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Vol. 55, Issue 2, 317-323, February 1999
Departments of
Pharmacology (M.D.G.) and
Physiology (G.P.P.), The
University of Michigan Medical School, Ann Arbor, Michigan; and
Department of Pharmacology, Universidade Federal de Santa Catarina,
Florianopolis, SC, Brazil (J.A.)
Septic shock is a dangerous condition with high mortality rates. In
sepsis, the inducible form of nitric oxide (NO) synthase is induced,
releasing high amounts of NO. Glucocorticoids have potent
anti-inflammatory properties and are very effective in inhibiting the
induction of this enzyme if administered before the shock onset. It is
known that glucocorticoid receptor (GR) has critical cysteine residues
for steroid binding in its hormone-binding and DNA-binding domains. It
has also been reported that NO reacts with ---SH groups, forming
S-nitrosothiols. Therefore, we examined the potential
effect of NO on the ligand-binding ability of GR. NO donors
(S-nitroso-acetyl-DL-penicillamine,
S-nitroso-DL-penicillamine, or
S-nitroso-glutathione) decreased, in a time- and
dose-dependent manner, the binding of [3H]triamcinolone
to immunoprecipitated GR from mouse L929 fibroblasts. The
nonnitrosylated parent molecules,
N-acetyl-DL-penicillamine, and reduced
gluthatione were without effect. Scatchard plots revealed that the
number of ligand binding sites and Kd were
reduced (50%) by NO donors. Western blot analysis ruled out the
possibility that dissociation of GR/heat shock protein 90 heterocomplex
or decrease in GR protein would account for the inhibitory effect of
NO. Decreased ligand binding to GR was found when NO donors were
incubated with intact fibroblasts. Incubation with NO donors also
decreased the steroid-induced reduction in [3H]uridine
incorporation into RNA. All of these NO effects were inhibited by the
thiol-protecting agent dithiothreitol. Therefore, S-nitrosylation of critical ---SH groups in GR by NO
with consequent decreases in binding and affinity may be the mechanisms
which explain the failure of glucocorticoids to exert their
anti-inflammatory effects in septic shock.
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