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 essent ial in resolving infections by intracellular pathogens. As such, several di fferent cytokines including, interleukin-12 (IL-12) and IL-18, can induce I FN-gamma, To resolve Salmonella infections, the stimulation of IL-12 and IF N-gamma are important for mediating its clearance, In this present study, t he relevance of IL-18 in protection against oral challenge with Salmonella typhimurium was investigated to determine the role of this IFN-gamma-promot ing cytokine. Rabbit anti-murine IL-18 antisera nas generated and administe red 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 t ime nas 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 m ice was observed compared to vehicle-treated mice. To investigate the contr ibution of IL-18 to resolving Salmonella infections, an attenuated are-nega tive 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, w hile IL-18 levels peaked at 3 days suggesting sequential support by these c ytokines for IFN-gamma. Anti-IL-18 treatment exerted its greatest effect up on the mucosal compartment, limiting early IFN-gamma production. However, a nti-IL-18 treatment had little effect upon splenic IFN-gamma levels until l ate 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 reduc ed by this treatment. These results suggest that IL-18 does contribute to t he clearance of S, typhimurium and that endogenously induced IL-18 could no t substitute for IL-12.