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Updated: Jun 6, 2026
Induction of Drug-Induced, Autoimmune Hepatitis in BALB/c Mice for the Study of Its Pathogenic Mechanisms
Published on: May 29, 2020
IL-4 mediates dicloxacillin-induced liver injury in mice
Satonori Higuchi1, Masanori Kobayashi, Yukitaka Yoshikawa
1Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
Abstract:
Drug-induced liver injury (DILI) is a major problem in drug development and clinical drug therapy. In most cases, the mechanisms are still unknown. It is difficult to predict DILI in humans due to the lack of experimental animal models. Dicloxacillin, penicillinase-sensitive penicillin, rarely causes cholestatic or mixed liver injury, and there is some evidence for immunoallergic idiosyncratic reaction in human. In this study, we investigated the mechanisms of dicloxacillin-induced liver injury. Plasma ALT and total-bilirubin (T-Bil) levels were significantly increased in dicloxacillin-administered (600 mg/kg, i.p.) mice. Dicloxacillin administration induced Th2 (helper T cells)-mediated factors and increased the plasma interleukin (IL)-4 level. Neutralization of IL-4 suppressed the hepatotoxicity of dicloxacillin, and recombinant mouse IL-4 administration (0.5 or 2.0 μg/mouse, i.p.) exacerbated it. Chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2) is a cognate receptor for prostaglandin (PG) D(2), and is suggested to be involved in Th2-dependent allergic inflammation. We investigated the effect of 13,14-Dihydro-15-keto-PGD(2) (DK-PGD(2); 10 μg/mouse, i.p.) administration on dicloxacillin-induced liver injury. DK-PGD(2)/dicloxacillin coadministration resulted in a significant increase of alanine aminotransferases and a remarkable increase of macrophage inflammatory protein 2 expression. In conclusion, to the best of our knowledge, this is the first report to demonstrate that dicloxacillin-induced liver injury is mediated by a Th2-type immune reaction and exacerbated by DK-PGD(2).
Insights
Dicloxacillin causes liver injury through a Th2 immune response. This drug-induced liver injury (DILI) is worsened by prostaglandin D2, a key factor in allergic inflammation.
Area of Science:
- Immunology
- Hepatology
- Pharmacology
Background:
- Drug-induced liver injury (DILI) poses significant challenges in drug development and clinical practice.
- The precise mechanisms underlying DILI are often unknown, hindering prediction and prevention.
- Lack of reliable animal models complicates the study of DILI.
Purpose of the Study:
- To elucidate the underlying mechanisms of dicloxacillin-induced liver injury.
- To investigate the role of Th2-type immune responses in dicloxacillin hepatotoxicity.
- To examine the influence of prostaglandin D2 on dicloxacillin-induced liver damage.
Main Methods:
- Mice were administered dicloxacillin (600 mg/kg, i.p.) to induce liver injury.
- Plasma levels of alanine aminotransferase (ALT) and total bilirubin (T-Bil) were measured.
- Interleukin-4 (IL-4) neutralization and recombinant IL-4 administration were performed.
- The effect of 13,14-Dihydro-15-keto-PGD2 (DK-PGD2) on dicloxacillin-induced liver injury was assessed.
Main Results:
- Dicloxacillin administration significantly increased plasma ALT and T-Bil levels in mice.
- Dicloxacillin induced Th2-mediated factors, including elevated plasma IL-4.
- IL-4 neutralization attenuated dicloxacillin hepatotoxicity, while IL-4 administration exacerbated it.
- Co-administration of DK-PGD2 with dicloxacillin significantly increased ALT levels and macrophage inflammatory protein 2 expression.
Conclusions:
- Dicloxacillin-induced liver injury is mediated by a Th2-type immune reaction.
- Prostaglandin D2 exacerbates dicloxacillin-induced liver injury.
- This study provides novel insights into the immunologic mechanisms of DILI.
