PMID- 15572588
OWN - NLM
STAT- MEDLINE
DCOM- 20050503
LR  - 20210206
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 105
IP  - 7
DP  - 2005 Apr 1
TI  - z-VAD-fmk augmentation of TNF alpha-stimulated neutrophil apoptosis is compound 
      specific and does not involve the generation of reactive oxygen species.
PG  - 2970-2
AB  - In most cell types constitutive and ligand-induced apoptosis is a 
      caspase-dependent process. In neutrophils, however, the broad-spectrum caspase 
      inhibitor z-VAD-fmk enhances tumor necrosis factor-alpha (TNF alpha)-induced cell 
      death, and this has been interpreted as evidence for caspase-dependent and 
      -independent cell death pathways. Our aim was to determine the specificity of the 
      effect of z-VAD-fmk in neutrophils and define the potential mechanism of action. 
      While confirming that z-VAD-fmk (> 100 microM) enhances TNF alpha-induced 
      neutrophil apoptosis, lower concentrations (1-30 microM) completely blocked TNF 
      alpha-stimulated apoptosis. Boc-D-fmk, a similar broad-spectrum caspase 
      inhibitor, and z-IETD-fmk, a selective caspase-8 inhibitor, caused a 
      concentration-dependent inhibition of only TNF alpha-stimulated apoptosis. 
      Moreover, the caspase-9 inhibitor, Ac-LEHD-cmk, had no effect on TNF 
      alpha-induced apoptosis, and z-VAD-fmk and Boc-D-fmk inhibited TNF 
      alpha-stimulated reactive oxygen species (ROS) generation. These data suggest 
      that TNF alpha-induced apoptosis in neutrophils is fully caspase dependent and 
      uses a mitochondrial-independent pathway and that the proapoptotic effects of 
      z-VAD-fmk are compound specific and ROS independent.
FAU - Cowburn, Andrew S
AU  - Cowburn AS
AD  - Department of Medicine, University of Cambridge, Box 157, Addenbrooke's Hospital, 
      Hills Road, Cambridge, CB2 2QQ, United Kingdom. asc32@cam.ac.uk
FAU - White, Jessica F
AU  - White JF
FAU - Deighton, John
AU  - Deighton J
FAU - Walmsley, Sarah R
AU  - Walmsley SR
FAU - Chilvers, Edwin R
AU  - Chilvers ER
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20041130
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Amino Acid Chloromethyl Ketones)
RN  - 0 (Cysteine Proteinase Inhibitors)
RN  - 0 (NF-kappa B)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Receptors, Tumor Necrosis Factor, Type I)
RN  - 0 (Receptors, Tumor Necrosis Factor, Type II)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone)
SB  - IM
MH  - Amino Acid Chloromethyl Ketones/*pharmacology
MH  - Apoptosis/*drug effects/immunology
MH  - Cells, Cultured
MH  - Cysteine Proteinase Inhibitors/*pharmacology
MH  - Drug Synergism
MH  - Humans
MH  - NF-kappa B/metabolism
MH  - Neutrophils/cytology/*drug effects/metabolism
MH  - Oxidative Stress/drug effects/immunology
MH  - Reactive Oxygen Species/metabolism
MH  - Receptors, Tumor Necrosis Factor, Type I/metabolism
MH  - Receptors, Tumor Necrosis Factor, Type II/metabolism
MH  - Tumor Necrosis Factor-alpha/*pharmacology
EDAT- 2004/12/02 09:00
MHDA- 2005/05/04 09:00
CRDT- 2004/12/02 09:00
PHST- 2004/12/02 09:00 [pubmed]
PHST- 2005/05/04 09:00 [medline]
PHST- 2004/12/02 09:00 [entrez]
AID - S0006-4971(20)45700-3 [pii]
AID - 10.1182/blood-2004-07-2870 [doi]
PST - ppublish
SO  - Blood. 2005 Apr 1;105(7):2970-2. doi: 10.1182/blood-2004-07-2870. Epub 2004 Nov 
      30.