title: Application of interleukin-22 mediates protection in experimental acetaminophen-induced acute liver injury.
abstract: Acetaminophen (APAP, paracetamol)-induced hepatotoxicity, although treatable by timely application of N-acetylcysteine, can be fatal. Because it is among the common causes of acute liver failure in intensive care units and in light of its gradually increasing incidence, the need for novel therapeutic strategies aimed at severe intoxication is apparent. Recently, it has been shown that IL-22, a STAT3-activating cytokine, has the capability to mediate liver protection. Herein, the protective potential of IL-22 in murine APAP-induced hepatotoxicity was assessed. Intravenous administration of prophylactic IL-22 significantly reduced serum alanine aminotransferase levels and histopathologic damage in APAP-induced liver injury, a process that coincided with increased hepatocyte proliferation in vivo. Concomitant gene expression analysis revealed hepatic induction of genes prototypically up-regulated by the IL-22/STAT3 axis, among others suppressor of cytokine signaling-3, lipocalin-2, and α1-antichymotrypsin. Notably, in a translational setting of therapeutic treatment 2 hours after APAP, IL-22 supported protection in the context of suboptimal N-acetylcysteine dosing. IL-22 likewise connected to augmented hepatocyte proliferation in this experimental setting. As detected by analysis of inflammatory cytokine production, systemically applied IL-22 did not display acute immunomodulation/stimulation in otherwise untreated or endotoxemic mice. Those latter observations clearly confirm acute tolerability of systemically applied IL-22. Observations presented altogether suggest that therapeutic IL-22 administration is a conceivable tissue-protective regimen aimed at hard-to-treat patients with severe APAP-induced hepatotoxicity.
authors: Pharmazentrum Frankfurt/Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit ZAFES, General Pharmacology and Toxicology, University Hospital Goethe-University Frankfurt, 60590 Frankfurt am Main, Germany.
authors: Patrick
authors: P
authors: Scheiermann
authors: Malte
authors: M
authors: Bachmann
authors: Itamar
authors: I
authors: Goren
authors: Bernhard
authors: B
authors: Zwissler
authors: Josef
authors: J
authors: Pfeilschifter
authors: Heiko
authors: H
authors: Mühl
mesh_terms: D000082:Acetaminophen; D000208:Acute Disease; D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000473:pathology; D016207:Cytokines / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects; D056747:Immunomodulation / Q000187:drug effects; D018836:Inflammation Mediators / Q000097:blood; D007378:Interleukins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020011:Protective Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000097043:Interleukin-22
chemical_list: D000082:Acetaminophen; D016207:Cytokines; D018836:Inflammation Mediators; D007378:Interleukins; D020011:Protective Agents; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D000097043:Interleukin-22