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Infection and Immunity, January 2001, p. 463-471, Vol. 69, No. 1
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

Martin D. Lehner,1 Josepha Ittner,1 Daniela S. Bundschuh,2 Nico van Rooijen,3 Albrecht Wendel,1 and Thomas Hartung1,*

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.

* 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.

Infection and Immunity, January 2001, p. 463-471, Vol. 69, No. 1
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.1.463-471.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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