Neutralization of IL-18 reduces neutrophil tissue accumulation and protects mice against lethal Escherichia coli and Salmonella typhimurium endotoxemia.
In addition to stimulating IFN-gamma synthesis, IL-18 also possesses inflammatory effects by inducing synthesis of the proinflammatory cytokines TNF and IL-1beta and the chemokines IL-8 and macrophage inflammatory protein-1alpha. We hypothesized that neutralization of IL-18 would have a beneficial effect in lethal endotoxemia in mice. IL-1beta converting enzyme (ICE)-deficient mice, lacking the ability to process mature IL-18 and IL-1beta, were completely resistant to lethal endotoxemia induced by LPS derived from either Escherichia coli or Salmonella typhimurium. In contrast, both wild-type and IL-1beta-/- mice were equally susceptible to the lethal effects of LPS, implicating that absence of mature IL-18 or IFN-gamma but not IL-1beta 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.
Netea
M G
MG
Departments ofMedicine and Surgery, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
Fantuzzi
G
G
Kullberg
B J
BJ
Stuyt
R J
RJ
Pulido
E J
EJ
McIntyre
R C
RC
Joosten
L A
LA
Van der Meer
J W
JW
Dinarello
C A
CA
D000818:Animals; D002465:Cell Movement / Q000276:immunology*; D018925:Chemokines / Q000096:biosynthesis; D019446:Endotoxemia / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000517:prevention & control; D004927:Escherichia coli Infections / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000517:prevention & control; D007106:Immune Sera / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D020382:Interleukin-18 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology*; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008099:Liver / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D012481:Salmonella Infections, Animal / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000517:prevention & control; D012486:Salmonella typhimurium / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D018925:Chemokines; D007106:Immune Sera; D020382:Interleukin-18; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D009195:Peroxidase