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.
Division of Basic Traumatology, National Defense Medical College Research Institute, National Defense Medical College, Namiki, Tokorozawa, Japan.
Manabu
M
Kinoshita
Shuhji
S
Seki
Satoshi
S
Ono
Nariyoshi
N
Shinomiya
Hoshio
H
Hiraide
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