Beneficial paracrine effects of cannabinoid receptor 2 on liver injury and regeneration.
The cannabinoid receptor 2 (CB2) plays a pleiotropic role in innate immunity and is a crucial mediator of liver disease. In this study, we investigated the impact of CB2 receptors on the regenerative process associated with liver injury. Following acute hepatitis induced by carbon tetrachloride (CCl(4)), CB2 was induced in the nonparenchymal cell fraction and remained undetectable in hepatocytes. Administration of CCl(4) to CB2(-/-) mice accelerated liver injury, as shown by increased alanine/aspartate aminotransferase levels and hepatocyte apoptosis, and delayed liver regeneration, as reflected by a retarded induction of hepatocyte proliferating cell nuclear antigen expression; proliferating cell nuclear antigen induction was also delayed in CB2(-/-) mice undergoing partial hepatectomy. Conversely, following treatment with the CB2 agonist JWH-133, CCl(4)-treated WT mice displayed reduced liver injury and accelerated liver regeneration. The CCl(4)-treated CB2(-/-) mice showed a decrease in inducible nitric oxide synthase and tumor necrosis factor-alpha expression, and administration of the nitric oxide donor moldomine (SIN-1) to these animals reduced hepatocyte apoptosis, without affecting liver regeneration. Impaired liver regeneration was consecutive to an interleukin-6 (IL-6)-mediated decrease in matrix metalloproteinase 2 (MMP-2) activity. Indeed, CCl(4)-treated CB2(-/-) mice displayed lower levels of hepatic IL-6 messenger RNA and increased MMP-2 activity. Administration of IL-6 to these mice decreased MMP-2 activity and improved liver regeneration, without affecting hepatocyte apoptosis. Accordingly, administration of the MMP inhibitor CTTHWGFTLC to CCl(4)-treated CB2(-/-) mice improved liver regeneration. Finally, in vitro studies demonstrated that incubation of hepatic myofibroblasts with JWH-133 increased tumor necrosis factor-alpha and IL-6 and decreased MMP-2 expressions.


CONCLUSIONS
CB2 receptors reduce liver injury and promote liver regeneration following acute insult, via distinct paracrine mechanisms involving hepatic myofibroblasts. These results suggest that CB2 agonists display potent hepatoprotective properties, in addition to their antifibrogenic effects.
Teixeira-Clerc
Fatima
F
INSERM, U955, Créteil, France.
Belot
Marie-Pierre
MP
Manin
Sylvie
S
Deveaux
Vanessa
V
Cadoudal
Thomas
T
Chobert
Marie-Noele
MN
Louvet
Alexandre
A
Zimmer
Andreas
A
Tordjmann
Thierry
T
Mallat
Ariane
A
Lotersztajn
Sophie
S
D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001219:Aspartate Aminotransferases / Q000378:metabolism; D002186:Cannabinoids / Q000494:pharmacology; D002251:Carbon Tetrachloride / Q000009:adverse effects; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D006498:Hepatectomy; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism; D008115:Liver Regeneration / Q000187:drug effects / Q000502:physiology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019899:Paracrine Communication / Q000502:physiology*; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D002186:Cannabinoids; D015850:Interleukin-6; D018809:Proliferating Cell Nuclear Antigen; D043885:Receptor, Cannabinoid, CB2; D014409:Tumor Necrosis Factor-alpha; D002251:Carbon Tetrachloride; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D020778:Matrix Metalloproteinase 2; C432747:1,1-dimethylbutyl-1-deoxy-Delta(9)-THC