A Prominent Role of Interleukin-18 in Acetaminophen-Induced Liver Injury Advocates Its Blockage for Therapy of Hepatic Necroinflammation.

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.

• Authors: Malte Bachmann, Josef Pfeilschifter, Heiko Mühl
• Journal: Frontiers in immunology (Front Immunol) Vol. 9 Pg. 161 ( 2018) ISSN: 1664-3224 [Print] Switzerland
• PMID: 29472923 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Fas Ligand Protein
• Inflammation Mediators
• Intercellular Signaling Peptides and Proteins
• Interleukin-18
• Interleukins
• Recombinant Proteins
• interleukin-18 binding protein
• Acetaminophen
• Interferon-gamma

Topics

• Acetaminophen (adverse effects)
• Animals
• Chemical and Drug Induced Liver Injury (drug therapy, immunology)
• Fas Ligand Protein (metabolism)
• Inflammation (chemically induced, drug therapy, immunology)
• Inflammation Mediators
• Intercellular Signaling Peptides and Proteins (administration & dosage)
• Interferon-gamma (metabolism)
• Interleukin-18 (antagonists & inhibitors, immunology)
• Interleukins (administration & dosage)
• Liver (drug effects, immunology, pathology)
• Mice
• Mice, Inbred C57BL
• Necrosis (chemically induced, drug therapy, immunology)
• Recombinant Proteins (administration & dosage)
• Interleukin-22