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Infection and Immunity, December 1999, p. 6242-6248, Vol. 67, No. 12
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Role of Endogenous Interleukin-18 in Resolving Wild-Type and Attenuated Salmonella typhimurium Infections

Jody K. Dybing,dagger Nancy Walters, and David W. Pascual*

Veterinary Molecular Biology, Montana State University, Bozeman, Montana 59717-3610

Received 16 March 1999/Returned for modification 21 May 1999/Accepted 1 September 1999

The stimulation of gamma interferon (IFN-gamma ) has been shown to be essential in resolving infections by intracellular pathogens. As such, several different cytokines including, interleukin-12 (IL-12) and IL-18, can induce IFN-gamma . To resolve Salmonella infections, the stimulation of IL-12 and IFN-gamma are important for mediating its clearance. In this present study, the relevance of IL-18 in protection against oral challenge with Salmonella typhimurium was investigated to determine the role of this IFN-gamma -promoting cytokine. Rabbit anti-murine IL-18 antisera was generated and administered prior to the oral challenge of BALB/c and IL-12p40-deficient knockout (IL-12KO) mice with a wild-type S. typhimurium strain. The median survival time was reduced by 2 days for the anti-IL-18-treated BALB/c mice, while no significant reduction in survival rate for the anti-IL-18-treated IL-12KO mice was observed compared to vehicle-treated mice. To investigate the contribution of IL-18 to resolving Salmonella infections, an attenuated aro-negative mutant (H647) was orally administered to BALB/c mice. This Salmonella infection induced both IL-12 and IFN-gamma in both the Peyer's patches and the spleens. In vehicle-treated mice, Peyer's patch IL-12 peaked by 24 h, while IL-18 levels peaked at 3 days, suggesting sequential support by these cytokines for IFN-gamma . Anti-IL-18 treatment exerted its greatest effect upon the mucosal compartment, limiting early IFN-gamma production. However, anti-IL-18 treatment had little effect upon splenic IFN-gamma levels until late in the response. Infection of IL-12KO mice with H647 strain induced IFN-gamma , but it was not supported by IL-18, although IL-18 levels were reduced by this treatment. These results suggest that IL-18 does contribute to the clearance of S. typhimurium and that endogenously induced IL-18 could not substitute for IL-12.

* Corresponding author. Mailing address: Veterinary Molecular Biology, Montana State University, Bozeman, MT 59717-3610. Phone: (406) 994-6244. Fax: (406) 994-4303. E-mail: dpascual{at}montana.edu.

dagger Present address: U.S. Department of Agriculture, Agriculture Research Service, Southeast Poultry Research Laboratory, Athens, GA 30605.

Infection and Immunity, December 1999, p. 6242-6248, Vol. 67, No. 12
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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