Hepatoprotective role of endogenous interleukin-13 in a murine model of acetaminophen-induced liver disease
ABSTRACT Recent evidence suggests that a deficiency in one or more hepatoprotective regulatory mechanisms may contribute to determining susceptibility in drug-induced liver disease. In the present study, we investigated the role of interleukin (IL)-13 in acetaminophen (APAP)-induced liver disease (AILD). Following APAP (200 mg/kg) administration to male C57BL/6 wild-type (WT) mice, hepatotoxicity developed up to 24 h post-APAP, with a concomitant increase in serum IL-13 concentration. Pretreatment of these mice with an IL-13-neutralizing antibody exacerbated liver injury, as did APAP administration to IL-13 knockout (KO) mice in comparison to WT mice. No difference was observed in either overall APAP-protein adduct formation or liver glutathione levels between KO and WT mice following APAP administration, suggesting that the increased susceptibility of IL-13 KO mice to AILD was not due to enhanced APAP bioactivation but rather injurious downstream events. In this regard, multiplex antibody arrays were used to identify potential IL-13-regulated biomarkers, including various cytokines and chemokines, as well as nitric oxide (NO), associated with AILD that were present at higher concentrations in the sera of APAP-treated IL-13 KO mice than in WT mice. Subsequent inhibition studies determined interferon-gamma, NO, neutrophils, natural killer cells, and natural killer cells with T-cell receptors had pathologic roles in AILD in IL-13 KO mice. Taken together, these results suggest that IL-13 is a critical hepatoprotective factor modulating the susceptibility to AILD and may provide hepatoprotection, in part, by down-regulating protoxicant factors and cells associated with the innate immune system.
SourceAvailable from: Dolores B Njoku[Show abstract] [Hide abstract]
ABSTRACT: Drug-induced hepatotoxicity is a significant cause of acute liver failure and is usually the primary reason that therapeutic drugs are removed from the commercial market. Multiple mechanisms can culminate in drug hepatotoxicity. Metabolism, genetics and immunology separately and in concert play distinct and overlapping roles in this process. This review will cover papers we feel have addressed these mechanisms of drug-induced hepatotoxicity in adults following the consumption of commonly used medications. The aim is to generate discussion around "trigger point" papers where the investigators generated new science or provided additional contribution to existing science. Hopefully these discussions will assist in uncovering key areas that need further attention.International Journal of Molecular Sciences 04/2014; 15(4):6990-7003. DOI:10.3390/ijms15046990 · 2.34 Impact Factor
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ABSTRACT: The drug development industry faces multiple challenges in the realization of safe effective drugs. Computational modeling approaches can be used to support these efforts. One approach, mechanistic modeling, is new to the realm of drug safety. It holds the promise of not only predicting toxicity for novel compounds but also illuminating the mechanistic underpinnings of toxicity. To increase the scientific community's familiarity with mechanistic modeling in drug safety, this article seeks to provide perspective on the type of data used, how they are used, and where they are lacking. Examples are derived from the development of the DILIsym® model, a mechanistic model of drug-induced liver injury (DILI). The DILIsym® model simulates the mechanistic interactions and events from compound administration through the progression of liver injury and regeneration. Modeling mitochondrial toxicity illustrates the type and use of in vitro data to represent biological interactions, as well as insights on key differences between in vitro and in vivo conditions. Modeling bile acid toxicity illustrates a case where the over-arching mechanism is well-accepted, but many mechanistic details are lacking. Modeling was used to identify measurements predicted to strongly impact toxicity. Finally, modeling innate immune responses illustrates the importance of time-series data, particularly in the presence of positive and negative feedback loops, as well as the need for data from different animal species for better translation. These concepts are germane to most mechanistic models, although the details will vary. The use of mechanistic models is expected to improve the rational design of new drugs. This article is protected by copyright. All rights reserved.Biopharmaceutics & Drug Disposition 01/2014; 35(1). DOI:10.1002/bdd.1878 · 2.18 Impact Factor
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ABSTRACT: Clinical evidence suggests that many cases of serious idiosyncratic drug-induced liver injury (I-DILI) are mediated by the adaptive immune system in response to hepatic drug-protein adducts, also referred to as drug-induced allergic hepatitis (DIAH), but detailed mechanistic proof has remained elusive due to the lack of animal models. We have hypothesized that DIAH is as rare in animals as it is in humans due at least in part to the tolerogenic nature of the liver. Herein we provide evidence that immune tolerance can be overcome in a murine model of halothane-induced liver injury initiated by trifluoroacetylated protein adducts (TFAPA) of halothane formed in the liver. Twenty-four hours after female Balb/cJ mice were initially treated with halothane, perivenous necrosis and an infiltration of CD11b(+) Gr-1(high) cells were observed in the liver. Further study revealed a subpopulation of myeloid-derived suppressor cells (MDSCs) within the CD11b(+) Gr-1(high) cell fraction, that inhibited the proliferation of both CD4(+) and CD8(+) T cells. When CD11b(+) Gr-1(high) cells were depleted from the liver with Gr-1 antibody treatment, enhanced liver injury was observed at nine days after halothane rechallenge. Toxicity was associated with increased serum levels of IL-4 and immunoglobulins (Ig) IgG1 and IgE directed against hepatic TFAPA, as well as increased hepatic infiltration of eosinophils and CD4(+) T cells, all features of an allergic reaction. When hepatic CD4(+) T cells were depleted 5 days after halothane rechallenge, TFAPA-specific serum Ig and hepatotoxicity were reduced. Conclusion: Our data provides a rational approach for developing animal models of DIAH mediated by the adaptive immune system and suggests that impaired liver tolerance may predispose patients to this disease. This article is protected by copyright. All rights reserved. Copyright © 2015 American Association for the Study of Liver Diseases.Hepatology 02/2015; DOI:10.1002/hep.27764 · 11.19 Impact Factor