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Cited by 29Liver physiology and pathologyDrug-Induced Hepatotoxicity and Protectioninterferon and immune responses

Mechanisms of concanavalin A-induced cytokine synthesis by hepatic stellate cells: Distinct roles of interferon regulatory factor-1 in liver injury

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Rani, Richa, Kumar, Sudhir, Sharma, Akanksha, Mohanty, Sujit K., Donnelly, Bryan, Tiao, Gregory M., Gandhi, Chandrashekhar R.·2018·Journal of Biological Chemistry
DOI 10.1074/jbc.ra118.005583PMC PMC6290141
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Abstract

Mice depleted of hepatic stellate cells (HSCs) are protected from concanavalin A (ConA)-induced liver injury that is mediated by the activation of interferon regulatory factor 1 (IRF1). The aim of this study was to determine the mechanisms of ConA-mediated signaling and synthesis/release of mediators by HSCs that damage hepatocytes. Primary cultures of wildtype (WT) and IRF1-knockout (KO) HSCs and hepatocytes were used, and ConA-induced liver damage in interferon (IFN)αβ receptor-deficient (IFNαβR-KO) mice was determined. Specific binding of ConA to HSCs induced rapid activation of JAK2 and STAT1. ConA-induced expression of IRF1, IFNβ, tumor necrosis factor α, and CXCL1 was abrogated by selective inhibition of JAK2 and STAT1. Despite activating JAK2/STAT1, ConA failed to stimulate expression of inflammatory cytokines in HSCs from IRF1-KO mice. ConA-conditioned WT-HSC medium caused activation of JNK and caspase 3, and apoptosis of hepatocytes from WT but not from IRF1-KO or IFNαβR-KO mice. Conversely, ConA-conditioned medium of IRF1-KO HSCs failed to cause apoptosis of WT or IRF1-KO hepatocytes. IFNαβR-KO mice were protected from ConA-induced liver damage, and ConA-induced hepatic expression of IRF1 and pro-inflammatory cytokines and chemokines, and infiltration of neutrophils were significantly lower in IFNαβR-KO than in WT mice. These results demonstrate distinct roles of IRF1 in hepatic inflammation (HSCs) and injury (hepatocytes) and can be an important target for intervention in acute liver injury.

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  • HSC depletion with lower potency and specificity, using gliotoxin or GFAP-TK, has yielded inconsistent effects on liver regeneration and injury.

    “HSC depletion with lower potency and specificity, using gliotoxin or GFAP-TK, has yielded inconsistent effects on liver regeneration and injury15–18.”

    From Hepatic stellate cells control liver zonation, size and functions via R-spondin 3 (2025) · cites this paper as [18]

    The Abstract (page unavailable) reports that HSC-depleted mice were protected from ConA-induced liver injury and cites protection from two other forms of acute liver injury. It does not describe gliotoxin or GFAP-TK depletion, assess their potency or specificity, or report inconsistent effects on liver regeneration and injury. (LLM, conf=0.79)

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Cited by

Sorted by citations

Authors
Rani, R., Kumar, S., Sharma, A., Mohanty, S. K., Donnelly, B., Tiao, G. M., & Gandhi, C. R.
Affiliations
Cincinnati Children's Hospital Medical Center (US)
Corresponding author
Gandhi, Chandrashekhar R.
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2018-11
Volume
293
Issue
48
Pages
18466-18476
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.ra118.005583
PMC
PMC6290141
OpenAlex
W2897472286
Cited by
29
References
3
Citations by year
2026: 2 · 2025: 4 · 2024: 3 · 2023: 2 · 2022: 6 · 2021: 4 · 2020: 4 · 2019: 3 · 2017: 1
FWCI
1.72
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Veterans Affairs (VA) (1IOBX001174)
  • U.S. Department of Defense (DOD) (W81XWH-14-PRMRP-IIRA)
Topics
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
  • Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
Keywords
concanavalin A, hepatic stellate cells, IRF1, liver injury, IFNAR, JAK2/STAT1 signaling, hepatocyte apoptosis, inflammatory cytokines, CXCL1, neutrophil infiltration, acute liver injury, hepatocyte activation
MeSH terms
Superoxide Dismutase-1, Animals, Cells, Cultured, Concanavalin A, Interferon-gamma, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Signal Transduction, Cytokines, Culture Media, Conditioned, Mice, Knockout, Interferon Regulatory Factor-1, Receptor, Interferon alpha-beta, Hepatic Stellate Cells, Chemical and Drug Induced Liver Injury

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