ArticleChemical research in toxicology2012
Endogenous interleukin-4 regulates glutathione synthesis following acetaminophen-induced liver injury in mice.
Article in Chemical research in toxicology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 49 citations in OpenAlex.
- Loss of Vacuole Membrane Protein 1 protects against acetaminophen-induced liver injury by modulating inflammation and hepatocyte proliferation.Toxicological sciences : an official journal of the Society of Toxicology · 2026Article
- Macrophages: Subtypes, Distribution, Polarization, Immunomodulatory Functions, and Therapeutics.MedComm · 2025Review
- Good Cells Go Bad: Immune Dysregulation in the Transition from Acute Liver Injury to Liver Failure After Acetaminophen Overdose.Drug metabolism and disposition: the biological fate of chemicals · 2024Review
- Central Mechanisms of Acetaminophen Hepatotoxicity: Mitochondrial Dysfunction by Protein Adducts and Oxidant Stress.Drug metabolism and disposition: the biological fate of chemicals · 2024Review
- High-throughput screening of novel TFEB agonists in protecting against acetaminophen-induced liver injury in mice.Acta pharmaceutica Sinica. B · 2024Article
- Hepatocyte-specific deletion of small heterodimer partner protects mice against acetaminophen-induced hepatotoxicity via activation of Nrf2.Toxicological sciences : an official journal of the Society of Toxicology · 2023Article
- Molecular pathogenesis of acetaminophen-induced liver injury and its treatment options.Journal of Zhejiang University. Science. B · 2022Review
- Oxidant Stress and Acetaminophen Hepatotoxicity: Mechanism-Based Drug Development.Antioxidants & redox signaling · 2021Article
- Liver regeneration and inflammation: from fundamental science to clinical applications.Nature reviews. Molecular cell biology · 2021Review
- Spatial Reconstruction of the Early Hepatic Transcriptomic Landscape After an Acetaminophen Overdose Using Single-Cell RNA-Sequencing.Toxicological sciences : an official journal of the Society of Toxicology · 2021Article
- Novel Therapeutic Approaches Against Acetaminophen-induced Liver Injury and Acute Liver Failure.Toxicological sciences : an official journal of the Society of Toxicology · 2020Review
- p53 Up-regulated Modulator of Apoptosis Induction Mediates Acetaminophen-Induced Necrosis and Liver Injury in Mice.Hepatology (Baltimore, Md.) · 2019Article
- Acetaminophen Hepatotoxicity.Seminars in liver disease · 2019Article
- Double deletion of PINK1 and Parkin impairs hepatic mitophagy and exacerbates acetaminophen-induced liver injury in mice.Redox biology · 2019Article
- Mechanisms of Inflammatory Liver Injury and Drug-Induced Hepatotoxicity.Current pharmacology reports · 2018Article
- The impact of sterile inflammation in acute liver injury.Journal of clinical and translational research · 2017Article
- Glutathione and Glutathione Transferase Omega 1 as Key Posttranslational Regulators in Macrophages.Microbiology spectrum · 2017Review
- Removal of acetaminophen protein adducts by autophagy protects against acetaminophen-induced liver injury in mice.Journal of hepatology · 2016Article
- Hepatic macrophages in homeostasis and liver diseases: from pathogenesis to novel therapeutic strategies.Cellular & molecular immunology · 2016Review
- Chronic Deletion and Acute Knockdown of Parkin Have Differential Responses to Acetaminophen-induced Mitophagy and Liver Injury in Mice.The Journal of biological chemistry · 2015Article
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
In a recent study, we reported that interleukin (IL)-4 had a protective role against acetaminophen (APAP)-induced liver injury (AILI), although the mechanism of protection was unclear. Here, we carried out more detailed investigations and have shown that one way IL-4 may control the severity of AILI is by regulating glutathione (GSH) synthesis. In the present studies, the protective role of IL-4 in AILI was established definitively by showing that C57BL/6J mice made deficient in IL-4 genetically (IL-4(-/-)) or by depletion with an antibody, were more susceptible to AILI than mice not depleted of IL-4. The increased susceptibility of IL-4(-/-) mice was not due to elevated levels of hepatic APAP-protein adducts but was associated with a prolonged reduction in hepatic GSH that was attributed to decreased gene expression of γ-glutamylcysteine ligase (γ-GCL). Moreover, administration of recombinant IL-4 to IL-4(-/-) mice postacetaminophen treatment diminished the severity of liver injury and increased γ-GCL and GSH levels. We also report that the prolonged reduction of GSH in APAP-treated IL-4(-/-) mice appeared to contribute toward increased liver injury by causing a sustained activation of c-Jun-N-terminal kinase (JNK) since levels of phosphorylated JNK remained significantly higher in the IL-4(-/-) mice up to 24 h after APAP treatment. Overall, these results show for the first time that IL-4 has a role in regulating the synthesis of GSH in the liver under conditions of cellular stress. This mechanism appears to be responsible at least in part for the protective role of IL-4 against AILI in mice and may have a similar role not only in AILI in humans but also in pathologies of the liver caused by other drugs and etiologies.
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