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

Mihai G. Netea^*,, Giamila Fantuzzi^*, Bart Jan Kullberg, Rogier J. L. Stuyt^*, Edward J. Pulido, Robert C. McIntyre, Jr., Leo A. B. Joosten^§, Jos W. M. Van der Meer and Charles A. Dinarello^2,*

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.