Reply:
Authors: Ariane Mallat, Christophe Hezode, Sophie Lotersztajn
Journal: Hepatology (2005)

We thank Schwabe et al. for their interesting comments. In our recent study of 277 patients with chronic hepatitis C of known duration, we found that daily cannabis smoking over the course of infection is an independent predictor of progression of liver fibrosis.1 These findings indicate that chronic stimulation of CB1 and/or CB2 cannabinoid receptors by exogenous cannabinoids enhances liver fibrogenesis, either by directly affecting the liver fibrogenic response and/or by indirect effects such as altered immunomodulation, as suggested in the comments to our study. As stated in our manuscript1 we have strong evidence that the cannabinoid system directly affects liver fibrogenesis via activation of CB1 and CB2 receptors with opposite pro- and antifibrogenic effects, respectively. Indeed, we previously showed by both RT-PCR and immunohistochemistry that CB1 and CB2 receptors are markedly upregulated in human liver samples with cirrhosis compared with normal liver, predominantly in hepatic myofibroblasts.2-4 In addition, we found that CB1 knockout (KO) mice showed reduced liver fibrosis following chronic CCl4 intoxication, an effect related to reduced accumulation of hepatic myofibroblasts (Grenard et al.2 and Teixeira-Clerc et al., personal results). These results therefore strongly suggest that activation of CB1 receptors enhances liver fibrogenesis. In contrast, using CB2−/− KO mice, we demonstrated that activation of CB2 receptors elicits opposite antifibrogenic effects by decreasing hepatic myofibroblast survival and accumulation.3 Therefore, overall, our current experimental findings indicate dual opposite effects of cannabinoid receptors on liver fibrogenesis and suggest that selective antagonists of CB1 and selective agonists of CB2 might open new prospects in the treatment of liver fibrosis. These data do not exclude additional indirect effects of exogenous cannabinoids. Indeed, a large body of evidence has documented complex effects on inflammation and the immune system. Thus, although cannabinoids predominantly decrease production of proinflammatory cytokines in experimental models of inflammation and in humans, increased inflammatory responses have also been reported.5 In addition, cannabinoids modulate innate and adaptative immune response and appear to induce a shift from a Th1 to a Th2 cell response in a variety of disorders.5 Importantly, these effects on inflammation and immunity have not been fully characterized and may involve CB2 or CB1 receptors, as well as CB1 and CB2 independent responses according to situations.5 In particular, there are no data available as yet on the effects of cannabinoids on inflammation and immune response during liver injury. Therefore, further clinical and experimental studies are clearly warranted in order to delineate whether in addition to directly altering properties of hepatic fibrogenic cells, cannabinoids may also indirectly regulate liver fibrogenesis by modulating inflammatory and/or immune hepatic response to chronic liver injury. Ariane Mallat* , Christophe Hezode*, Sophie Lotersztajn , * Department of Hepatology and Gastorenterology, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Université Paris XII, Créteil, France, INSERM U581, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Université Paris XII, Créteil, France.