Suppressive and pro-inflammatory roles for IL-4 in the pathogenesis of experimental drug-induced liver injury: A review

Importance of the field: Idiosyncratic drug reactions resulting in drug-induced liver injury (DILI) account for ∼13%of acute liver failure cases in the US. Idiosyncratic drug reactions are the third most common cause of liver transplantation, exceeded only by acetaminophen and indeterminate causes. Clinical evidence suggests that idiosyncratic DILI is triggered by drug hapten-altered self proteins resulting in hepatocellular injury. An example of this type of DILI is hepatitis that develops in susceptible individuals following administration of halogenated volatile anesthetics, dihydralazine, carbamazepine or diclofenac. Areas covered in this review: In this review, we describe research in animal models that supports a critical role for suppressive and pro-inflammatory roles for IL-4 in the pathogenesis of immune-mediated DILI. What the reader will gain: The reader will gain insights into the roles of IL-4 in the development of experimental DILI. The reader will gain tools to assist in the translation of these findings to those in patients with immune-mediated DILI, as well as other inflammatory diseases of the liver. The reader will then be made aware of gaps in knowledge in the pathogenesis of DILI where research could result in significant advances in the care of these complicated patients. Take home message: In experimental immune-mediated DILI, IL-4 suppresses regulatory responses to CYP2E1 autoantigens but induces pro-inflammatory responses to drug haptens.