title: The direct profibrotic and indirect immune antifibrotic balance of blocking the cannabinoid 2 receptor.
abstract: Cannabinoid 2 (CB2) receptors expressed on immune cells are considered to be antifibrogenic. Hepatic stellate cells (HSCs) directly interact with phagocytosis lymphocytes, but the nature of this interaction is obscure. We aimed to study the effects of CB2 receptors on hepatic fibrosis via their role in mediating immunity. Hepatic fibrosis was induced by carbon-tetrachloride (CCl(4)) administration in C57BL/6 wild-type (WT) and CB2 knockout (CB2(-/-)) mice. Irradiated animals were reconstituted with WT or CB2(-/-) lymphocytes. Lymphocytes from naïve/fibrotic WT animals and healthy/cirrhotic hepatitis C virus were preincubated in vitro with or without CB2 antagonist, evaluated for proliferation and apoptosis, and then cocultured with primary mouse HSCs or a human HSC line (LX2), respectively. Lymphocyte phagocytosis was then evaluated. Following CCl(4)-administration, CB2(-/-) mice developed significant hepatic fibrosis but less necroinflammation. WT mice harbored decreased liver CD4(+) and NK(+) cells but increased CD8(+) subsets. Naïve CB2(-/-) mice had significantly decreased T cell subsets. Adoptive transfer of CB2(-/-) lymphocytes led to decreased fibrosis in the irradiated WT recipient compared with animals receiving WT lymphocytes. Moreover, necroinflammation also tended to decrease. In vitro, a CB2-antagonist directly increased human HSC activation and increased apoptosis and decreased proliferation of mice/human T cells (healthy/fibrotic) and their phagocytosis. We concluded that CB2(-/-) lymphocytes exert an antifibrotic activity, whereas lack of CB2 receptor in HSCs promotes fibrosis. These findings broaden our understanding of cannabinoid signaling in hepatic fibrosis beyond their activity solely in HSCs.
authors.affiliation: Department of Human Nutrition and Metabolism, Braun School of Public Health, Faculty of Medicine, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Yosefa
authors.initials: Y
authors.lastname: Avraham
authors.forename: Johnny
authors.initials: J
authors.lastname: Amer
authors.forename: Sarit
authors.initials: S
authors.lastname: Doron
authors.forename: Lina
authors.initials: L
authors.lastname: Abu-Tair
authors.forename: Mahmud
authors.initials: M
authors.lastname: Mahamid
authors.forename: Areej
authors.initials: A
authors.lastname: Khatib
authors.forename: Elliot M
authors.initials: EM
authors.lastname: Berry
authors.forename: Rifaat
authors.initials: R
authors.lastname: Safadi
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D001892:Camphanes / Q000494:pharmacology; D002251:Carbon Tetrachloride; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000276:immunology* / Q000473:pathology; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology; D011720:Pyrazoles / Q000494:pharmacology; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors*
chemical_list: D001892:Camphanes; D011720:Pyrazoles; D043885:Receptor, Cannabinoid, CB2; C110630:SR 144528; D002251:Carbon Tetrachloride