Journal
JOURNAL OF IMMUNOLOGY
Volume 164, Issue 5, Pages 2644-2649Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.164.5.2644
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- NIAID NIH HHS [AI-15614] Funding Source: Medline
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [R56AI015614, R01AI015614, R37AI015614] Funding Source: NIH RePORTER
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In addition to stimulating IFN-gamma synthesis, IL-18 also possesses inflammatory effects by inducing synthesis of the proinflammatory cytokines TNF and IL-1 beta and the chemokines IL-8 and macrophage inflammatory protein-1 alpha. We hypothesized that neutralization of IL-18 would have a beneficial effect in lethal endotoxemia in mice. IL-1 beta converting enzyme (ICE)-deficient mice, lacking the ability to process mature IL-18 and IL-1 beta, were completely resistant to lethal endotoxemia induced by LPS derived from either Escherichia coli or Salmonella typhimurium, In contrast, both wild-type and IL-1 beta(-/-) mice were equally susceptible to the lethal effects of LPS, implicating that absence of mature IL-18 or IFN-gamma but not IL-1 beta in ICE-/- mice is responsible for this resistance. However, IFN-gamma-deficient mice were not resistant to S, typhimurium LPS, suggesting an IFN-gamma-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-gamma and macrophage inflammatory protein-2 in anti-IL-18-treated animals challenged with E, coli LPS, whereas IFN-gamma 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-gamma 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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