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Departments of
*
Medicine and
Surgery, University of Colorado Health Sciences Center, Denver, CO 80262; and Departments of
Medicine and
§
Rheumatology, University Hospital, Nijmegen, The Netherlands
In addition to stimulating IFN-
synthesis, IL-18 also possesses
inflammatory effects by inducing synthesis of the proinflammatory
cytokines TNF and IL-1ß and the chemokines IL-8 and macrophage
inflammatory protein-1
. We hypothesized that neutralization of IL-18
would have a beneficial effect in lethal endotoxemia in mice. IL-1ß
converting enzyme (ICE)-deficient mice, lacking the ability to process
mature IL-18 and IL-1ß, were completely resistant to lethal
endotoxemia induced by LPS derived from either Escherichia
coli or Salmonella typhimurium. In contrast,
both wild-type and IL-1ß-/- mice were equally
susceptible to the lethal effects of LPS, implicating that absence of
mature IL-18 or IFN-
but not IL-1ß in ICE-/- mice is
responsible for this resistance. However, IFN-
-deficient mice were
not resistant to S. typhimurium LPS, suggesting an
IFN-
-independent role for IL-18. Anti-IL-18 Abs protected mice
against a lethal injection of either LPS. Anti-IL-18 treatment also
reduced neutrophil accumulation in liver and lungs. The increased
survival was accompanied by decreased levels of IFN-
and macrophage
inflammatory protein-2 in anti-IL-18-treated animals challenged
with E. coli LPS, whereas IFN-
and TNF concentrations
were decreased in treated mice challenged with S.
typhimurium. In conclusion, neutralization of IL-18 during
lethal endotoxemia protects mice against lethal effects of LPS. This
protection is partly mediated through inhibition of IFN-
production,
but mechanisms involving decreased neutrophil-mediated tissue damage
due to the reduction of either chemokines (E. coli LPS)
or TNF (S. typhimurium LPS) synthesis by anti-IL-18
treatment may also be involved.
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