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Original research
Interleukin-11 drives human and mouse alcohol-related liver disease
  1. Maria Effenberger1,
  2. Anissa A Widjaja2,
  3. Felix Grabherr1,
  4. Benedikt Schaefer1,
  5. Christoph Grander1,
  6. Lisa Mayr1,
  7. Julian Schwaerzler1,
  8. Barbara Enrich1,
  9. Patrizia Moser3,
  10. Julia Fink1,
  11. Alisa Pedrini1,
  12. Nikolai Jaschke1,
  13. Alexander Kirchmair4,
  14. Alexandra Pfister1,
  15. Bela Hausmann5,6,
  16. Reto Bale7,
  17. Daniel Putzer7,
  18. Heinz Zoller1,
  19. Sebastian Schafer2,8,
  20. Petra Pjevac5,9,
  21. Zlatko Trajanoski4,
  22. Georg Oberhuber3,
  23. Timon Adolph1,
  24. Stuart Cook2,10,
  25. Herbert Tilg1
  1. 1Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria
  2. 2Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore
  3. 3INNPATH, Innsbruck Medical University Hospital, Innsbruck, Austria
  4. 4Biocenter, Institute of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria
  5. 5Joint Microbiome Facility of the Medical University of Vienna and the University of Vienna, Medical University of Vienna, University of Vienna, Vienna, Austria
  6. 6Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
  7. 7Department of Radiology, Section of Interventional Oncology-Microinvasive Therapy (SIP), Medical University of Innsbruck, Innsbruck, Austria
  8. 8National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore
  9. 9Centre for Microbiology and Environmental Systems Science, Department of Microbiology and Ecosystem Science, Division of Microbial Ecology, University of Vienna, Vienna, Austria
  10. 10MRC-London Institute of Medical Sciences, Hammersmith Hospital Campus, London, UK
  1. Correspondence to Professor Dr. Herbert Tilg, Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, Innsbruck, Austria; herbert.tilg{at}i-med.ac.at

Abstract

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.

  • CIRRHOSIS
  • ALCOHOLIC LIVER DISEASE
  • INFLAMMATION
  • INTERLEUKINS

Data availability statement

All data relevant to the study are included in the article or uploaded as online supplemental information. Not applicable.

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Data availability statement

All data relevant to the study are included in the article or uploaded as online supplemental information. Not applicable.

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Footnotes

  • Contributors ME and HT designed the project and wrote the paper. FG, AAW, LM, AP, JS, NJ and BE contributed to murine studies, JF, ZT, AK, RB, DP, and AP purchased human data. GO performed the histological analysis. BS and CG verified the analytical methods and analysed the data. RB and DP were involved in patient's recruitment. SC, AAW contributed to in vitro experiments. BH and PP analysed the murine stool samples. TA, HZ, SS and SC provided critical feedback and contributed to data analysis and manuscript preparation. SC, AAW and SS contributed to the manuscript preparation along with TA and HZ. HT is responsible for the overall content.

  • Funding This study is supported by the excellence initiative VASCage (Centre for Promoting Vascular Health in the Ageing Community), an R&D K-Centre (COMET program-Competence Centers for Excellent Technologies) funded by the Austrian Ministry for Transport, Innovation and Technology, the Austrian Ministry for Digital and Economic Affairs and the federal states Tyrol, Salzburg and Vienna. We are grateful for the support received from the Austrian Science Fund (FWF P33070) and the European Research Council (ERC-STG: 101039320).

  • Competing interests SC, SS and AAW are coinventors of the patent application US 2020/0262910 and other patents relating to IL11 biology. SC and SS are coshareholders of Enleofen Bio PTE.

  • Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.