INTERLEUKIN-18 (IL-18) IS INVOLVED IN ACETAMINOPHEN (APAP) INDUCED HEPATIC INJURY IN A FAS/FAS LIGAND INDEPENDENT MECHANISM

Introduction: IL-18 is a novel pro-inflammatory cytokine that participates in hepatocyte apoptosis in mice after treatment with a variety of hepatotoxins. The normal apoptotic pathway commences with Fas/Fas Ligand interactions. The role of IL-18 in APAP-induced hepatic injury has not been previously reported. Objective: To explore the role of IL-18 in APAP-induced hepatic injury and determine if this mechanism is Fas/Fas Ligand mediated. Methods: C57BL/6 female mice (N = 10, 20-25g) were injected i.p. with 700 mg/kg APAP. Control mice (N = 10) received an equal volume of saline by the same route. Blood and liver were collected for ALT and IL-18 determinations at 1, 2, 4, 8, 24 hours following APAP injection. A second group (N = 25) was injected i.p. with neutralizing antibodies to IL-18 one hour prior to APAP injection. ALT and IL-18 levels were measured at 8 hours following APAP injection. Control mice (N = 25) received control protein followed one hour by APAP. Ten Fas deficient mice (Lpr/Lpr) were also injected i.p. with APAP to explore Fas/Fas Ligand participation. Results: IL-18 was detected in serum and liver one hour following APAP injection and peaked at 8 hours. Anti-IL18 antibodies significantly reduced hepatic injury: mean serum ALT ([+ or -] SD) was 523 [+ or -] 428 IU/L compared to 1653 [+ or -] 1043 IU/L for controls (p [is less than] 0.0001). Mean serum ALT for Lpr/ Lpr mice was not different from wild type mice. Conclusion: In this model liver IL-18 is involved in APAP-induced hepatotoxicity, but IL-18 antibodies do not completely prevent hepatic injury. The mechanism by which IL-18 is involved in APAP hepatotoxicity seems to be Fas independent.
Waksman JC(1,3), Fantuzzi G(2), Bogdan GB(1), Dart RC(1,3), Dinarello C(2). (1) Rocky Mountain Poison and Drug Center--Denver Health, (2) Division of Infectious Diseases, (3) University of Colorado Health Sciences Center, [...]