International Immunology, Vol 10, 1261-1272, Copyright © 1998 by Oxford University Press
K Furuke and ET Bloom
We previously reported that intracellular oxidation-reduction (redox)
regulates NK cell functions and that IL-2-activated NK cells undergo
apoptosis upon contact with NK-sensitive target cells. We now report that
apoptosis in activated human NK cells is also regulated by redox. Thiol
deprivation increased apoptosis in NK cells induced by anti-Fas mAb or Fas
ligand-transfected cells, and pretreatment of cells with N- acetyl
cysteine, which increased intracellular glutathione, partially inhibited
the apoptosis and reversed the effect of thiol-deficient medium, suggesting
that Fas-induced apoptosis in NK cells is also redox sensitive. Thiol
deprivation did not alter cell surface Fas expression, but did increase
ceramide generation following Fas engagement. Although exogenous ceramides
induced apoptosis of NK cells, thiol depletion had no effect on this
apoptosis. Thiol deprivation increased CPP32 activation induced by Fas
engagement, but not by ceramides. These findings suggest that, if ceramide
is required for Fas-induced apoptosis, thiol deprivation affects the
Fas-mediated signaling pathway at the generation of ceramide and/or
upstream thereof. Though tyrosine phosphorylation following Fas engagement
was not significantly affected by thiol deprivation, tyrosine
dephosphorylation was delayed, suggesting that tyrosine phosphatases may
also be redox sensitive. The notion that dephosphorylation is important in
the Fas signaling pathway is supported by the finding that tyrosine
phosphatase inhibitors significantly enhanced both CPP32 activity and
apoptosis following Fas ligation. We conclude that events downstream of
tyrosine phosphorylation and upstream of CPP32 activation, including
tyrosine dephosphorylation and possibly ceramide generation, are sensitive
to regulation by redox in human NK cells, requiring a reducing environment
for optimal protection from apoptosis induced by Fas ligation.
ARTICLES
Redox-sensitive events in Fas-induced apoptosis in human NK cells include ceramide generation and protein tyrosine dephosphorylation
Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
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