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Vol. 62, Issue 3, 698-704, September 2002
The Immunopharmacological Research Group, Medical School,
University of Tampere, Tampere, Finland; and Tampere University
Hospital, Tampere, Finland
Nitric oxide (NO) production through the inducible nitric-oxide
synthase (iNOS) pathway is increased in inflammatory diseases and leads
to cellular injury. Anti-inflammatory steroids inhibit the expression
of various inflammatory genes, including iNOS. In the present study, we
investigated the mechanism how dexamethasone decreased NO production in
murine J774 macrophages. Dexamethasone (0.1-10 µM) inhibited the
production of NO and iNOS protein in a dose-dependent manner in cells
stimulated with lipopolysaccharides (LPS). In contrast, in cells
treated with a combination of LPS and interferon-
(IFN-),
dexamethasone did not reduce iNOS expression and NO formation.
Dissociated glucocorticoid RU24858 inhibited iNOS expression and
NO production to levels comparable with that of dexamethasone,
suggesting that the reduced iNOS expression by dexamethasone is not a
GRE-mediated event. In further studies, the effect of dexamethasone on
iNOS mRNA levels was tested by actinomycin assay. The half-life of iNOS
mRNA after LPS treatment was 5 h 40 min, and dexamethasone reduced
it to 3 h. The increased degradation of iNOS mRNA was reversed by
a protein synthesis inhibitor cycloheximide. iNOS mRNA was more stabile
in cells treated with a combination of LPS plus IFN- (half-life = 8 h 20 min), and dexamethasone had a minor effect in these
conditions. In conclusion, dexamethasone decreases iNOS-dependent NO
production by destabilizing iNOS mRNA in LPS-treated cells by a
mechanism that requires de novo protein synthesis. Also, decreased iNOS
mRNA and protein expression and NO formation by dexamethasone was not
found in cells treated with a combination of LPS plus IFN-,
suggesting that the effect of dexamethasone is stimulus-dependent.
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