RT Journal Article
SR Electronic
T1 Interleukin-11 drives human and mouse alcohol-related liver disease
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 168
OP 179
DO 10.1136/gutjnl-2021-326076
VO 72
IS 1
A1 Maria Effenberger
A1 Anissa A Widjaja
A1 Felix Grabherr
A1 Benedikt Schaefer
A1 Christoph Grander
A1 Lisa Mayr
A1 Julian Schwaerzler
A1 Barbara Enrich
A1 Patrizia Moser
A1 Julia Fink
A1 Alisa Pedrini
A1 Nikolai Jaschke
A1 Alexander Kirchmair
A1 Alexandra Pfister
A1 Bela Hausmann
A1 Reto Bale
A1 Daniel Putzer
A1 Heinz Zoller
A1 Sebastian Schafer
A1 Petra Pjevac
A1 Zlatko Trajanoski
A1 Georg Oberhuber
A1 Timon Adolph
A1 Stuart Cook
A1 Herbert Tilg
YR 2023
UL http://gut.bmj.com/content/72/1/168.abstract
AB Objective Alcoholic hepatitis (AH) reflects acute exacerbation of alcoholic liver disease (ALD) and is a growing healthcare burden worldwide. Interleukin-11 (IL-11) is a profibrotic, proinflammatory cytokine with increasingly recognised toxicities in parenchymal and epithelial cells. We explored IL-11 serum levels and their prognostic value in patients suffering from AH and cirrhosis of various aetiology and experimental ALD.Design IL-11 serum concentration and tissue expression was determined in a cohort comprising 50 patients with AH, 110 patients with cirrhosis and 19 healthy volunteers. Findings were replicated in an independent patient cohort (n=186). Primary human hepatocytes exposed to ethanol were studied in vitro. Ethanol-fed wildtype mice were treated with a neutralising murine IL-11 receptor-antibody (anti-IL11RA) and examined for severity signs and markers of ALD.Results IL-11 serum concentration and hepatic expression increased with severity of liver disease, mostly pronounced in AH. In a multivariate Cox-regression, a serum level above 6.4 pg/mL was a model of end-stage liver disease independent risk factor for transplant-free survival in patients with compensated and decompensated cirrhosis. In mice, severity of alcohol-induced liver inflammation correlated with enhanced hepatic IL-11 and IL11RA expression. In vitro and in vivo, anti-IL11RA reduced pathogenic signalling pathways (extracellular signal-regulated kinases, c-Jun N-terminal kinase, NADPH oxidase 4) and protected hepatocytes and murine livers from ethanol-induced inflammation and injury.Conclusion Pathogenic IL-11 signalling in hepatocytes plays a crucial role in the pathogenesis of ALD and could serve as an independent prognostic factor for transplant-free survival. Blocking IL-11 signalling might be a therapeutic option in human ALD, particularly AH.All data relevant to the study are included in the article or uploaded as online supplemental information. Not applicable.