109 DEPLETION OF CASPASE-8 IN MICE MODULATES TNF-INDUCED COMPLEX FORMATION AND CELL CYCLE SIGNALING IN HEPATOCYTES FOLLOWING PARTIAL HEPATECTOMY

Abstract

an inflammatory process, initiated by the production of TNF alpha and interleukin-6 (IL-6). Since cannabinoid receptors 2 (CB2) play a major role in the regulation of inflammation, we investigated herein whether they regulate liver regeneration. Liver regeneration was studied in a model of acute hepatitis induced by a single injection of carbon tetrachloride (CCl4) or following two-third hepatectomy. Experiments were performed in CB2 knockout (CB2−/−) and wild type (WT) mice, or in WT mice pretreated with the CB2 agonist JWH-133. Hepatic CB2 receptor expression was markedly induced following partial hepatectomy and CCl4-induced liver injury. Liver injury was increased in CB2−/− mice compared to WT mice following acute CCl4 administration, as assessed by serum ALT and TUNEL labelling. In addition, PCNA expression was significantly delayed in CB2−/− animals as compared to WT mice (72 vs 48 hrs). Conversely, treatment of WT mice with a single dose of CB2 specific agonist, JWH-133, reduced liver injury and accelerated liver regeneration in response to CCl4 exposure. Similar delay in PCNA expression was observed in CB2−/− animals submitted to partial hepatectomy. Impaired regeneration in CB2−/− mice was associated with a reduction in the expression of IL-6; consistent with these data, IL-6 administration to CB2−/− mice partially restored PCNA expression. Finally, MMP-2 activity was enhanced in CB2−/− mice injected with CCl4, in keeping with the reported effects of MMP-2 in liver injury. These data demonstrate that the CB2 receptors reduce liver injury and promote liver regeneration following acute insult, by a mechanism involving IL-6 production and inhibition of MMP-2 activity. These results suggest that CB2 agonists elicit useful hepatoprotective properties, in addition to their antifibrogenic effects.