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-Glutamyl Transpeptidase Regulates Antiproliferative Effects of S-Nitrosoglutathione on Human T and B Lymphocytes1
,
*
Simmons Arthritis Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75235; and Departments of
Medicine and
Immunology, University of Colorado Health Sciences Center, Denver, CO 80262
Expression of the ectoenzyme 
-glutamyl transpeptidase (GGT) is
regulated on T lymphocytes. It is present at a low level on naive T
cells, at a high level on activated T cells, and at an intermediate
level on resting memory T cells. GGT cleaves the glutamyl group from
glutathione, which is the first step in the uptake of extracellular
glutathione. In vitro, purified GGT also metabolizes the naturally
occurring nitrosothiol, S-nitrosoglutathione (GSNO).
Because of this relationship, the effects of cellular GGT on the
metabolism of and cellular response to GSNO were tested. The
GGT-negative lymphoblasts Ramos and SupT1 were transfected with cDNA
for human GGT. In the presence of cells lacking GGT, GSNO is extremely
stable. In contrast, GGT-expressing cells rapidly metabolize GSNO
leading to nitric oxide release. The nitric oxide causes a rapid
(<2-h) inhibition of DNA synthesis. There is a concomitant decrease in
the concentration of intracellular deoxyribonucleotides, suggesting
that one effect of the nitric oxide generated from GSNO is the
previously described inactivation of the enzyme ribonucleotide
reductase. GSNO also caused a rapid, GGT-dependent cytostatic effect in
Hut-78, a human T cell lymphoma, as well as in activated peripheral
blood T cells. Although DNA synthesis was decreased to 16% of control
values in anti-CD3-stimulated Hut-78, the production of IL-2 was
unchanged by GSNO. These data show that GGT, a regulated ectoenzyme on
T cells, controls the rate of nitric oxide production from GSNO and
thus markedly affects the physiological response to this biologically
active nitrosothiol.
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