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1 Klinik und Poliklinik für Anästhesiologie und Operative Intensivmedizin, Universitätsklinikum Münster, Münster, Germany; and Departments of 2 Critical Care Medicine, 3 Surgery, and 4 Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261
Cellular
adaptation to hypoxia depends, in part, on the transcription factor
hypoxia-inducible factor-1 (HIF-1). Normoxic cells exposed to an
inflammatory milieu often manifest phenotypic changes, such as
increased glycolysis, that are reminiscent of those observed in hypoxic
cells. Accordingly, we investigated the effects of cytomix, a mixture
containing IFN-
, TNF, and IL-1
on the expression of
HIF-1-dependent proteins under normoxic and hypoxic conditions.
Incubation of intestine-derived epithelial cells (IEC-6) under 1%
O2 increased HIF-1 DNA binding and expression of aldolase
A, enolase-1, and VEGF mRNA. Incubation of normoxic cells with cytomix
for 48 h also markedly increased HIF-1 DNA binding and expression
of mRNAs for these proteins. Incubation of hypoxic cells with cytomix
did not inhibit HIF-1 DNA binding or upregulation of HIF-1-dependent
genes in response to hypoxia. Neither cytomix nor hypoxia increased
steady-state levels of HIF-1
mRNA. Incubation of IEC-6 cells with
cytomix induced nitric oxide (NO·) biosynthesis, which was blocked if
the cultures contained L-NG-(1-iminoethyl)lysine
hydrochloride (L-NIL). Treatment with L-NIL, however, failed to significantly alter aldolase A, enolase-1, and VEGF
mRNA levels in normoxic cytomix-treated cells. Proinflammatory cytokines activate the HIF-1 pathway and increase expression of glycolytic genes in nontransformed rat intestinal epithelial cells, largely through an NO·-independent mechanism.
nitric oxide; glycolysis; epithelium; intestinal; aldolase A; enolase-1; vascular endothelial growth factor; hypoxia-inducible factor-1; deoxyribonucleic acid
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