TY - JOUR T1 - Interleukin-11 drives human and mouse alcohol-related liver disease JF - Gut JO - Gut DO - 10.1136/gutjnl-2021-326076 SP - gutjnl-2021-326076 AU - Maria Effenberger AU - Anissa A Widjaja AU - Felix Grabherr AU - Benedikt Schaefer AU - Christoph Grander AU - Lisa Mayr AU - Julian Schwaerzler AU - Barbara Enrich AU - Patrizia Moser AU - Julia Fink AU - Alisa Pedrini AU - Nikolai Jaschke AU - Alexander Kirchmair AU - Alexandra Pfister AU - Bela Hausmann AU - Reto Bale AU - Daniel Putzer AU - Heinz Zoller AU - Sebastian Schafer AU - Petra Pjevac AU - Zlatko Trajanoski AU - Georg Oberhuber AU - Timon Adolph AU - Stuart Cook AU - Herbert Tilg Y1 - 2022/03/31 UR - http://gut.bmj.com/content/early/2022/03/31/gutjnl-2021-326076.abstract N2 - 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. ER -