Moreover, in vitro studies also provide a link between HO-1 induc

Moreover, in vitro studies also provide a link between HO-1 induction in Kupffer cells and the anti-inflammatory properties of CB2 receptors, as shown

by the abolition of CB2-mediated effects on NF-κB activation and M1 polarization by the specific HO-1 inhibitor, ZnPP. Interestingly, in addition to limiting M1 polarization, recent data also suggest that HO-1 is selectively expressed by M2 macrophages44 and may drive Kupffer-cell polarization toward an anti-inflammatory phenotype,33 suggesting that HO-1 is a master regulator of Kupffer-cell phenotype. In keeping with this, our data identify HO-1 as a downstream-signaling pathway, by which CB2 regulates M1/M2 balance in response to chronic alcohol exposure. We previously reported the antifibrogenic properties of CB2 receptors in experimental models of liver fibrosis.23 These beneficial properties have been ascribed both to direct effects on hepatic myofibroblasts23 and to a reduction of inflammatory infiltration of the liver.45 Recent data suggest that M1-polarized macrophages may promote the progression of liver fibrosis by releasing inflammatory mediators that activate liver fibrogenic cells.46-48 Moreover, mice carrying a specific deletion of the M2 marker, Arg1, in macrophages are prone to liver fibrosis.49 Altogether, these data suggest a critical role of the

M1/M2 Kupffer-cell balance in the control of fibrosis progression. Whether antifibrogenic selleck screening library properties of CB2 receptors may also involve the inhibition of M1 polarization warrants further investigation. In conclusion, this study demonstrates that activation of CB2 receptors display beneficial effects on alcohol-induced inflammation and fatty liver. The mechanism involves paracrine interactions between

Kupffer cells and hepatocytes. In light of the previously demonstrated hepatoprotective24 and antifibrogenic23 effects of CB2 receptors and of their beneficial impact on liver regeneration,24 our data strongly suggest that CB2 agonists may provide meaningful advances for the management of alcoholic liver disease. The authors thank Fouad Lafdil for helpful comments, Jean-Pierre Couty for his useful advice for Kupffer-cell isolation, the Toxicology Department for serum-ethanol measurement, the Imaging platform and Xavier Ducroy for confocal image capture, Aïda Habib for HO-1 antibody, and Sophia Balustre for her help during in vivo experiments. Additional Supporting Information may be found in the online version of this article. “
“MicroRNA-221 (miR-221) is one of the most frequently and consistently up-regulated microRNAs (miRNAs) in human cancer. It has been hypothesized that miR-221 may act as a tumor promoter. To demonstrate this, we developed a transgenic (TG) mouse model that exhibits an inappropriate overexpression of miR-221 in the liver. Immunoblotting and immunostaining confirmed a concomitant down-regulation of miR-221 target proteins.

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