Toxicological Sciences, Vol 49, 68-77, Copyright © 1999 by Society of Toxicology
AH Close, TL Guo and BJ Shenker
Mercurials have been shown to cause apoptosis in human T cells. The
objective of this study was to evaluate and compare the relative
susceptibility of resting versus activated T cells to methyl mercury
chloride (MeHgCl)-induced cell death. Apoptosis was assessed by Hoechst
33258 and 7-AAD staining and annexin V binding. Our results show that
activation of T cells by PHA, PMA, and ionomycin, or IL-2, reduces
mercury-induced apoptosis by approximately 50%. We have previously shown
that the underlying basis for these toxic effects involves perturbation of
mitochondrial function leading to oxidative stress and the release of
cytochrome c to the cytosol. Therefore, the ability of MeHgCl to alter the
mitochondrial transmembrane potential (delta psi m) and to induce the
generation of reactive oxygen species (ROS) was evaluated in activated
T-cells. Both resting and activated cells treated with MeHgCl exhibited a
decrease in delta psi m when compared to respective control cells. ROS
production was elevated in resting cells following treatment with mercury;
in contrast, fewer activated T cells exhibit increased levels of ROS in the
presence of MeHgCl. Similarly, MeHgCl treatment resulted in the release of
cytochrome c to the cytoplasm in non-activated T cells but failed to do so
in the activated population. These results lead us to examine intracellular
levels of bcl-2, a protein that has been shown to regulate apoptosis,
presumably via its ability to associate with the mitochondrial membrane.
Bcl-2 levels were found, in resting cells, to be low in the presence or
absence of mercury. In comparison, activated T cells expressed elevated
levels of bcl-2. The relationship between mercury- induced apoptosis in
human T cells, mitochondrial dysfunction, and intracellular levels of bcl-2
are discussed.
ARTICLES
Activated human T lymphocytes exhibit reduced susceptibility to methylmercury chloride-induced apoptosis
Department of Pathology, University of Pennsylvania School of Dental Medicine, Philadelphia 19104, USA.
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