International Immunology, Vol 9, 117-125, Copyright © 1997 by Oxford University Press
O Deas, C Dumont, B Mollereau, D Metivier, C Pasquier, G Bernard-Pomier, F Hirsch, B Charpentier and A Senik
Fas and CD2 receptors can transduce apoptotic signals through two
independent biochemical pathways. In this study, we first evaluated the
role of intracellular GSH in these signaling pathways by inducing
variations in the GSH pool of activated peripheral T lymphocytes.
Increasing the concentration of intracellular GSH by means of N-acetyl-
L-cysteine (NAC) and GSH ethyl ester (OEt) resulted in total protection
against cell death, while inhibiting GSH synthesis with buthionine
sulfoximine (BSO) greatly enhanced cell sensitivity to Fas and CD2
apoptotic signaling. The protection exerted by NAC and GSH OEt was
essentially based on their capacity to establish an intracellular reducing
environment as it still occurred in BSO-treated cells. Thiol- containing
compounds (cysteine, captopril, D-penicillamine and 2- mercaptoethanol)
inhibited apoptosis while a series of non-thiol antioxidants (including
catalase and vitamin E) failed to do so, suggesting that protection was
secondary to thiols/disulfides exchange reactions at the level of cysteine
residues in proteins and not to detoxification of reactive oxygen
intermediates. This conclusion was further supported by the finding that no
enhanced generation of O.-2 and H2O2 could be detected in cells
experiencing early stages of apoptosis such as a decreased concentration of
intracellular GSH and cell shrinkage. Also, protection occurred in the
presence of protein synthesis inhibitors, indicating that it was due to
post-translational sulfhydryl redox regulation of critical molecules
involved in the apoptotic cascade. These data suggest that GSH, the most
abundant intracellular thiol antioxidant, may be important in counteracting
Fas- and CD2-mediated apoptosis of T lymphocytes.
ARTICLES
Thiol-mediated inhibition of FAS and CD2 apoptotic signaling in activated human peripheral T cells
Equipe d'Immunologie Cellulaire et de transplantation, UPR 420 CNRS, Villejuif, France.
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