Paradoxical effect of IL-18 therapy on the severe and mild Escherichia coli infections in burn-injured mice.
OBJECTIVE
To investigate the effects of IL-18 therapy on severe and mild bacterial infection after burn injury.


BACKGROUND
IL-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.


METHODS
Burn 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).


RESULTS
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-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.


CONCLUSIONS
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.
Kinoshita
Manabu
M
Division of Basic Traumatology, National Defense Medical College Research Institute, National Defense Medical College, Namiki, Tokorozawa, Japan.
Seki
Shuhji
S
Ono
Satoshi
S
Shinomiya
Nariyoshi
N
Hiraide
Hoshio
H
D000704:Analysis of Variance; D000818:Animals; D001707:Biopsy, Needle; D002056:Burns / Q000150:complications* / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004926:Escherichia coli / Q000302:isolation & purification*; D004927:Escherichia coli Infections / Q000150:complications / Q000188:drug therapy*; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D015601:Injury Severity Score; D007371:Interferon-gamma / Q000187:drug effects / Q000378:metabolism*; D020382:Interleukin-18 / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011336:Probability; D011897:Random Allocation; D012016:Reference Values; D016896:Treatment Outcome
D020382:Interleukin-18; D007371:Interferon-gamma