AUGMENTED INTRACELLULAR GLUTATHIONE INHIBITS FAS-TRIGGERED APOPTOSIS OF ACTIVATED HUMAN NEUTROPHILS

Agonist signals delivered through cell surface Fas induce apoptosis. H owever, the apoptotic program can be modulated by signals from the env ironment, and in particular, by signals delivered through adhesion mol ecules. Because neutrophil functional activity in inflammation is cont ingent on cell survival, and because circulating neutrophils normally die rapidly through a constitutively expressed apoptotic program, we e valuated Fas-mediated apoptosis in resting and inflammatory human neut rophils. We show that normal neutrophils respond to Fas engagement wit h accelerated rates of apoptosis, but cross-linking of beta(2) integri ns or priming with bacterial lipopolysaccharide (LPS) prevents this in crease. Adhesion molecule cross-linking results in increased intracell ular glutathione (GSH). Augmentation of intracellular GSH with exogeno us GSH or N-acetylcysteine is sufficient to reduce the Fas-triggered i ncrease in apoptotic rates. Prevention of the activation induced GSH i ncrease by buthionine sulfoximine, a cell permeable inhibitor of GSH b iosynthesis, 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 bloc ked in a redox sensitive manner by costimulatory signals delivered thr ough beta(2) integrins or activation by LPS, and provide a biologic ex planation for sustained neutrophil survival in the inflammatory enviro nment. (C) 1997 by The American Society of Hematology.