• Manabu Kinoshita, Shuhji Seki, Satoshi Ono, Nariyoshi Shinomiya, and Hoshio Hiraide.
• Division of Basic Traumatology, National Defense Medical College Research Institute, National Defense Medical College, Namiki, Tokorozawa, Japan.
• Ann. Surg. 2004 Aug 1; 240 (2): 313320313-20.

ObjectiveTo investigate the effects of IL-18 therapy on severe and mild bacterial infection after burn injury.Summary Background DataIL-18 therapy restores IFN-gamma 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-gamma could induce an exaggerated inflammation. Therefore, in this study, we focus on the beneficial and deleterious effects of IL-18-induced IFN-gamma and investigate the behavior of IL-18 in infections.MethodsBurn injury was induced in C57BL/6 mice and then they were i.p. injected with IL-18 (0.2 microg) on alternate days. After 1 week, severe and mild infections were made in mice by an Escherichia coli challenge (5 x 10 CFU and 1 x 10 CFU i.v., respectively).ResultsIL-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-gamma production from the liver and spleen MNCs in mice with severe infection. Both the serum IFN-gamma concentrations recovered while the bacterial count in the liver decreased. In contrast, the serum IFN-gamma 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-gamma 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-gamma Ab pretreatment.ConclusionIL-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.

33 keywords...

hide…