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B
and inhibiting NF-B
Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania 15261
Cytokine-stimulated inducible nitric oxide
synthase (iNOS) gene expression is dependent on nuclear factor-
B
(NF-B) activation and is suppressed by glucocorticoids (GC). In this
study we examined the molecular mechanisms of GC inhibition of iNOS
expression in rat hepatocytes. Combinations of tumor necrosis
factor-
, interleukin-1
, and interferon-
(cytokine mixture CM)
induced high levels of iNOS mRNA and NO synthesis. The synthetic GC
dexamethasone markedly repressed iNOS mRNA and protein expression, and
nuclear run-on assays showed that this inhibition was occurring at the
level of transcription. In addition, transfection studies showed that CM-stimulated activity of a 1.6-kb murine iNOS promoter fragment linked
upstream of luciferase was suppressed by dexamethasone. Electromobility
shift assays demonstrated that CM induced the appearance of an NF-B
complex composed of p50 and p65 subunits; the addition of dexamethasone
markedly decreased this band shift. I-B expression was decreased
by CM and upregulated in the presence of dexamethasone. Subsequently,
nuclear p65 levels were decreased by dexamethasone compared with
CM-treated cells. Thus GC repress NF-B DNA-binding activity in rat
hepatocytes in part through the upregulation of its inhibitor
I-B. These data indicate that one mechanism by which GC
block iNOS expression is through the inhibition of NF-B activation
resulting in decreased iNOS transcription.
inducible nitric oxide synthase; nuclear factor-B; tumor
necrosis-; interleukin-1; interferon-; glucocorticoids; gene
regulation
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