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Protective effects of specific cannabinoid receptor 2 agonist GW405833 on concanavalin A-induced acute liver injury in mice

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Abstract

Cannabinoid receptor 2 (CB2R) is highly expressed in immune cells and plays an important role in regulating immune responses. In the current study, we investigated the effects of GW405833 (GW), a specific CB2R agonist, on acute liver injury induced by concanavalin A (Con A). In animal experiments, acute liver injury was induced in mice by injection of Con A (20 mg/kg, i.v.). The mice were treated with GW (20 mg/kg, i.p., 30 min after Con A injection) or GW plus the selective CB2R antagonist AM630 (2 mg/kg, i.p., 15 min after Con A injection). We found that Con A caused severe acute liver injury evidenced by significantly increased serum aminotransferase levels, massive hepatocyte apoptosis, and necrosis, as well as lymphocyte infiltration in liver tissues. Treatment with GW significantly ameliorated Con A-induced pathological injury in liver tissue, decreased serum aminotransferase levels, and decreased hepatocyte apoptosis. The therapeutic effects of GW were prevented by AM630. In cell experiments, we showed that CB2Rs were highly expressed in Jurkat T cells, but little expression in L02 liver cells. Treatment with GW (10−40 μg/mL) dose-dependently decreased the viability of Jurkat T cells and induced cell apoptosis, which was reversed by AM630. In the coculture of Jurkat T cells with L02 liver cells, GW dose-dependently protected L02 cells from apoptosis induced by Con A (5 μg/mL). The protective effect of GW was reversed by AM630 (1 μg/mL). Our results suggest that GW protects against Con A-induced acute liver injury in mice by inhibiting Jurkat T-cell proliferation through the CB2Rs.

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References

  1. 1.

    Chen J, Zhao SS, Liu XX, Huang ZB, Huang Y. Comparison of the efficacy of tenofovir versus tenofovir plus entecavir in the treatment of chronic hepatitis B in patients with poor efficacy of entecavir: a systematic review and Meta-analysis. Clin Ther. 2017;39:1870–80.

  2. 2.

    Vellozzi C, Averhoff F. An opportunity for further control of hepatitis B in China? Lancet Infect Dis. 2016;16:10–11.

  3. 3.

    Huang ZB, Zhao SS, Huang Y, Dai XH, Zhou RR, Yi PP, et al. Comparison of the efficacy of lamivudine plus adefovir versus entecavir in the treatment of Lamivudine-resistant chronic hepatitis B: a systematic review and meta-analysis. Clin Ther. 2013;35:1997–2006.

  4. 4.

    Bernal W, Jalan R, Quaglia A, Simpson K, Wendon J, Burroughs A. Acute-on-chronic liver failure. Lancet. 2015;386:1576–87.

  5. 5.

    Hammerich L, Bangen JM, Govaere O, Zimmermann HW, Gassler N, Huss S, et al. Chemokine receptor CCR6-dependent accumulation of gammadelta T cells in injured liver restricts hepatic inflammation and fibrosis. Hepatology. 2014;59:630–42.

  6. 6.

    Crispe IN. Immune tolerance in liver disease. Hepatology. 2014;60:2109–17.

  7. 7.

    Nakamoto Y, Kaneko S. Mechanisms of viral hepatitis induced liver injury. Curr Mol Med. 2003;3:537–44.

  8. 8.

    Horras CJ, Lamb CL, Mitchell KA. Regulation of hepatocyte fate by interferon-gamma. Cytokine Growth Factor Rev. 2011;22:35–43.

  9. 9.

    Lim HS, Jin SE, Kim OS, Shin HK, Jeong SJ. Alantolactone from Saussurea lappa exerts antiinflammatory effects by inhibiting chemokine production and STAT1 phosphorylation in TNF-alpha and IFN-gamma-induced in HaCaT cells. Phytother Res. 2015;29:1088–96.

  10. 10.

    Feldstein AE, Werneburg NW, Canbay A, Guicciardi ME, Bronk SF, Rydzewski R, et al. Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway. Hepatology. 2004;40:185–94.

  11. 11.

    Wang L, Zhang W, Ge CH, Yin RH, Xiao Y, Zhan YQ, et al. Toll-like receptor 5 signaling restrains T-cell/natural killer T-cell activation and protects against concanavalin A-induced hepatic injury. Hepatology. 2017;65:2059–73.

  12. 12.

    Cabral GA, Ferreira GA, Jamerson MJ. Endocannabinoids and the immune system in health and disease. Handb Exp Pharmacol. 2015;231:185–211.

  13. 13.

    Robinson RH, Meissler JJ, Fan X, Yu D, Adler MW, Eisenstein TK. ACB2-selective cannabinoid suppresses T-cell activities and increases Tregs and IL-10. J Neuroimmune Pharmacol. 2015;10:318–32.

  14. 14.

    Robinson RH, Meissler JJ, Breslow-Deckman JM, Gaughan J, Adler MW, Eisenstein TK. Cannabinoids inhibit T-cells via cannabinoid receptor 2 in an in vitro assay for graft rejection, the mixed lymphocyte reaction. J Neuroimmune Pharmacol. 2013;8:1239–50.

  15. 15.

    Kong Y, Wang W, Zhang C, Wu Y, Liu Y, Zhou X. Cannabinoid WIN55,2122 mesylate inhibits ADAMTS4 activity in human osteoarthritic articular chondrocytes by inhibiting expression of syndecan1. Mol Med Rep. 2016;13:4569–76.

  16. 16.

    Valenzano KJ, Tafesse L, Lee G, Harrison JE, Boulet JM, Gottshall SL, et al. Pharmacological and pharmacokinetic characterization of the cannabinoid receptor 2 agonist, GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and catalepsy. Neuropharmacology. 2005;48:658–72.

  17. 17.

    Gui H, Sun Y, Luo ZM, Su DF, Dai SM, Liu X. Cannabinoid receptor 2 protects against acute experimental sepsis in mice. Mediators Inflamm. 2013;2013:741303.

  18. 18.

    Kato J, Okamoto T, Motoyama H, Uchiyama R, Kirchhofer D, Van Rooijen N, et al. Interferon-gamma-mediated tissue factor expression contributes to T-cell-mediated hepatitis through induction of hypercoagulation in mice. Hepatology. 2013;57:362–72.

  19. 19.

    Hegde VL, Hegde S, Cravatt BF, Hofseth LJ, Nagarkatti M, Nagarkatti PS. Attenuation of experimental autoimmune hepatitis by exogenous and endogenous cannabinoids: involvement of regulatory T cells. Mol Pharmacol. 2008;74:20–33.

  20. 20.

    Liu J, Yang D, Shi S, Lin L, Xiao M, Yuan Z, et al. Overexpression of vasostatin-1 protects hypoxia/reoxygenation injuries in cardiomyocytes-endothelial cells transwell co-culture system. Cell Biol Int. 2014;38:26–31.

  21. 21.

    Nakamoto N, Amiya T, Aoki R, Taniki N, Koda Y, Miyamoto K, et al. Commensal lactobacillus controls immune tolerance during acute liver injury in mice. Cell Rep. 2017;21:1215–26.

  22. 22.

    Mansi Y, Ghaffar SA, Sayed S, El-Karaksy H. The effect of nutritional status on outcome of hospitalization in paediatric liver disease patients. J Clin Diagn Res. 2016;10:SC01–SC05.

  23. 23.

    Zhou RR, Liu HB, Peng JP, Huang Y, Li N, Xiao MF, et al. High mobility group box chromosomal protein 1 in acute-on-chronic liver failure patients and mice with ConA-induced acute liver injury. Exp Mol Pathol. 2012;93:213–9.

  24. 24.

    Xu L, Zhao Y, Qin Y, Xu Q. A novel model of acute liver injury in mice induced by T cell-mediated immune response to lactosylated bovine serum albumin. Clin Exp Immunol. 2006;144:125–33.

  25. 25.

    Denaes T, Lodder J, Chobert MN, Ruiz I, Pawlotsky JM, Lotersztajn S, et al. The cannabinoid receptor 2 protects against alcoholic liver disease via a macrophage autophagy-dependent pathway. Sci Rep. 2016;6:28806.

  26. 26.

    Louvet A, Teixeira-Clerc F, Chobert MN, Deveaux V, Pavoine C, Zimmer A, et al. Cannabinoid CB2 receptors protect against alcoholic liver disease by regulating Kupffer cell polarization in mice. Hepatology. 2011;54:1217–26.

  27. 27.

    Huang Z, Wang H, Wang J, Zhao M, Sun N, Sun F, et al. Cannabinoid receptor subtype 2 (CB2R) agonist, GW405833 reduces agonist-induced Ca2+oscillations in mouse pancreatic acinar cells. Sci Rep. 2016;6:29757.

  28. 28.

    Michler T, Storr M, Kramer J, Ochs S, Malo A, Reu S, et al. Activation of cannabinoid receptor 2 reduces inflammation in acute experimental pancreatitis via intra-acinar activation of p38 and MK2-dependent mechanisms. Am J Physiol Gastrointest Liver Physiol. 2013;304:G181–92.

  29. 29.

    Danoy M, Shinohara M, Rizki-Safitri A, Collard D, Senez V, Sakai Y. Alteration of pancreatic carcinoma and promyeloblastic cell adhesion in liver microvasculature by co-culture of hepatocytes, hepatic stellate cells and endothelial cells in a physiologically-relevant model. Integr Biol (Camb). 2017;9:350–61.

  30. 30.

    Melton AC, Melrose J, Alajoki L, Privat S, Cho H, Brown N, et al. Regulation of IL-17A production is distinct from IL-17F in a primary human cell co-culture model of T cell-mediated B cell activation. PLoS ONE. 2013;8:e58966.

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (81700561), the Natural Science Foundation of Hunan Province, China (2016JJ3164, 2017JJ3496, 2017JJ2385), and the Project of Science and Technology Agency of Hunan Province, China (2014SK4066).

Author contributions

ZBH and YXZ performed animal experiments and wrote the manuscript; NL designed the research; SLC performed part of the cell experiments; YH designed the research; JW performed part of the cell experiments; XWH and YW wrote part of the manuscript; XGF designed the experiments and edited the manuscript; JW designed the experiments, analyzed the data, revised all figures, and revised the manuscript.The authors declare no competing fnancial interests.

Author information

Correspondence to Jie Wu or Xue-gong Fan.

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DOI

https://doi.org/10.1038/s41401-019-0213-0

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