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Infect Immun, April 1998, p. 1309-1316, Vol. 66, No. 4
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Expression and Bactericidal Activity of Nitric
Oxide Synthase in Brucella suis-Infected Murine
Macrophages
Antoine
Gross,
Sandra
Spiesser,
Annie
Terraza,
Bruno
Rouot,
Emmanuelle
Caron, and
Jacques
Dornand*
INSERM U431, IFR Eugène Bataillon,
Université de Montpellier-II, 34095 Montpellier Cedex 5, France
Received 8 September 1997/Returned for modification 7 November
1997/Accepted 9 January 1998
We examined the expression and activity of inducible nitric oxide
synthase (iNOS) in both gamma interferon (IFN-
)-treated and
untreated murine macrophages infected with the gram-negative bacterium
Brucella suis. The bacteria were opsonized with a mouse serum containing specific antibrucella antibodies
(ops-Brucella) or with a control nonimmune serum
(c-Brucella). The involvement of the produced NO in the
killing of intracellular B. suis was evaluated. B. suis survived and replicated within J774A.1 cells. Opsonization
with specific antibodies increased the number of phagocytized bacteria
but lowered their intramacrophage development. IFN-
enhanced the
antibrucella activity of phagocytes, with this effect being greater in
ops-Brucella infection. Expression of iNOS, interleukin-6,
and tumor necrosis factor alpha (TNF-
) mRNAs was induced in both
c-Brucella- and ops-Brucella-infected cells and
was strongly potentiated by IFN-
. In contrast to that of cytokine
mRNAs, iNOS mRNA expression was independent of opsonization. Similar
levels of iNOS mRNAs were expressed in IFN-
-treated cells infected
with c-Brucella or ops-Brucella; however,
expression of iNOS protein and production of NO were detected only in
IFN-
-treated cells infected with ops-Brucella. These
discrepencies between iNOS mRNA and protein levels were not due to
differences in TNF-
production. The iNOS inhibitor
N
-nitro-L-arginine methyl ester increased
B. suis multiplication specifically in IFN-
-treated cells infected with ops-Brucella, demonstrating a
microbicidal effect of the NO produced. This observation was in
agreement with in vitro experiments showing that B. suis
was sensitive to NO killing. Together our data indicate that in
B. suis-infected murine macrophages, the
posttranscriptional regulation of iNOS necessitates an additive signal
triggered by macrophage Fc
receptors. They also support the
possibility that in mice, NO favors the elimination of
Brucella, providing that IFN-
and antibrucella
antibodies are present, i.e., following expression of acquired
immunity.
*
Corresponding author. Mailing address: INSERM U431, IFR
Eugène Bataillon, Université de Montpellier-II CC100, Place
Eugène Bataillon, 34095 Montpellier Cedex 5, France. Phone: 33 (0)4 67144244. Fax: 33 (0)4 67143338. E-mail:
dornand{at}crit.univ-montp2.fr.
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