title: Role of caspase-1 and interleukin-1beta in acetaminophen-induced hepatic inflammation and liver injury.
abstract: Acetaminophen (APAP) overdose can result in serious liver injury and potentially death. Toxicity is dependent on metabolism of APAP to a reactive metabolite initiating a cascade of intracellular events resulting in hepatocellular necrosis. This early injury triggers a sterile inflammatory response with formation of cytokines and innate immune cell infiltration in the liver. Recently, IL-1beta signaling has been implicated in the potentiation of APAP-induced liver injury. To test if IL-1beta formation through caspase-1 is critical for the pathophysiology, C57Bl/6 mice were treated with the pan-caspase inhibitor Z-VD-fmk to block the inflammasome-mediated maturation of IL-1beta during APAP overdose (300 mg/kg APAP). This intervention did not affect IL-1beta gene transcription but prevented the increase in IL-1beta plasma levels. However, APAP-induced liver injury and neutrophil infiltration were not affected. Similarly, liver injury and the hepatic neutrophilic inflammation were not attenuated in IL-1-receptor-1 deficient mice compared to wild-type animals. To evaluate the potential of IL-1beta to increase injury, mice were given pharmacological doses of IL-1beta after APAP overdose. Despite increased systemic activation of neutrophils and recruitment into the liver, there was no alteration in injury. We conclude that endogenous IL-1beta formation after APAP overdose is insufficient to activate and recruit neutrophils into the liver or cause liver injury. Even high pharmacological doses of IL-1beta, which induce hepatic neutrophil accumulation and activation, do not enhance APAP-induced liver injury. Thus, IL-1 signaling is irrelevant for APAP hepatotoxicity. The inflammatory cascade is a less important therapeutic target than intracellular signaling pathways to attenuate APAP-induced liver injury.
authors.affiliation: Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
authors.forename: C David
authors.initials: CD
authors.lastname: Williams
authors.forename: Anwar
authors.initials: A
authors.lastname: Farhood
authors.forename: Hartmut
authors.initials: H
authors.lastname: Jaeschke
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D039481:CD11b Antigen / Q000096:biosynthesis; D020170:Caspase 1 / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D061945:Caspase Inhibitors; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D053583:Interleukin-1beta / Q000097:blood / Q000235:genetics / Q000276:immunology*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D039481:CD11b Antigen; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D053583:Interleukin-1beta; D017382:Reactive Oxygen Species; D000082:Acetaminophen; D053148:Caspase 3; D020170:Caspase 1