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The Journal of Immunology, 2000, 164: 2644-2649.
Copyright © 2000 by The American Association of Immunologists

Neutralization of IL-18 Reduces Neutrophil Tissue Accumulation and Protects Mice Against Lethal Escherichia coli and Salmonella typhimurium Endotoxemia1

Mihai G. Netea*,{ddagger}, Giamila Fantuzzi*, Bart Jan Kullberg{ddagger}, Rogier J. L. Stuyt*, Edward J. Pulido{dagger}, Robert C. McIntyre, Jr.{dagger}, Leo A. B. Joosten§, Jos W. M. Van der Meer{ddagger} and Charles A. Dinarello2,*

Departments of * Medicine and {dagger} Surgery, University of Colorado Health Sciences Center, Denver, CO 80262; and Departments of {ddagger} Medicine and § Rheumatology, University Hospital, Nijmegen, The Netherlands

In addition to stimulating IFN-{gamma} 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{alpha}. 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-{gamma} but not IL-1ß 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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