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

Abstract

In addition to stimulating IFN-γ synthesis, IL-18 also possesses inflammatory effects by inducing synthesis of the proinflammatory cytokines TNF and IL-1β and the chemokines IL-8 and macrophage inflammatory protein-1α. We hypothesized that neutralization of IL-18 would have a beneficial effect in lethal endotoxemia in mice. IL-1β converting enzyme (ICE)-deficient mice, lacking the ability to process mature IL-18 and IL-1β, were completely resistant to lethal endotoxemia induced by LPS derived from either Escherichia coli or Salmonella typhimurium. In contrast, both wild-type and IL-1β−/− mice were equally susceptible to the lethal effects of LPS, implicating that absence of mature IL-18 or IFN-γ but not IL-1β in ICE−/− mice is responsible for this resistance. However, IFN-γ-deficient mice were not resistant to S. typhimurium LPS, suggesting an IFN-γ-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-γ and macrophage inflammatory protein-2 in anti-IL-18-treated animals challenged with E. coli LPS, whereas IFN-γ 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-γ 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.

Role of endogenous IL‐18 in the lung during endotoxin‐induced systemic inflammation

“…12,14 The present study also showed that mRNA levels of MIP-2, KC, and ICAM-1 were significantly induced by LPS challenge. Netea et al showed that IL-18 induced LPS-mediated accumulation of neutrophils by increasing MIP-2 expression in the lung.…”

“…Netea et al showed that IL-18 induced LPS-mediated accumulation of neutrophils by increasing MIP-2 expression in the lung. 12 However, our results showed that IL-18 did not significantly affect MIP-2 (CXCL2) mRNA expression, whereas IL-18 induced ICAM-1 mRNA expression in the lung. One reason for this discrepancy is the peak time of these molecules.…”

“…Netea et al showed that neutralization of IL-18 reduced LPS-induced accumulation of neutrophils in the lung and liver. 12 Leung et al showed that intraperitoneal injection of IL-18 induced the accumulation of neutrophils in the peritoneal cavity. 13 Our data showed that LPS injection caused an accumulation of neutrophils in the lung associated with thickening of interstitial space and increased MPO activity in WT mice.…”

Caspase-12: an overview

“…2,3 This is likely due to the lack of mature IL-18 in these mice, since protection from LPS-induced lethality is not observed in IL-1b-deficient animals, while neutralization of IL-18 confers complete resistance to lethal endotoxemia. 5,6 Is caspase-12 involved in responses to infection and inflammation? Contrary to caspase-1, but similar to caspase-11, coexpression of caspase-12 with the precursor of the proinflammatory cytokine interleukin-1b (pro-IL-1b) does not result in the maturation of pro-IL-1b 1 (and Lamkanfi et al, unpublished results).…”

Early cytokine response of gnotobiotic piglets to Salmonella enterica serotype Typhimurium

“…In addition to stimulating IFN-γ synthesis, IL-18 also exhibits inflammatory effects and its neutralisation protects mice infected with ST against the effect of LPS and TNF [22]. We have found high levels of IL-18 in ileum lavages but not in the plasma of infected piglets.…”