6A). both AN3365 CB1 and CB2 antagonists. We also observed that endogenous cannabinoid anandamide was able to reduce hepatitis by suppressing cytokine levels. In addition, deficiency or inhibition of endocannabinoid hydrolyzing enzyme fatty acid amide hydrolase (FAAH), which AN3365 leads to increased levels of endogenous cannabinoids, resulted in decreased liver injury upon ConA challenge. Our data demonstrate that targeting cannabinoid receptors using exogenous or endogenous cannabinoids and use of FAAH inhibitors may constitute novel therapeutic modalities to treat immune-mediated liver inflammation. Liver diseases are a serious human health problem worldwide. The pathogenesis of immune-mediated liver diseases is very complex, and it involves several inflammatory cells and cytokines. Growing evidence suggests that major human liver diseases such as autoimmune and viral hepatitis are caused, in general, by activated T-cell-mediated immune responses (Chisari and Ferrari, 1995; Kita et al., 2001). Autoimmune hepatitis (AIH) is a severe form of liver disease characterized by progressive destruction of the hepatic parenchyma, cellular infiltration, hypergammaglobulinemia, and autoantibodies. The prevalence of AIH is estimated to range between 50 and 200 cases per million population, and it accounts for 5.9% of all liver transplantations in the United States. AIH affects women more than men (3.6:1), and all ages and ethnic groups are susceptible to AIH (Czaja and Freese, 2002). T-cell-mediated hepatitis can be induced in mice by intravenous injection of the mitogenic plant lectin concanavalin A (ConA), which leads to polyclonal activation of T cells, resulting in clinical and histological symptoms of acute hepatitis, including elevation of transaminase activities within 8 to 24 h (Tiegs et al., 1992). It is a well established mouse model for AIH. Activated CD4+ T cells, natural killer T (NKT) cells, and Kupffer cells are the most prominent effector cells in this model. Together with macrophages and eosinophils, they induce hepatocyte killing by contact or indirectly by producing large amounts of inflammatory cytokines (Tiegs et al., 1992; Gantner et al., 1995; Schmann et al., 2000; Takeda et al., 2000). Among several proinflammatory cytokines involved, TNF-and IFN-play a critical role in direct induction of liver cytotoxicity, because anti-TNF-and anti-IFN-monoclonal antibodies (mAbs) protect mice from ConA-induced liver injury (Gantner et al., 1995; Ksters et al., 1996). test was used to compare two data sets, and 0.05; **, 0.01 compared with ConA + vehicle. Liver histological examination was also used to determine the protective effect of THC in ConA-induced hepatitis. Light microscopy showed normal tissue histology for vehicle-injected mice, but dramatic leukocyte AN3365 infiltration and massive tissue damage in ConA-injected mice. ConA-injected mice administered with THC showed dramatic decrease in hepatic tissue injury (Fig. 1C). THC alone did not cause any liver damage. TUNEL staining showed massive hepatocyte apoptosis in mice challenged with ConA compared with control group, which was markedly reduced upon THC treatment (Fig. IL10A 1D). THC Protects against ConA-Induced Hepatitis by Suppressing Cytokines and Chemokines ConA-induced hepatitis is associated with the production of various cytokines. To determine whether THC was acting by modulating cytokine and chemokine levels, we measured various cytokine and chemokines at different times (6, 12, and 24 h). As shown in Fig. 2, ConA challenge lead to elevation of most of the cytokines and chemokines tested compared with vehicle-injected control group, including IL-2, TNF- 0.05). Analysis of T-Cell Subpopulations and T-Cell Apoptosis in Liver Previous studies from our laboratory have shown that THC can trigger apoptosis in T cells (McKallip et al., 2005). In addition, T cells and NKT cells play critical roles in ConA-induced hepatitis. Thus, we investigated whether THC-induced suppression of hepatic.