The role of the IL–17 axis in a mouse model of drug-induced liver injury

Objectives: Acetaminophen (APAP) overdose results in severe liver damage due to hepatocellular necrosis. Injury is triggered by release of pro-inflammatory cytokines and infiltration of immune cells. In this study, we investigated the involvement of the IL–17 axis during drug-induced liver damage. Methods: Primary hepatocytes (HCs) isolated from wildtype (WT), IL17A-, IL17A+F-, or IL23p19-deficient mice were exposed to different concentrations of APAP in vitro for 24hrs. Cell death was assessed by measuring LDH release. Moreover, APAP-induced hepatotoxicity was investigated in vivo by challenging WT, CCR6-, IL17A-, IL–17A/F-KO mice with APAP (i.p., 400mg/kg). Liver injury was quantified by measurement of plasma transaminase activities and release of cytokines upon APAP challenge. Results: In vitro exposure of HCs to 15mM APAP strongly reduced the cell viability. However, APAP treatment did not result in significant differences with respect to cell death in HCs isolated from WT, IL17A-, IL17A/F-, or IL23p19-KO mice. In contrast, transaminase activities and pro-inflammatory cytokine production were slightly reduced in IL17A-deficient mice in comparison to WT mice, whereas these parameters were significantly reduced in IL17A/F double KO and CCR6 KO mice upon in vivo APAP challenge. Conclusions: We demonstrated that primary HCs isolated from WT, IL17A-, IL17A/F, or IL23p19-KO mice were susceptible to APAP exposure in vitro to a similar extent. However, in vivo APAP-induced hepatotoxicity was different in these genotypes due to the involvement of several IL17-releasing cell types of both the innate and adaptive immune system. This suggests a pro-inflammatory role of IL17-producing cells in the model of APAP-induced liver damage. Further studies are intended to identify the IL17-producing cell populations and the role of the tissue-protective cytokine IL–22 in IL–23p19 KO mice, since these mice have a defect in both IL–17 and IL–22 production.