We Protein Tyrosine Kinase inhibitor show that in the CCl4 model, administration of the CB2 agonist JWH-133 reduces the extent

of liver injury, whereas CB2−/− mice are more susceptible to the toxic insult. These findings corroborate previous studies demonstrating hepatoprotective properties of CB2 receptors in experimental models of acute liver injury elicited by ischemia/reperfusion injury, thioacetamide or concanavalin A.6, 19, 34 In addition, we identify iNOS as a central mediator in the beneficial effects mediated by CB2 receptors. Indeed, CCl4-treated CB2−/− mice show impaired induction of hepatic iNOS, and treatment of these mice with the NO donor SIN-1 reduces their exacerbated susceptibility to liver injury. These findings are in line with the reported protective effects of hepatocyte iNOS on liver injury. Thus, iNOS−/− mice display enhanced hepatocyte apoptosis when exposed to either CCl4,26, 27 or to partial hepatectomy.28 In addition, cultured hepatocytes are more resistant to apoptosis in the presence of NO donors, or following induction of iNOS with cytokines, such as TNF-α.29 Interestingly,

our data also indicate that CCl4-treated CB2−/− mice show decreased induction of TNF-α, a well-characterized inducer of iNOS expression. Whether TNF-α release triggered by CB2 receptors in nonparenchymal cells may contribute GSK2126458 cost to the iNOS-dependent antiapoptotic effects in hepatocytes remains to be determined. It is well demonstrated that liver injury triggered by CCl4 is followed by a regenerative response orchestrated by the activation cAMP of multiple coordinated pathways, involving cross-talk between hepatocytes and nonparenchymal cells.25 We demonstrate that CB2 receptors display beneficial effects on liver regeneration in this model, as well as in the partial hepatectomy model. We also demonstrate that beneficial effects of CB2 receptors are mediated by a pathway distinct from its protective effects against hepatocyte apoptosis, that involves IL-6. Thus, CCl4-treated CB2−/− mice display reduced hepatic expression of IL-6, and administration of IL-6 to these animals partially

restores PCNA expression. Interestingly, CB2−/− mice and IL-6−/− mice behave similarly in response to acute and chronic liver injury, with increased liver damage, decreased liver regeneration and increased fibrogenesis.17, 35 However, our data indicate that although IL-6 mediates CB2 receptor impact on liver regeneration, the cytokine is not involved in CB2 receptor-dependent antiapoptotic effect. These data are in line with the reported beneficial effects of IL-6 on liver regeneration,25 but contrast with studies reporting the protective role of IL-6 against liver damage.31, 36, 37 The mechanisms underlying these discrepancies, although not fully elucidated, may rely on the duration of IL-6 treatment, as suggested in a recent study.