Low Interleukin-22 Binding Protein Is Associated With High Mortality in Alcoholic Hepatitis and Modulates Interleukin-22 Receptor Expression. Issue 8 (19th August 2020)

• Record Type: Journal Article
• Authors: Støy, Sidsel; Laursen, Tea Lund; Glavind, Emilie; Eriksen, Peter Lykke; Terczynska-Dyla, Ewa; Magnusson, Nils Erik; Hamilton-Dutoit, Stephen; Mortensen, Frank Viborg; Veidal, Sanne Skovgård; Rigbolt, Kristoffer; Riggio, Oliviero; Deleuran, Bent; Vilstrup, Hendrik; Sandahl, Thomas Damgaard.
• Is Part Of: Clinical and translational gastroenterology. Volume 11:Issue 8(2020)
• Page Start: e00197
• Publication Date: 2020-08-19
• Subjects: Stomach -- Diseases -- Periodicals; Intestines -- Diseases -- Periodicals; Gastroenterology; Gastrointestinal Diseases; Liver Diseases; Intestines -- Diseases; Stomach -- Diseases; Periodical; Periodicals; Fulltext; Internet Resources; Periodicals; Electronic journals; 616.33
• DOI: 10.14309/ctg.0000000000000197
• Languages: English
• ISSNs: 2155-384X

Abstract

Abstract : INTRODUCTION: In alcoholic hepatitis (AH), high interleukin (IL)-22 production is associated with disease improvement, purportedly through enhanced infection resistance and liver regeneration. IL-22 binding protein (BP) binds and antagonizes IL-22 bioactivity, but data on IL-22BP in liver disease suggest a complex interplay. Despite the scarcity of human data, IL-22 is in clinical trial as treatment of AH. We, therefore, in patients with AH, described the IL-22 system focusing on IL-22BP and associations with disease course, and mechanistically pursued the human associations in vitro . METHODS: We prospectively studied 41 consecutive patients with AH at diagnosis, days 7 and 90, and followed them for up to 1 year. We measured IL-22 pathway proteins in liver biopsies and blood and investigated IL-22BP effects on IL-22 in hepatocyte cultures. RESULTS: IL-22BP was produced in the gut and was identifiable in the patients with AH' livers. Plasma IL-22BP was only 50% of controls and the IL-22/IL-22BP ratio thus elevated. Consistently, IL-22-inducible genes were upregulated in AH livers at diagnosis. Low plasma IL-22BP was closely associated with high 1-year mortality. In vitro, IL-22 stimulation reduced IL-22 receptor (R) expression, but coincubation with IL-22BP sustained IL-22R expression. In the AH livers, IL-22R mRNA expression was similar to healthy livers, although IL-22R liver protein was higher at diagnosis. DISCUSSION: Plasma IL-22BP was associated with an adverse disease course, possibly because its low level reduces IL-22R expression so that IL-22 bioactivity was reduced. This suggests the IL-BP interplay to be central in AH pathogenesis, and in future treatment trials (see Visual abstract, Supplementary Digital Content 5, http://links.lww.com/CTG/A338 ).