-linking results in increased intracellular glutathione (GSH). Augmentation of intracellular GSH with exogenous GSH or N-acetylcysteine is sufficient to reduce the Fas-triggered increase in apoptotic rates. Prevention of the activation induced GSH increase by buthionine sulfoximine, a cell permeable inhibitor of GSH biosynthesis, restored Fas responsiveness in activated neutrophils, an effect that could be blocked with exogenous GSH. Taken together, these data show that Fas-induced signaling for neutrophil apoptosis is blocked in a redox sensitive manner by costimulatory signals delivered through beta2 integrins or activation by LPS, and provide a biologic explanation for sustained neutrophil survival in the inflammatory environment.
Watson
R W
RW
Department of Surgery, The Toronto Hospital, University of Toronto, Canada.
Rotstein
O D
OD
Jimenez
M
M
Parodo
J
J
Marshall
J C
JC
D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D005978:Glutathione / Q000502:physiology*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000473:pathology* / Q000502:physiology; D019014:fas Receptor / Q000502:physiology*
D008070:Lipopolysaccharides; D019014:fas Receptor; D005978:Glutathione