Effect of IL-15 on APAP Hepatitis Figure 4. The similar activation of hepatic Nrf2-related and ROS detoxification genes in APAP-injected mice. (A) The hepatic mRNA and (B) protein levels of GCLC at 0 and 8 hr after APAP challenge; representative and quantitative data are in upper and lower panels, respectively. Hepatic mRNA levels of Nrf2-related genes (C) NQO-1, GstPi-1, MRP-2, and MRP-3, and ROS detoxification genes (D) SOD-1, SOD-2 and catalase at 0 and 8 hr after APAP challenge. *P,0.05; #P,0.05 compared with WT at 0 hr; n.s., not significant. Data are mean 6 SEM from 7,8 mice per group in (A), and 4,5 mice per group in (B). doi:10.1371/journal.pone.0044880.g004 Injection of recombinant IL-15 into Il152/2 mice or IL-15 neutralizing antibody into WT counterparts did not alter the susceptibility of animals to APAP The increased IL-15 levels in serum and KCs fraction during AILI in WT mice implicated its involvement in APAP hepatitis (Figure 2A,C). Previously, subcutaneous injection of recombinant IL-15 protected mice against concanavalin A-induced hepatitis [25]. Therefore, recombinant murine IL-15 was injected, subcu- taneously or intraperitoneally, into Il152/2 mice to test the effect of the exogenous cytokine on APAP hepatotoxicity. Intriguingly, there was no significant difference among mice pretreated with recombinant IL-15, subcutaneously or intraperitoneally, or saline based on serum ALT level at 8 hr post-APAP (Figure 9A). In addition, hepatic histopathological examination showed unre- markable result among these groups (Figure 9B). Similarly, by effect assessments of serum ALT levels or hepatic histopathologies at 8 hr post-APAP (Figure 9C,D), pretreatment of WT mice with IL-15 neutralizing antibody did not change the APAP sensitivity. PLOS ONE | www.plosone.org 6 September 2012 | Volume 7 | Issue 9 | e44880