Potential conflict of interest: Nothing to report.
Cannabinoid receptor 2 counteracts interleukin-17-induced immune and fibrogenic responses in mouse liver
Article first published online: 19 NOV 2013
© 2013 by the American Association for the Study of Liver Diseases
Volume 59, Issue 1, pages 296–306, January 2014
How to Cite
Guillot, A., Hamdaoui, N., Bizy, A., Zoltani, K., Souktani, R., Zafrani, E.-S., Mallat, A., Lotersztajn, S. and Lafdil, F. (2014), Cannabinoid receptor 2 counteracts interleukin-17-induced immune and fibrogenic responses in mouse liver. Hepatology, 59: 296–306. doi: 10.1002/hep.26598
This work was supported by the Inserm (National Institute of Health and Medical Research), the Université Paris-Est Créteil, by grants for young investigators from Université Paris-Est Créteil (to F.L.), and from the Agence Nationale de la Recherche (ANR retour Post-doc; to F.L.). A.G. was the recipient of a fellowship from the French Ministry of Education and Research.
- Issue published online: 20 DEC 2013
- Article first published online: 19 NOV 2013
- Accepted manuscript online: 28 JUN 2013 01:41PM EST
- Manuscript Accepted: 17 JUN 2013
- Manuscript Received: 21 DEC 2012
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)