Bile Acids Induce Inflammatory Genes in Hepatocytes

Allen, Katryn; Jaeschke, Hartmut; Copple, Bryan L.

doi:10.1016/j.ajpath.2010.11.026

Cited by 501Liver physiology and pathologyImmune Response and InflammationDrug-Induced Hepatotoxicity and Protection

Bile Acids Induce Inflammatory Genes in Hepatocytes

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Allen, Katryn, Jaeschke, Hartmut, Copple, Bryan L.·2011·The American Journal of Pathology

DOI 10.1016/j.ajpath.2010.11.026PMC PMC3070591

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Abstract

Inflammation contributes to liver injury during cholestasis. The mechanism by which cholestasis initiates an inflammatory response in the liver, however, is not known. Two hypotheses were investigated in the present studies. First, activation of Toll-like receptor 4 (TLR4), either by bacterial lipopolysaccharide or by damage-associated molecular pattern molecules released from dead hepatocytes, triggers an inflammatory response. Second, bile acids act as inflammagens, and directly activate signaling pathways in hepatocytes that stimulate production of proinflammatory mediators. Liver inflammation was not affected in lipopolysaccharide-resistant C3H/HeJ mice after bile duct ligation, indicating that Toll-like receptor 4 is not required for initiation of inflammation. Treatment of hepatocytes with bile acids did not directly cause cell toxicity but increased the expression of numerous proinflammatory mediators, including cytokines, chemokines, adhesion molecules, and other proteins that influence immune cell levels and function. Up-regulation of several of these genes in hepatocytes and in the liver after bile duct ligation required early growth response factor-1, but not farnesoid X receptor. In addition, early growth response factor-1 was up-regulated in the livers of patients with cholestasis and correlated with levels of inflammatory mediators. These data demonstrate that Toll-like receptor 4 is not required for the initiation of acute inflammation during cholestasis. In contrast, bile acids directly activate a signaling network in hepatocytes that promotes hepatic inflammation during cholestasis.

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Bile salts are toxic at high concentrations.
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Authors: Allen, K., Jaeschke, H., & Copple, B. L.
Affiliations: University of Kansas Medical Center (US)
Corresponding author: Copple, Bryan L.
ORCID: Jaeschke, Hartmut
Venue: The American Journal of Pathology
Publisher: Elsevier BV
Published: 2011-01
Volume: 178
Issue: 1
Pages: 175-186
ISSN: 0002-9440 (ISSN-L)
DOI: 10.1016/j.ajpath.2010.11.026
PMC: PMC3070591
OpenAlex: W1534017202
Cited by: 501
References: 65
Citations by year: 2026: 25 · 2025: 35 · 2024: 33 · 2023: 47 · 2022: 37 · 2021: 39 · 2020: 44 · 2019: 42 · 2018: 33 · 2017: 43 · 2016: 35 · 2015: 22 · 2014: 28 · 2013: 22 · 2012: 7
FWCI: 13.17
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 3268 d)
Locations: American Journal Of Pathology (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (AA12916, DK073566)
University of Kansas Medical Center (P20 RR016475)
National Center for Research Resources
Topics: Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Keywords: bile acids, cholestasis, liver inflammation, TLR4, lipopolysaccharide, damage-associated molecular patterns, early growth response factor-1, farnesoid X receptor, hepatocytes, bile duct ligation, pro-inflammatory mediators, cytokines, chemokines, adhesion molecules, liver injury
MeSH terms: Receptor, Farnesoid X-Activated, Animals, Bile Acids and Salts, Cell Survival, Cholestasis, Gene Expression Regulation, Hepatitis, Lipopolysaccharides, Liver, Mice, Inbred C57BL, Neutrophils, Receptors, Cytoplasmic and Nuclear, Intercellular Adhesion Molecule-1, Vascular Cell Adhesion Molecule-1, ras-GRF1, Hepatocytes, Toll-Like Receptor 4, Mice, Early Growth Response Protein 1, Chemokine CCL7, Chemokine CXCL2, Serpin E2

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Bile Acids Induce Inflammatory Genes in Hepatocytes

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