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J. Biol. Chem., Vol. 275, Issue 28, 21130-21139, July 14, 2000
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From the Oxygen Signaling and § Lung Membrane Transport
Groups, Center for Research into Human Development, Tayside Institute
of Child Health, Faculty of Medicine, Ninewells Hospital and Medical
School, University of Dundee, Dundee,
DD1 9SY, Scotland, United Kingdom
The O2 and redox-sensitive
transcription factors hypoxia inducible factor-1
Antioxidant/Pro-oxidant Equilibrium Regulates HIF-1
and
NF-
B Redox Sensitivity
EVIDENCE FOR INHIBITION BY GLUTATHIONE OXIDATION IN ALVEOLAR
EPITHELIAL CELLS*
,
(HIF-1) and
nuclear factor-
B (NF-B) are differentially regulated in the
alveolar epithelium over fetal to neonatal oxygen tensions. We have
used fetal alveolar type II epithelial cells to monitor their
regulation in association with redox responsiveness to antioxidant
pretreatment in vitro. N-Acetyl-L-cysteine, a
glutathione (GSH) precursor and a potent scavenger of reactive oxygen
species, induced HIF-1 and ameliorated NF-B nuclear abundance and
DNA binding activity, respectively, in a dose-dependent
manner. Analysis of variations in glutathione homeostasis at ascending
pO2 regimen with
N-acetyl-L-cysteine reveals increased GSH at
the expense of the oxidized form of glutathione (GSSG), thereby
shifting GSH/GSSG into reduction equilibrium. Pyrrolidine
dithiocarbamate (PDTC), which exerts both antioxidant and pro-oxidant
effects, provoked a substantial increase in HIF-1 nuclear abundance,
with no apparent effect on its activation. PDTC reduced NF-B nuclear
abundance and its inhibitory effects on binding activity are
dose-dependent. Assessment of glutathione homeostasis with
PDTC shows increasing levels of GSSG at the expense of GSH, lowering
GSH/GSSG in favor of an oxidative equilibrium. Our results indicate the
hypoxic activation of HIF-1 and the hyperoxic induction of NF-B
in the fetal epithelium is redox-sensitive and, thus, tightly regulated by the GSH/GSSG equilibrium. This highlights glutathione as a key
regulatory component for determining genetic responsiveness to
oxidant/antioxidant imbalance in normal lung development and pathophysiological conditions.
*
This work was supported by grants from the Medical Research
Council, Anonymous Trust, and Tenovus-Scotland (to S. C. L.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
This work is part of the doctoral dissertation of this author, who
is a recipient of the George John Livanos Prize Ph.D. scholarship (London).
¶
To whom reprint requests and correspondence should be
addressed. Tel.: 44 (0) 1382 496268; Fax: 44 (0) 1382 632597; E-mail: s.c.land@dundee.ac.uk.
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