Inserm, U955, Créteil, France; Université Paris-Est, Faculté de Médecine, UMR-S955, Créteil, France.
Hepatology. 2014 Jan;59(1):296-306. doi: 10.1002/hep.26598. Epub 2013 Nov 19.
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.
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.
白细胞介素（IL）-17 是一种促炎和纤维化细胞因子，主要由辅助性 T 细胞（Th）17 淋巴细胞产生，同时还产生具有肝保护和抗纤维化作用的白细胞介素-22。大麻素受体 2（CB2）主要表达于免疫细胞，具有抗炎和抗纤维化作用。在本研究中，我们进一步研究了 CB2 受体抗纤维化特性的机制，并探讨了其对白细胞介素-17 致纤维化特性的影响。胆管结扎（BDL）后，CB2（-/-）小鼠肝脏 Th17 标志物表达和白细胞介素-17 产生增强，与这些动物的纤维化增加相关。相比之下，两组动物的白细胞介素-22 诱导表达相似。洋地黄毒苷抑制 Th17 分化可降低 Th17 标志物基因表达和白细胞介素-17 产生，并强烈减少 CB2（-/-）BDL 小鼠的肝纤维化。在体外，CB2 激动剂 JWH-133 可降低 CD4（+）幼稚 T 细胞向 Th17 淋巴细胞的分化，并与 Th17 标志物信使 RNA 表达和白细胞介素-17 产生减少相关，而不改变白细胞介素-22 的释放。JWH-133 对白细胞介素-17 产生的抑制作用依赖于信号转导和转录激活因子（STAT）5 磷酸化。事实上，JWH133 处理的 Th17 淋巴细胞中 STAT5 磷酸化和核转位增强，添加 STAT5 抑制剂可逆转 CB2 激动剂对白细胞介素-17 产生的抑制作用，而不影响白细胞介素-22 水平。最后，体外研究还表明，CB2 受体在巨噬细胞和肝肌成纤维细胞中的激活可通过 STAT5 依赖性途径减弱白细胞介素-17 诱导的促炎基因表达，从而减轻白细胞介素-17 对其靶细胞的促炎作用，同时保留白细胞介素-22 的产生。
这些数据表明，CB2 受体的激活通过选择性地降低 Th17 淋巴细胞产生白细胞介素-17，通过 STAT5 依赖性途径减少肝纤维化，通过减轻白细胞介素-17 对其靶细胞的促炎作用，同时保留白细胞介素-22 的产生，从而减弱白细胞介素-17 的致纤维化作用。
