Regulation of Fas antibody induced neutrophil apoptosis is both caspase and mitochondrial dependent

FEBS Letters

Fitzpatrick, John M.³  Brannigen, Ann E.³  Watson, R.William G.³  O'Neill, Amanda³  Brady, Hugh R.²  Coffey, Ronan³  Marshall, John C.¹ 

[1] Division of General Surgery, The Toronto Hospital, Toronto, Ont., Canada;Department of Medicine and Therapeutics, University College Dublin, Mater Misericordiae Hospital, 40 Eccles Street, Dublin, Ireland;Department of Surgery, University College Dublin, Mater Misericordiae Hospital, 47 Eccles Street, Dublin, Ireland

关键词: Fas antibody;    Neutrophil apoptosis;    Caspase;    Mitochondrion;    NAC;    N-acetylcysteine;    GSH;    glutathione;    GM-CSF;    granulocyte macrophage-colony stimulating factor;    DiOC6;    3;    3′-dihexyloxacarbocyanine iodide;    FADD;    Fas-associating protein with death domain;   

DOI  :  10.1016/S0014-5793(99)00688-2

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

Resolution of neutrophil mediated inflammation is achieved, in part, through induction of neutrophil apoptosis. This constitutively expressed programme can be delayed by inflammatory mediators and induced by ligation of the Fas receptor. However, functional activation of the neutrophil results in resistance to Fas signalled death. We evaluated the effects of Fas antibody engagement on caspase activation and mitochondrial permeability, and the impact of co-stimulation by lipopolysaccharide (LPS) or granulocyte macrophage-colony stimulating factor (GM-CSF) on these events. Fas engagement by an agonistic anti-Fas antibody resulted in enhanced caspase 3 and 8 activity and increased mitochondrial permeability. Studies with pharmacological inhibitors of caspase activity showed that activation of caspase 8 occurred before, and activation of caspase 3 occurred after mitochondrial disruption. The mitochondrial stabilising agent bongkrekic acid also inhibited caspase activation and apoptosis. LPS, GM-CSF and increased glutathione stabilised the mitochondria and inhibited caspase 3. Caspase 8 activity was also inhibited by co-stimulation through a mechanism independent of mitochondrial stabilisation. Glutathione directly inhibited caspase 3 and 8 activity. We conclude inhibition of Fas antibody induced apoptosis by inflammatory proteins is associated with augmented mitochondrial stability and reduced caspase 3 activity that may be glutathione mediated.

【 授权许可】

Unknown