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

Abstract

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.

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    INSERM, U955, Créteil, France.

    , , , , , , , , ,

    Source

    Hepatology (Baltimore, Md.) 52:3 2010 Sep pg 1046-59

    MeSH

    Alanine Transaminase
    Animals
    Apoptosis
    Aspartate Aminotransferases
    Cannabinoids
    Carbon Tetrachloride
    Cells, Cultured
    Chemical and Drug Induced Liver Injury
    Disease Models, Animal
    Hepatectomy
    Hepatocytes
    Interleukin-6
    Liver Regeneration
    Matrix Metalloproteinase 2
    Mice
    Mice, Inbred C57BL
    Mice, Knockout
    Paracrine Communication
    Proliferating Cell Nuclear Antigen
    Receptor, Cannabinoid, CB2
    Tumor Necrosis Factor-alpha

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    20597071

    Citation

    Teixeira-Clerc, Fatima, et al. "Beneficial Paracrine Effects of Cannabinoid Receptor 2 On Liver Injury and Regeneration." Hepatology (Baltimore, Md.), vol. 52, no. 3, 2010, pp. 1046-59.
    Teixeira-Clerc F, Belot MP, Manin S, et al. Beneficial paracrine effects of cannabinoid receptor 2 on liver injury and regeneration. Hepatology. 2010;52(3):1046-59.
    Teixeira-Clerc, F., Belot, M. P., Manin, S., Deveaux, V., Cadoudal, T., Chobert, M. N., ... Lotersztajn, S. (2010). Beneficial paracrine effects of cannabinoid receptor 2 on liver injury and regeneration. Hepatology (Baltimore, Md.), 52(3), pp. 1046-59. doi:10.1002/hep.23779.
    Teixeira-Clerc F, et al. Beneficial Paracrine Effects of Cannabinoid Receptor 2 On Liver Injury and Regeneration. Hepatology. 2010;52(3):1046-59. PubMed PMID: 20597071.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Beneficial paracrine effects of cannabinoid receptor 2 on liver injury and regeneration. AU - Teixeira-Clerc,Fatima, AU - Belot,Marie-Pierre, AU - Manin,Sylvie, AU - Deveaux,Vanessa, AU - Cadoudal,Thomas, AU - Chobert,Marie-Noele, AU - Louvet,Alexandre, AU - Zimmer,Andreas, AU - Tordjmann,Thierry, AU - Mallat,Ariane, AU - Lotersztajn,Sophie, PY - 2010/7/3/entrez PY - 2010/7/3/pubmed PY - 2010/10/12/medline SP - 1046 EP - 59 JF - Hepatology (Baltimore, Md.) JO - Hepatology VL - 52 IS - 3 N2 - UNLABELLED: 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. SN - 1527-3350 UR - https://www.unboundmedicine.com/medline/citation/20597071/abstract/Beneficial_paracrine_effects_of_cannabinoid_receptor_2_on_liver_injury_and_regeneration_ L2 - https://doi.org/10.1002/hep.23779 DB - PRIME DP - Unbound Medicine ER -