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Upregulation of intracellular glutathione by fibroblast-derived factor(s):
enhanced survival of activated T cells in the presence of low Bcl-2
H Hyde, NJ Borthwick, G Janossy, M Salmon and AN Akbar
Department of Clinical Immunology, Royal Free Hospital School of Medicine,
London, UK.
Activated interleukin-2 (IL-2)-dependent T cells express high levels of
Bcl-2 protein. On cytokine withdrawal, Bcl-2 expression decreases and the
cells die rapidly by apoptosis. We have previously shown that the survival
of IL-2-deprived T cells can be promoted by factor(s) secreted by
fibroblasts. Here we report that reduced glutathione (GSH), but not its
oxidized counterpart GSSG, also enhances the in vitro survival of these
cells. Exogenous GSH mediates its effect intracellularly, as (1) endogenous
glutathione concentrations are increased up to fivefold in the presence of
GSH, and (2) acivicin, an inhibitor of transmembrane GSH transport,
abrogates GSH-dependent survival. The GSH-rescued T cells do not
proliferate and express only low levels of Bcl-2, resembling W138
fibroblast-rescued T cells. We, therefore, investigated a role for GSH in
fibroblast-promoted T-cell survival. We show that W138-promoted survival
results in elevated GSH levels in surviving T cells and is abrogated by
buthionine sulfoximine (BSO), an inhibitor of GSH synthesis. Furthermore,
both W138-promoted T-cell survival and GSH upregulation are associated with
large molecular weight molecules (>30 kD). Thus, the upregulation of GSH
by W138 fibroblasts appears to be crucial in their ability to enhance the
survival of cytokine-deprived activated T cells in vitro.
Volume 89,
Issue 7,
pp. 2453-2460,
04/01/1997
Copyright © 1997 by The American Society of Hematology
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