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.
- ALCOHOLIC LIVER DISEASE
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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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.
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