IL-4 mediates dicloxacillin-induced liver injury in mice

Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.
Toxicology Letters (Impact Factor: 3.26). 02/2011; 200(3):139-45. DOI: 10.1016/j.toxlet.2010.11.006
Source: PubMed


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).

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    • "IL-6 was demonstrated to decrease both the rifampicin-and phenobarbital-mediated induction of CYP2B6, CYP2C8, CYP2C9, and CYP3A4, whereas, the transcriptional activity of PXR and CAR is not affected by IL-6 (Pascussi et al., 2000). With respect to cytokines and drug-induced liver injury (DILI), halothane-and a-naphthylisothiocyanate-induced liver injury is reported to be mediated by IL-17 (Kobayashi et al., 2009, 2010), whereas IL-4 mediates dicloxacillin-and flutamide-induced liver injury in mice (Higuchi et al., 2011). Furthermore, IL-6 and IL-4 are essential for the differentiation of Th17 and Th2 cells, respectively, from naı¨ve T cells. "
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