title: Application of IL-36 receptor antagonist weakens CCL20 expression and impairs recovery in the late phase of murine acetaminophen-induced liver injury.
abstract: Overdosing of the analgesic acetaminophen (APAP, paracetamol) is a major cause of acute liver injury. Whereas toxicity is initiated by hepatocyte necrosis, course of disease is regulated by mechanisms of innate immunity having the potential to serve in complex manner pathogenic or pro-regenerative functions. Interleukin (IL)-36γ has been identified as novel IL-1-like cytokine produced by and targeting epithelial (-like) tissues. Herein, we investigated IL-36γ in acute liver disease focusing on murine APAP-induced hepatotoxicity. Enhanced expression of hepatic IL-36γ and its prime downstream chemokine target CCL20 was detected upon liver injury. CCL20 expression coincided with the later regeneration phase of intoxication. Primary murine hepatocytes and human Huh7 hepatocellular carcinoma cells indeed displayed enhanced IL-36γ expression when exposed to inflammatory cytokines. Administration of IL-36 receptor antagonist (IL-36Ra) decreased hepatic CCL20 in APAP-treated mice. Unexpectedly, IL-36Ra likewise increased late phase hepatic injury as detected by augmented serum alanine aminotransferase activity and histological necrosis which suggests disturbed tissue recovery upon IL-36 blockage. Finally, we demonstrate induction of IL-36γ in inflamed livers of endotoxemic mice. Observations presented introduce IL-36γ as novel parameter in acute liver injury which may contribute to the decision between unleashed tissue damage and initiation of liver regeneration during late APAP toxicity.
authors: 1] pharmazentrum frankfurt/ZAFES, University Hospital Goethe-University Frankfurt [2] Clinic for Anesthesiology, University Hospital Ludwig-Maximilians-University Munich.
authors: Patrick
authors: P
authors: Scheiermann
authors: pharmazentrum frankfurt/ZAFES, University Hospital Goethe-University Frankfurt.
authors: Malte
authors: M
authors: Bachmann
authors: pharmazentrum frankfurt/ZAFES, University Hospital Goethe-University Frankfurt.
authors: Lorena
authors: L
authors: Härdle
authors: Medical Clinic I, University Hospital Goethe-University Frankfurt, Germany.
authors: Thomas
authors: T
authors: Pleli
authors: Medical Clinic I, University Hospital Goethe-University Frankfurt, Germany.
authors: Albrecht
authors: A
authors: Piiper
authors: Clinic for Anesthesiology, University Hospital Ludwig-Maximilians-University Munich.
authors: Bernhard
authors: B
authors: Zwissler
authors: pharmazentrum frankfurt/ZAFES, University Hospital Goethe-University Frankfurt.
authors: Josef
authors: J
authors: Pfeilschifter
authors: pharmazentrum frankfurt/ZAFES, University Hospital Goethe-University Frankfurt.
authors: Heiko
authors: H
authors: Mühl
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D054418:Chemokine CCL20 / Q000235:genetics*; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D007375:Interleukin-1 / Q000235:genetics; D008297:Male; D051379:Mice; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000082:Acetaminophen; D054418:Chemokine CCL20; D007375:Interleukin-1; D017472:Receptors, Interleukin-1; C569167:IL1F9 protein, mouse; C569500:Il1rl2 protein, mouse