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Infection and Immunity, January 2001, p. 463-471, Vol. 69, No. 1
Biochemical Pharmacology, University of
Konstanz,1 and Department of
Pharmacology, Byk Gulden,2 Konstanz,
Germany, and Department of Cell Biology & Immunology, Faculty
of Medicine, Free University, Amsterdam, The
Netherlands3
Received 24 July 2000/Returned for modification 28 September
2000/Accepted 10 October 2000
During infection with gram-negative bacteria, exposure of immune
cells to lipopolysaccharide (LPS) from the bacterial cell membrane
induces a rapid cytokine response which is essential for the activation
of host defenses against the invading pathogens. Administration of LPS
to mice induces a state of hyporesponsiveness, or tolerance,
characterized by reduced cytokine production upon subsequent LPS
challenge. In the model of experimental Salmonella enterica
serovar Typhimurium infection of mice, we assessed the question of
whether complete LPS tolerance induced by repetitive doses of LPS
interfered with cytokine production and host defense against
gram-negative bacteria. Although production of various cytokines in
response to serovar Typhimurium was attenuated by LPS pretreatment,
LPS-tolerant mice showed improved antibacterial activity, evidenced by
a prolongation of survival and a continuously lower bacterial load. We
attribute this protective effect to three independent mechanisms. (i)
Peritoneal accumulation of leukocytes in the course of LPS pretreatment
accounted for enhanced defense against serovar Typhimurium during the
first 6 h of infection but not for decreased bacterial load in
late-stage infection. (ii) LPS-tolerant mice had an increased capacity
to recruit neutrophilic granulocytes during infection. (iii)
LPS-tolerant mice showed threefold-increased Kupffer cell numbers,
enhanced phagocytic activity of the liver, and strongly improved
clearance of blood-borne serovar Typhimurium. These results demonstrate
that despite attenuated cytokine response, acquired LPS tolerance is
associated with enhanced resistance to infections by gram-negative
bacteria and that this effect is mainly mediated by improved effector
functions of the innate immune system.
0019-9567/01/$04.00+0 DOI: 10.1128/IAI.69.1.463-471.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Improved Innate Immunity of Endotoxin-Tolerant Mice
Increases Resistance to Salmonella enterica Serovar
Typhimurium Infection despite Attenuated Cytokine Response
*
Corresponding author. Mailing address: Biochemical
Pharmacology, University of Konstanz, P.O. Box M655, D-78457 Konstanz, Germany. Phone: 49-7531-884116. Fax: 49-7531-884117. E-mail:
thomas.hartung{at}uni-konstanz.de.
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