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Interleukin-18 and host defense against infection
Charles A Dinarello1, Giamila Fantuzzi
1Department of Medicine, Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
The Journal of Infectious Diseases
|June 7, 2003
Summary
Interleukin-18 (IL-18) activity in sepsis models depends on caspase-1. Blocking IL-18 with an IL-18 binding protein protects against sepsis-induced liver damage, suggesting IL-18 blockade as a therapeutic target.
Area of Science:
- Immunology
- Molecular Biology
- Pathophysiology
Background:
- Interferon-gamma (IFN-gamma) is induced by both Interleukin-12 (IL-12) and Interleukin-18 (IL-18).
- The activity of IL-18, unlike IL-12, in sepsis models is contingent upon the protease caspase-1.
- Caspase-1 processes pro-IL-18 into active IL-18, and caspase-1-deficient mice exhibit resistance to lethal endotoxemia.
Purpose of the Study:
- To elucidate the role of IL-18 and its processing by caspase-1 in the pathogenesis of sepsis.
- To investigate the therapeutic potential of targeting IL-18 in sepsis models.
Main Methods:
- Utilized caspase-1-deficient mice to assess resistance to lethal endotoxemia.
- Administered neutralizing antibodies to IL-18 and IL-18 binding protein in endotoxin-challenged mice.
- Monitored IFN-gamma levels and neutrophil accumulation in liver and lungs.
Main Results:
- Caspase-1-deficient mice were resistant to lethal endotoxemia, correlating with the absence of IFN-gamma.
- Neutralizing IL-18 with antibodies or IL-18 binding protein conferred resistance to endotoxin-induced lethality and hepatic damage.
- Anti-IL-18 treatment reduced neutrophil infiltration in the liver and lungs.
Conclusions:
- IL-18 processing by caspase-1 is critical for lethal endotoxemia.
- Targeting IL-18, particularly through blockade with IL-18 binding protein, offers a promising therapeutic strategy for sepsis.
- IFN-gamma-mediated mechanisms are implicated in the protective effects of IL-18 blockade in sepsis.