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Biochem Pharmacol. 2000 Feb 1;59(3):305-14.

Induction of human neutrophil apoptosis by nitric oxide donors: evidence for a caspase-dependent, cyclic-GMP-independent, mechanism.

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Department of Medicine (RIE), University of Edinburgh Medical School, UK.


This study investigated the regulatory effects of the major inflammatory mediator, nitric oxide (NO), on human neutrophil apoptosis in vitro. Co-culture of human neutrophils with the NO donors GEA 3162 (1,2,3,4-oxatriazolium,5-amino-3-(3,4-dichlorophenyl)-chloride) (10-100 microM) and 3-morpholino-sydnonimine (SIN-1) (0.3-3 mM) caused a dramatic and concentration-dependent induction of apoptosis. However, N-formyl-methionyl-leucyl-phenylalanine (FMLP)-induced neutrophil activation (actin reorganization and chemotaxis) was inhibited by GEA 3162 treatment. The pro-apoptotic effects of the NO donors were (i) unaffected by the soluble guanylate cyclase inhibitor LY-83583 (6-anilino-5,8-quinolinedione; 100 microM), (ii) antagonized by superoxide dismutase (6 microg/mL), (iii) mimicked by exogenous peroxynitrite (at concentrations >100 microM), and (iv) inhibited by the caspase inhibitor Z-Val-Ala-DL-Asp-fluoromethylketone (100 microM). The pro-apoptotic effect of the NO donors was not mimicked by the cell-permeable cyclic nucleotide analogue, N6,2-O-dibutyrylguanosine-3',5'-cyclic monophosphate (dibutyryl-cGMP) at concentrations < or =0.2 mM. Indeed, at high concentrations (> or =2 mM), dibutyryl-cGMP caused an inhibition of apoptosis. These results suggest that NO-mediated apoptosis, although caspase-dependent, is mediated by a cGMP-independent mechanism and involves the concurrent generation of oxygen free radicals and, potentially, peroxynitrite. Our data reveal a unique role for NO in inflammatory responses with differential effects upon neutrophil activation and survival, with important implications for the successful resolution of inflammation.

[Indexed for MEDLINE]

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