ArticleThe American journal of pathology2026
IL-6 trans-Signaling Regulates Neutrophilic Inflammation in Alcohol-Associated Hepatitis.
Article in The American journal of pathology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers, 1 of them a synthesis that pooled it.
What it found
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Who cites it
4 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Clinical outcomes of early versus standard liver transplantation in patients with alcohol-related liver disease: a meta-analysis.Langenbeck's archives of surgery · 2026Pooled it
- Gut-liver axis molecular mechanisms in alcohol-associated liver disease.Alcohol (Fayetteville, N.Y.) · 2026Review
- Gut-Liver Axis Failure in Critical Alcohol-Associated Liver Disease: From ICU Secondary Hits to Microbiome-Targeted Therapy.Mediators of inflammation · 2026Review
- ADAM17 as a proteolytic rheostat linking inflammation, tissue repair, and failure of inflammatory resolution in liver injury and fibrosis.Frontiers in pharmacology · 2026Review
Corrections and comments
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Authors and funding
12 authors.
Funding
Abstract
Alcohol-associated hepatitis (AH) is a form of acute-on-chronic liver failure characterized by intrahepatic neutrophilic inflammation. In hepatocytes, IL-6 signals through either membrane-bound (classical signaling) or soluble (trans-signaling; TS) IL-6 receptors (IL-6Rs) to regulate liver injury responses. This study investigated the role of IL-6TS in the pathophysiology of AH. RNA sequencing of liver biopsies from patients with alcohol-related liver disease demonstrated a progressive decline in IL-6R expression correlating with increasing AH severity. Transforming growth factor (TGF)-β1 emerged as the most potent negative regulator of IL-6R expression. Notably, STAT3-dependent gene expression was increased in severe AH. In vitro, treatment of HepG2 cells with TGF-β1 suppressed IL-6R expression. Subsequent treatment with either IL-6 to stimulate classical signaling, or hyper-IL-6, a recombinant IL-6/IL-6R α peptide, to activate trans-signaling activated STAT3. Hyper-IL-6, but not IL-6, restored STAT3 activation in the face of suppressed IL-6R. RNA sequencing of hyper-IL-6 stimulated cells identified a gene signature that stratified a subset of AH patients with: i) enhanced IL-6TS activity, ii) increased intrahepatic neutrophilic infiltration, and iii) transcriptional enrichment of leukocyte migration pathways. Female mice treated with 10-day chronic-plus-binge ethanol exhibited enhanced STAT3 activation despite reduced hepatic IL-6R expression, leading to increased expression of neutrophilic activators, with colocalization of Ly6G
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