Beneficial paracrine effects of cannabinoid receptor 2 on liver injury and regeneration

Autor: Alexandre Louvet, Thierry Tordjmann, Andreas Zimmer, Sylvie Manin, Marie-Pierre Belot, Vanessa Deveaux, Marie-Noële Chobert, Sophie Lotersztajn, Thomas Cadoudal, Fatima Teixeira-Clerc, Ariane Mallat
Přispěvatelé: Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Department of Molecular Psychiatry, Rheinische Friedrich-Wilhelms-Universität Bonn, Signalisation calcique et interactions cellulaires dans le foie, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hépato-gastro-entérologie [APHP Henri Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), This work was supported by the INSERM, the Université Paris-Est, and by grants (to S.L) of the Agence Nationale de la Recherche and Fondation pour la Recherche Médicale, Guellaen, Georges, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10
Jazyk: angličtina
Rok vydání: 2010
Předmět:
medicine.medical_treatment
Apoptosis
Receptor
Cannabinoid
CB2
chemistry.chemical_compound
Liver disease
Mice
0302 clinical medicine
Carbon Tetrachloride
Cells
Cultured
Liver injury
Mice
Knockout
0303 health sciences
Alanine Transaminase
Liver regeneration
3. Good health
medicine.anatomical_structure
Hepatocyte
Matrix Metalloproteinase 2
030211 gastroenterology & hepatology
lipids (amino acids
peptides
and proteins)
Chemical and Drug Induced Liver Injury
medicine.medical_specialty
Biology
Nitric oxide
03 medical and health sciences
Internal medicine
Proliferating Cell Nuclear Antigen
Paracrine Communication
[SDV.BBM] Life Sciences [q-bio]/Biochemistry
Molecular Biology
medicine
Animals
Hepatectomy
[SDV.BBM]Life Sciences [q-bio]/Biochemistry
Molecular Biology
Aspartate Aminotransferases
030304 developmental biology
Hepatology
Cannabinoids
Interleukin-6
Tumor Necrosis Factor-alpha
Regeneration (biology)
medicine.disease
Liver Regeneration
Mice
Inbred C57BL
Disease Models
Animal
Endocrinology
chemistry
Alanine transaminase
biology.protein
Hepatocytes
Zdroj: Hepatology
Hepatology, Wiley-Blackwell, 2010, 52 (3), pp.1046-59. ⟨10.1002/hep.23779⟩
Hepatology, 2010, 52 (3), pp.1046-59. ⟨10.1002/hep.23779⟩
ISSN: 0270-9139
1527-3350
Popis: International audience; 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. CONCLUSION: 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.
Databáze: OpenAIRE
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