Interleukin-18 and host defense against infection.
Interferon (IFN)-gamma-inducing factor was previously termed interleukin (IL)-18. Although IL-12 is also an IFN-gamma-inducing factor, the activity of IL-18 (but not IL-12) in models of sepsis and death is dependent on the intracellular cysteine protease IL-1beta converting enzyme (caspase-1). Caspase-1 is required for cleavage of the inactive precursor form of IL-18 into an active cytokine, and caspase-1-deficient mice are resistant to lethal endotoxemia. The absence of IFN-gamma (but not IL-1beta) in caspase-1-deficient mice is responsible for this resistance. However, the role of IFN-gamma in murine defense against gram-negative infection is inconsistent. Mice deficient in IFN-gamma are not resistant to lethal endotoxemia but are resistant when treated with neutralizing antibodies to IL-18 and challenged with a lethal injection of some endotoxins. Anti-IL-18 treatment also reduces neutrophil accumulation in liver and lungs. Neutralizing IL-18 with the IL-18 binding protein protects mice against endotoxin- and ischemia-induced hepatic damage. Thus, blockade of IL-18 appears to be a viable clinical target to combat the pathologic consequences of sepsis via IFN-gamma mechanisms.
Dinarello
Charles A
CA
Department of Medicine, Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
Fantuzzi
Giamila
G
D000818:Animals; D001424:Bacterial Infections / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D020382:Interleukin-18 / Q000096:biosynthesis / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D014777:Virus Diseases / Q000276:immunology
D020382:Interleukin-18; D007371:Interferon-gamma