33 We,

33 We, Opaganib order therefore, investigated whether HO-1 might mediate CB2-induced anti-inflammatory effects in alcohol-fed mice and, first, characterized the impact of JWH-133 treatment on Kupffer-cell HO-1 protein expression by double immunohistochemistry combining antibodies to HO-1 and F4/80. Alcohol-fed mice treated with JWH-133 displayed a strong HO-1 protein increase in Kupffer cells, compared to alcohol-fed control animals (82% ± 2% versus 57% ± 3%, P < 0.05; Fig. 5A). In keeping with in vivo findings, JWH-133 induced HO-1 mRNA and protein expression in isolated Kupffer cells and in RAW264.7 macrophages, either

alone or in combination with LPS (Fig. 5B,C). We next investigated the impact of zinc protoporphyrin (ZnPP), a specific competitive inhibitor of HO-1 activity, on LPS-treated RAW264.7 macrophages exposed to JWH-133. Strikingly, ZnPP blunted the inhibitory effect of JWH-133 on LPS-induced nuclear factor-kappa B (NF-κB) translocation into the nucleus (Fig. 6A). In addition, ZnPP also prevented the inhibitory effect of JWH-133 on IL-6 and IL-1β expressions, whereas its effect on TNF-α did not reach statistical

significance (Fig. 6B). These data demonstrate that CB2 activation induces HO-1 in macrophages, thereby limiting NF-κB activation and the proinflammatory M1 response. The present study demonstrates that during alcoholic liver disease, activation of CB2 receptors expressed in Kupffer cells LEE011 purchase reduces proinflammatory M1 response and favors M2 polarization, thereby eliciting antisteatogenic effects via paracrine interactions with hepatocytes (Fig. 7). Sustained inflammation constitutes the initial hepatic response to chronic alcohol consumption.8, 12 Experimental and clinical studies have shown that Kupffer cells play a pivotal role in this process. Thus, Kupffer cells undergo activation by gut-derived LPS and release several inflammatory mediators, such as TNF-α or IL-1β, suggesting that

they may adopt MCE a proinflammatory M1 profile.8, 11, 34 In the present study, we provide evidence for a mixed M1/M2 response of Kupffer cells in alcohol-fed animals. Indeed, alcohol triggers hepatic induction of proinflammatory mediators characteristic of a classical M1 profile, including cytokines, such as TNF-α and IL-6, or chemokines, such as CCL3 and CCL4. At the same time, alcohol feeding also enhances liver expression of alternative M2 markers, such as Arg1, Mrc2, and CD163. As yet, mechanisms regulating M1/M2 Kupffer-cell polarization remain largely unexplored. Recent studies in experimental models of obesity have shown that the transcription factor, peroxisome proliferator-activated receptor delta, promotes the transition of Kupffer cells to an M2 phenotype, thereby reducing liver inflammation and fatty liver.

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