Abstract
Acetaminophen [paracetamol, N-acetyl-p-aminophenol (APAP)]-induced acute liver injury (ALI) not only remains a persistent clinical challenge but likewise stands out as well-characterized paradigmatic model of drug-induced liver damage. APAP intoxication associates with robust hepatic necroinflammation the role of which remains elusive with pathogenic but also pro-regenerative/-resolving functions being ascribed to leukocyte activation. Here, we shine a light on and put forward a unique role of the interleukin (IL)-1 family member IL-18 in experimental APAP-induced ALI. Indeed, amelioration of disease as previously observed in IL-18-deficient mice was further substantiated herein by application of the IL-18 opponent IL-18-binding protein (IL-18BPd:Fc) to wild-type mice. Data altogether emphasize crucial pathological action of this cytokine in APAP toxicity. Adding recombinant IL-22 to IL-18BPd:Fc further enhanced protection from liver injury. In contrast to IL-18, the role of prototypic pro-inflammatory IL-1 and tumor necrosis factor-α is controversially discussed with lack of effects or even protective action being repeatedly reported. A prominent detrimental function for IL-18 in APAP-induced ALI as proposed herein should relate to its pivotal role for hepatic expression of interferon-γ and Fas ligand, both of which aggravate APAP toxicity. As IL-18 serum levels increase in patients after APAP overdosing, targeting IL-18 may evolve as novel therapeutic option in those hard-to-treat patients where standard therapy with N-acetylcysteine is unsuccessful. Being a paradigmatic experimental model of ALI, current knowledge on ill-fated properties of IL-18 in APAP intoxication likewise emphasizes the potential of this cytokine to serve as therapeutic target in other entities of inflammatory liver diseases.
Highlights
Intended or unintended overdosing of acetaminophen [paracetamol, N-acetyl-p-aminophenol (APAP)] is regarded a major cause of acute liver failure provoking roughly 50,000 emergency room admissions, 2,500 hospitalizations, and 500 fatalities per year in the United States
The unresolved role of NUCLEAR FACTOR (NF)-κB-activating inflammatory cytokines including that of the caspase-1/IL-1β axis in APAP-induced acute liver injury (ALI) [20, 26, 72,73,74]—see Table 1—may reflect Janus-faced properties of theses mediators in the early injury and the later regeneration phase of intoxication
Regardless of whether being activated by caspase-1, caspase-8, or by extracellular proteases such as proteinase-3 [50, 54], the potential of mature IL-18 to upregulate hepatic IFNγ and Fas ligand (FasL) appears decisive for its function during APAP-induced ALI
Summary
Intended or unintended overdosing of acetaminophen [paracetamol, N-acetyl-p-aminophenol (APAP)] is regarded a major cause of acute liver failure provoking roughly 50,000 emergency room admissions, 2,500 hospitalizations, and 500 fatalities per year in the United States. Administration of a single supra-physiological dose of recombinant IL-22 or its provision by liver-targeted IL-22 gene therapy mediates significant protection against APAP-induced ALI [23,24,25] It adds to the overall complex nature of APAP-induced ALI that just sterile inflammation appears to be a prerequisite for activation of an efficient hepatic pro-regenerative program [20, 26]. Differences in mouse characteristics, including the microbiome [43], as well as variations in APAP dosing may foster divergent conclusions regarding the role of IL-1 and TNFα in APAP-induced ALI Those observations may echo an overlapping double-edged function of inflammation in the context of APAP overdosing. It is noteworthy that an early study reported on amelioration of APAP-induced ALI by application of recombinant IL-1α [49]
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