Antifibrogenic role of the cannabinoid receptor CB2 in the liver.
OBJECTIVE
Hepatic myofibroblasts are central for the development of liver fibrosis associated with chronic liver diseases, and blocking their accumulation may prevent fibrogenesis. Cannabinoids are the active components of marijuana and act via 2 G-protein-coupled receptors, CB1 and CB2. Here, we investigated whether liver fibrogenic cells are a target of cannabinoids.


METHODS
CB2 receptors were characterized in biopsy specimens of normal human liver and active cirrhosis by immunohistochemistry, and in cultures of hepatic stellate cells and hepatic myofibroblasts by reverse-transcription polymerase chain reaction (RT-PCR), immunocytochemistry, and GTPgammaS assays. Functional studies were performed in cultured hepatic myofibroblasts and activated hepatic stellate cells. Carbon tetrachloride-induced liver fibrosis was studied in mice invalidated for CB2 receptors.


RESULTS
In liver biopsy specimens from patients with active cirrhosis of various etiologies, CB2 receptors were expressed in nonparenchymal cells located within and at the edge of fibrous septa in smooth muscle alpha-actin-positive cells. In contrast, CB2 receptors were not detected in normal human liver. CB2 receptors were also detected in cultured hepatic myofibroblasts and in activated hepatic stellate cells. Their activation triggered potent antifibrogenic effects, namely, growth inhibition and apoptosis. Growth inhibition involved cyclooxygenase-2, and apoptosis resulted from oxidative stress. Finally, mice invalidated for CB2 receptors developed enhanced liver fibrosis following chronic carbon tetrachloride treatment as compared with wild-type mice.


CONCLUSIONS
These data constitute the first demonstration that CB2 receptors are highly up-regulated in the cirrhotic liver, predominantly in hepatic fibrogenic cells. Moreover, this study also highlights the antifibrogenic role of CB2 receptors during chronic liver injury.
Julien
Boris
B
INSERM, U581, Créteil, F-94010 France.
Grenard
Pascale
P
Teixeira-Clerc
Fatima
F
Van Nhieu
Jeanne Tran
JT
Li
Liying
L
Karsak
Meliha
M
Zimmer
Andreas
A
Mallat
Ariane
A
Lotersztajn
Sophie
S
D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis; D001095:Arachidonic Acids / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D013759:Dronabinol / Q000494:pharmacology; D063388:Endocannabinoids; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005989:Glycerides / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D051381:Rats; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism*
D001095:Arachidonic Acids; D063388:Endocannabinoids; D005989:Glycerides; D043885:Receptor, Cannabinoid, CB2; C088155:methanandamide; D013759:Dronabinol; C094503:glyceryl 2-arachidonate