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Infection and Immunity, November 2005, p. 7340-7347, Vol. 73, No. 11
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.11.7340-7347.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Endotoxin Priming Improves Clearance of Pseudomonas aeruginosa in Wild-Type and Interleukin-10 Knockout Mice

Tushar K. Varma,1,3 Megan Durham,1 Erle D. Murphey,1,3 Weihua Cui,1 Zhiyu Huang,3 Cheng Y. Lin,1 Tracy Toliver-Kinsky,1,3 and Edward R. Sherwood1,2,3*

Departments of Anesthesiology,1 Microbiology and Immunology, The University of Texas Medical Branch,2 Shriners Hospital for Children, Galveston, Texas3

Received 1 February 2005/ Returned for modification 8 March 2005/ Accepted 15 July 2005

Endotoxin (lipopolysaccharide [LPS]) tolerance is an altered state of immunity caused by prior exposure to LPS, in which production of many cytokines, including gamma interferon (IFN-{gamma}) and interleukin-12 (IL-12), are reduced but secretion of the anti-inflammatory cytokine IL-10 is increased in response to a subsequent LPS challenge. This pattern of cytokine production is also characteristic of postinflammatory immunosuppression. Therefore, we hypothesized that LPS-primed mice would exhibit an impaired ability to respond to systemic infection with the opportunistic pathogen Pseudomonas aeruginosa. We further hypothesized that depletion of IL-10 would reverse the endotoxin-tolerant state. To test this hypothesis, systemic clearance of Pseudomonas aeruginosa was measured for LPS-primed wild-type and IL-10-deficient mice. LPS-primed wild-type mice exhibited significant suppression of LPS-induced IFN-{gamma} and IL-12 but increased IL-10 production in blood and spleen compared to levels exhibited by saline-primed wild-type mice. The suppressed production of IFN-{gamma} and IL-12 caused by LPS priming was ablated in the spleens, but not blood, of IL-10 knockout mice. LPS-primed wild-type mice cleared Pseudomonas aeruginosa from lungs and blood more effectively than saline-primed mice. LPS-primed IL-10-deficient mice were particularly efficient in clearing Pseudomonas aeruginosa after systemic challenge. These studies show that induction of LPS tolerance enhanced systemic clearance of Pseudomonas aeruginosa and that this effect was augmented by neutralization of IL-10.

* Corresponding author. Mailing address: Department of Anesthesiology, The University of Texas Medical Branch, 301 University Blvd., Galveston, TX 77550-5050. Phone: (409) 772-1221. Fax: (409) 772-1224. E-mail: ERSherwo{at}UTMB.edu.

Editor: J. D. Clements

Infection and Immunity, November 2005, p. 7340-7347, Vol. 73, No. 11
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.11.7340-7347.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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