Paradoxical Effect of IL-18 Therapy on the Severe and Mild Escherichia coli Infections in Burn-Injured Mice

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Abstract
To investigate the effects of IL-18 therapy on severe and mild bacterial infection after burn injury. IL-18 therapy restores IFN-γ production in immunosuppressive mice following burn injury and up-regulate host response to LPS and experimental bacterial peritonitis. On the other hand, the overproduction of IFN-γ could induce an exaggerated inflammation. Therefore, in this study, we focus on the beneficial and deleterious effects of IL-18-induced IFN-γ and investigate the behavior of IL-18 in infections. Burn injury was induced in C57BL/6 mice and then they were i.p. injected with IL-18 (0.2 μg) on alternate days. After 1 week, severe and mild infections were made in mice by an Escherichia coli challenge (5 × 108 CFU and 1 × 108 CFU i.v., respectively). IL-18 therapy decreased the mortality of burn-injured mice followed by a severe infection, whereas it unexpectedly increased the mortality of burned mice with a mild infection. The IL-18 therapy increased the number of liver mononuclear cells (MNCs), especially NK cells, and greatly up-regulated the impaired IFN-γ production from the liver and spleen MNCs in mice with severe infection. Both the serum IFN-γ concentrations recovered while the bacterial count in the liver decreased. In contrast, the serum IFN-γ concentrations of the burned mice with mild infection did not decrease in comparison to the unburned mice, whereas IL-18 therapy greatly up-regulated the serum IFN-γ levels in burned mice. However, IL-18 therapy significantly elevated the serum ALT and creatinine levels, thus suggesting that the mortality was induced by an exaggerated form of shock/multiorgan failure. These beneficial and deleterious effects of IL-18 therapy in mice with severe and mild infections, respectively, were all inhibited by anti-IFN-γ Ab pretreatment. IL-18 therapy can be a potent therapeutic tool against severe bacterial infection in immunocompromised hosts, but careful attention should also be paid to its adverse effects.