title: The damage-associated molecular pattern HMGB1 is elevated in human alcoholic hepatitis, but does not seem to be a primary driver of inflammation.
abstract: The role of sterile inflammation caused by release of damage-associated molecular patterns (DAMP) remains unclear in human alcoholic hepatitis (AH). The DAMP, high mobility group box-1 protein (HMGB1) is released by tissue damage and inflammation. We aimed to investigate whether HMGB1 is a primary inflammatory driver in AH by determining HMGB1 serum levels and effects on inflammatory cells from AH patients. We measured serum HMGB1 in 34 AH patients and 10 healthy controls using ELISA. Toll-like receptor 4 (TLR4) and CD14 expressions were assessed by flow cytometry on HMGB1-stimulated peripheral blood mononuclear cells (PBMC) and ELISA was used to measure TNF-α and IL-1β in the supernatants. We observed 5-fold higher serum levels of HMGB1 in AH patients at the day of diagnosis and day 30, but no associations to clinical outcome. HMGB1 stimulation increased the expression of TLR4 on CD14+-monocytes compared with unstimulated cells in the AH patients. The TNF-α and IL-1β production in response to HMGB1 was diminished in AH patients. In conclusion, AH patients have increased levels of HMGB1 in their blood. This combined with an increased TLR4 expression, but an unaffected cytokine response to HMGB1 suggest that HMGB1 is not the primary driver of inflammation in AH.
authors.affiliation: Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Tea Lund
authors.initials: TL
authors.lastname: Laursen
authors.affiliation: Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Sidsel
authors.initials: S
authors.lastname: Støy
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Bent
authors.initials: B
authors.lastname: Deleuran
authors.affiliation: Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Vilstrup
authors.affiliation: Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Henning
authors.initials: H
authors.lastname: Grønbaek
authors.affiliation: Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Thomas Damgaard
authors.initials: TD
authors.lastname: Sandahl
mesh_terms: D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D003470:Culture Media / Q000737:chemistry; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D024243:HMGB1 Protein / Q000097:blood*; D006519:Hepatitis, Alcoholic / Q000473:pathology* / Q000503:physiopathology*; D006801:Humans; D053583:Interleukin-1beta / Q000032:analysis; D007963:Leukocytes, Mononuclear / Q000737:chemistry / Q000187:drug effects; D018950:Lipopolysaccharide Receptors / Q000032:analysis; D008297:Male; D008875:Middle Aged; D044967:Serum / Q000737:chemistry*; D051197:Toll-Like Receptor 4 / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D055815:Young Adult
chemical_list: D003470:Culture Media; D024243:HMGB1 Protein; C585491:HMGB1 protein, human; D053583:Interleukin-1beta; D018950:Lipopolysaccharide Receptors; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha
keywords: Alcoholic hepatitis; IL-1β; TNF-α and Toll-like receptor 4; high mobility group box-1 protein