Document Detail

Granzyme B of cytotoxic T cells induces extramitochondrial reactive oxygen species production via caspase-dependent NADPH oxidase activation.
MedLine Citation:
PMID:  20125115     Owner:  NLM     Status:  MEDLINE    
Induction of reactive oxygen species (ROS) is a hallmark of granzyme B (gzmB)-mediated pro-apoptotic processes and target cell death. However, it is unclear to what extent the generated ROS derive from mitochondrial and/or extra-mitochondrial sources. To clarify this point, we have produced a mutant EL4 cell line, termed EL4-rho(0), which lacks mitochondrial DNA, associated with a decreased mitochondrial membrane potential and a defective ROS production through the electron transport chain of oxidative phosphorylation. When incubated with either recombinant gzmB plus streptolysin or ex vivo gzmB(+) cytotoxic T cells, EL4-rho(0) cells showed phosphatydylserine translocation, caspase 3 activation, Bak conformational change, cytochrome c release and apoptotic morphology comparable to EL4 cells. Moreover, EL4-rho(0) cells produced ROS at levels similar to EL4 under these conditions. GzmB-mediated ROS production was almost totally abolished in both cell lines by the pan-caspase inhibitor, Z-VAD-fmk. However, addition of apocynin, a specific inhibitor of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, led to a significant reduction of ROS production and cell death only in EL4-rho(0) but not EL4 cells. These data suggest that gzmB-induced cell death is accompanied by a caspase-dependent pathway of extra-mitochondrial ROS production, most probably through activation of NADPH oxidase.
Juan I Aguiló; Alberto Anel; Elena Catalán; Alvaro Sebastián; Rebeca Acín-Pérez; Javier Naval; Reinhard Wallich; Markus M Simon; Julián Pardo
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-02-02
Journal Detail:
Title:  Immunology and cell biology     Volume:  88     ISSN:  1440-1711     ISO Abbreviation:  Immunol. Cell Biol.     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2010-07-02     Completed Date:  2010-09-28     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8706300     Medline TA:  Immunol Cell Biol     Country:  England    
Other Details:
Languages:  eng     Pagination:  545-54     Citation Subset:  IM    
Departamento de Bioquímica y Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain.
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MeSH Terms
Apoptosis / immunology
Caspases / immunology*,  metabolism
Cell Line
Enzyme Activation / immunology
Granzymes / immunology*,  metabolism
Mice, Inbred C57BL
Mitochondria / immunology,  metabolism
NADPH Oxidase / immunology,  metabolism
Reactive Oxygen Species / immunology*,  metabolism
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction / immunology*
T-Lymphocytes, Cytotoxic / immunology*,  metabolism
Reg. No./Substance:
0/Reactive Oxygen Species; EC Oxidase; EC 3.4.21.-/Granzymes; EC 3.4.22.-/Caspases
Comment In:
Immunol Cell Biol. 2010 Jul;88(5):500-1   [PMID:  20231855 ]

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