Role of endogenous interleukin-18 in resolving wild-type and attenuated Salmonella typhimurium infections.
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.
Dybing
J K
JK
Veterinary Molecular Biology, Montana State University, Bozeman, Montana 59717-3610, USA.
Walters
N
N
Pascual
D W
DW
D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D007106:Immune Sera / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D018664:Interleukin-12 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D020382:Interleukin-18 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010581:Peyer's Patches / Q000276:immunology; D011817:Rabbits; D012481:Salmonella Infections, Animal / Q000276:immunology*; D012486:Salmonella typhimurium / Q000276:immunology* / Q000472:pathogenicity; D013154:Spleen / Q000276:immunology
D007106:Immune Sera; D020382:Interleukin-18; D018664:Interleukin-12; D007371:Interferon-gamma