ArticlePloS one2013
Sex bias in experimental immune-mediated, drug-induced liver injury in BALB/c mice: suggested roles for Tregs, estrogen, and IL-6.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 48 citations in OpenAlex.
- Morphine-induced hepatotoxicity in rats: Sex and dose variations in liver enzymes, oxidative stress, inflammation, apoptosis, and histopathology.Biomolecules & biomedicine · 2026Article
- Inhibition of estrogen receptor alpha stabilizes regulatory T cell function in autoimmune hepatitis.JHEP reports : innovation in hepatology · 2026Article
- Influence of patient age and sex on drug-induced liver injury caused by antiseizure medications: a disproportionality analysis of VigiBase.International journal of clinical pharmacy · 2025Article
- Risk factors related to significant hepatic inflammation in patients with acute drug-induced liver injury.iLIVER · 2024Article
- Article
- Are Gender Differences Important for Autoimmune Liver Diseases?Life (Basel, Switzerland) · 2024Review
- Mechanisms and consequences of sex differences in immune responses.Nature reviews. Nephrology · 2024Review
- The Role of Sex in Acute and Chronic Liver Damage.International journal of molecular sciences · 2022Review
- Roles of Cofactors in Drug-Induced Liver Injury: Drug Metabolism and Beyond.Drug metabolism and disposition: the biological fate of chemicals · 2022Review
- Improved up-and-down procedure for acute toxicity measurement with reliable LDBMC pharmacology & toxicology · 2022Article
- Harnessing natural variation to identify cis regulators of sex-biased gene expression in a multi-strain mouse liver model.PLoS genetics · 2021Article
- Disruption of type I interferon signaling causes sexually dimorphic dysregulation of anti-viral cytokines.Cytokine: X · 2021Article
- Characteristics of Drug-Induced Liver Injury in Northeast China: Disease Spectrum and Drug Types.Digestive diseases and sciences · 2020Article
- Estrogenic control of mitochondrial function.Redox biology · 2020Review
- High Serum Estradiol Reduces Acute Hepatotoxicity Risk Induced by Epirubicin Plus Cyclophosphamide Chemotherapy in Premenopausal Women with Breast Cancer.Frontiers in pharmacology · 2020Article
- Buffalo liver transcriptome analysis suggests immune tolerance as its key adaptive mechanism during early postpartum negative energy balance.Functional & integrative genomics · 2019Article
- In drug-induced, immune-mediated hepatitis, interleukin-33 reduces hepatitis and improves survival independently and as a consequence of FoxP3+ T-cell activity.Cellular & molecular immunology · 2019Article
- Metabolic Comorbidities and Risk of Development and Severity of Drug-Induced Liver Injury.BioMed research international · 2019Review
- Identification of a Shared Cytochrome p4502E1 Epitope Found in Anesthetic Drug-Induced and Viral Hepatitis.mSphere · 2018Article
- Administration of 17β-Estradiol Improves Motoneuron Survival and Down-regulates Inflammasome Activation in Male SOD1(G93A) ALS Mice.Molecular neurobiology · 2017Article
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
BACKGROUND AND
aimsImmune-mediated, drug-induced liver injury (DILI) triggered by drug haptens is more prevalent in women than in men. However, mechanisms responsible for this sex bias are not clear. Immune regulation by CD4+CD25+FoxP3+ regulatory T-cells (Tregs) and 17β-estradiol is crucial in the pathogenesis of sex bias in cancer and autoimmunity. Therefore, we investigated their role in a mouse model of immune-mediated DILI.
methodsTo model DILI, we immunized BALB/c, BALB/cBy, IL-6-deficient, and castrated BALB/c mice with trifluoroacetyl chloride-haptenated liver proteins. We then measured degree of hepatitis, cytokines, antibodies, and Treg and splenocyte function.
resultsBALB/c females developed more severe hepatitis (p<0.01) and produced more pro-inflammatory hepatic cytokines and antibodies (p<0.05) than did males. Castrated males developed more severe hepatitis than did intact males (p<0.001) and females (p<0.05). Splenocytes cultured from female mice exhibited fewer Tregs (p<0.01) and higher IL-1β (p<0.01) and IL-6 (p<0.05) than did those from males. However, Treg function did not differ by sex, as evidenced by absence of sex bias in programmed death receptor-1 and responses to IL-6, anti-IL-10, anti-CD3, and anti-CD28. Diminished hepatitis in IL-6-deficient, anti-IL-6 receptor α-treated, ovariectomized, or male mice; undetectable IL-6 levels in splenocyte supernatants from ovariectomized and male mice; elevated splenic IL-6 and serum estrogen levels in castrated male mice, and IL-6 induction by 17β-estradiol in splenocytes from naïve female mice (p<0.05) suggested that 17β-estradiol may enhance sex bias through IL-6 induction, which subsequently discourages Treg survival. Treg transfer from naïve female mice to those with DILI reduced hepatitis severity and hepatic IL-6.
conclusions17β-estradiol and IL-6 may act synergistically to promote sex bias in experimental DILI by reducing Tregs. Modulating Treg numbers may provide a therapeutic approach to DILI.
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