Interleukin (IL)‐17 is a proinflammatory and fibrogenic cytokine mainly produced by T‐helper (Th)17 lymphocytes, together with the hepatoprotective and antifibrogenic cytokine, IL‐22. Cannabinoid receptor 2 (CB2) is predominantly expressed in immune cells and displays anti‐inflammatory and antifibrogenic effects. In the present study, we further investigated the mechanism underlying antifibrogenic properties of CB2 receptor and explored its effect on the profibrogenic properties of IL‐17. After bile duct ligation (BDL), the hepatic expression of Th17 markers and IL‐17 production were enhanced in CB2−/− mice, as compared to wild‐type (WT) counterparts, and correlated with increased fibrosis in these animals. In contrast, IL‐22‐induced expression was similar in both animal groups. Inhibition of Th17 differentiation by digoxin lowered Th17 marker gene expression and IL‐17 production and strongly reduced liver fibrosis in CB2−/− BDL mice. In vitro, differentiation of CD4+ naïve T cells into Th17 lymphocytes was decreased by the CB2 agonist, JWH‐133, and was associated with reduced Th17 marker messenger RNA expression and IL‐17 production, without modification of IL‐22 release. The inhibitory effect of JWH‐133 on IL‐17 production relied on signal transducer and activator of transcription (STAT)5 phosphorylation. Indeed, STAT5 phosphorylation and translocation into the nucleus was enhanced in JWH133‐treated Th17 lymphocytes, and the addition of a STAT5 inhibitor reversed the inhibitory effect of the CB2 agonist on IL‐17 production, without affecting IL‐22 levels. Finally, in vitro studies also demonstrated that CB2 receptor activation in macrophages and hepatic myofibroblasts blunts IL‐17‐induced proinflammatory gene expression. Conclusion: These data demonstrate that CB2 receptor activation decreases liver fibrosis by selectively reducing IL‐17 production by Th17 lymphocytes via a STAT5‐dependent pathway, and by blunting the proinflammatory effects of IL‐17 on its target cells, while preserving IL‐22 production. (Hepatology 2014;58:296–306)
Hepatology – Wiley
Published: Jan 1, 2014
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