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Cited by 99Drug-Induced Hepatotoxicity and ProtectionImmunotoxicology and immune responsesLiver physiology and pathology

Co-culture of Hepatocytes and Kupffer Cells as an In Vitro Model of Inflammation and Drug-Induced Hepatotoxicity

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Rose, Kelly A., Holman, Natalie S., Green, Angela M., Andersen, Melvin E., LeCluyse, Edward L.·2016·Journal of Pharmaceutical Sciences
DOI 10.1016/s0022-3549(15)00192-6PMC PMC5330391
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Abstract

Immune-mediated drug-induced hepatotoxicity is often unrecognized as a potential mode of action due to the lack of appropriate in vitro models. We have established an in vitro rat donor-matched hepatocyte and Kupffer cell co-culture (HKCC) model to study immune-related responses to drug exposure. Optimal cell culture conditions were identified for the maintenance of co-cultures based on cell longevity, monolayer integrity, and cytokine response after lipopolysaccharide (LPS) exposure. Hepatocyte monocultures and HKCCs were then used to test a subset of compounds associated with hepatotoxic effects with or without LPS. Cytokine levels and metabolic activity (cytochrome P450 3A [Cyp3A]) were measured after a 48-h exposure to monitor endotoxin-induced changes in acute phase and functional end points. LPS-activated HKCCs, but not hepatocyte monocultures, treated with trovafloxacin or acetaminophen, compounds associated with immune-mediated hepatotoxicity, showed LPS-dependent decreases in interleukin-6 production with concomitant increases in Cyp3A activity. Differential endotoxin- and model-dependent alterations were observed in cytokine profiles and Cyp3A activity levels that corresponded to specific compounds. These results indicate the utility of the HKCC model system to discern compound-specific effects that may lead to enhanced or mitigate hepatocellular injury due to innate or adaptive immune responses.

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  • Measured levels of IL-6 and TNFα in vehicle-treated Liver-Chips were low (300-400 pg/mL for IL-6 and 5-25 pg/mL for TNFα), indicative of non-activated cells and comparable to literature values.

    “The measured levels in vehicle-treated Liver-Chips were low (300–400 pg/mL for IL-6 and 5–25 pg/mL for TNFα), indicative of non-activated cells and comparable to literature values42.”

    From Performance assessment and economic analysis of a human Liver-Chip for predictive toxicology (2022) · cites this paper as [42]

    In Results, under “Immune-Mediated Toxicity Testing Using the Modified HKCC System” (page unavailable), the paper reports that LPS activation markedly increased IL-6 and TNF-α relative to vehicle controls without LPS. This supports the qualitative comparison with non-activated cells, but the paper studies rat hepatocyte–Kupffer-cell co-cultures, not Liver-Chips, and the cited passages do not establish the stated 300–400 and 5–25 pg/mL ranges. (LLM, conf=0.82)

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Sorted by citations

Authors
Rose, K. A., Holman, N. S., Green, A. M., Andersen, M. E., & LeCluyse, E. L.
Affiliations
  • The Hamner Institutes for Health Sciences (US)
  • University of North Carolina at Chapel Hill (US)
Corresponding author
LeCluyse, Edward L.
ORCID
Venue
Journal of Pharmaceutical Sciences
Publisher
Elsevier BV
Published
2016-02
Volume
105
Issue
2
Pages
950-964
ISSN
0022-3549 (ISSN-L)
DOI
10.1016/s0022-3549(15)00192-6
PMC
PMC5330391
OpenAlex
W2302134090
Cited by
99
References
1
Citations by year
2026: 6 · 2025: 11 · 2024: 12 · 2023: 5 · 2022: 7 · 2021: 12 · 2020: 14 · 2019: 5 · 2018: 11 · 2017: 10 · 2016: 6
FWCI
13.41
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Journal of Pharmaceutical Sciences (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
  • UNC Libraries
Funders
  • American Chemistry Council
  • National Institute of Environmental Health Sciences (T32ES007126)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords
drug-induced liver injury, inflammation, lipopolysaccharide, CYP3A, cytokines, interleukin-6, trovafloxacin, paracetamol, in vitro toxicity models, innate immune response
MeSH terms
Animals, Cells, Cultured, Dose-Response Relationship, Drug, Glucocorticoids, Inflammation, Kupffer Cells, Lipopolysaccharides, Male, Rats, Sprague-Dawley, Inflammation Mediators, Coculture Techniques, Hepatocytes, Rats, Chemical and Drug Induced Liver Injury

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