Cannabinoids are well known for their psychoactive and immunomodulatory properties. The discovery of the existence of CB1 and CB2 cannabinoid receptors and the isolation of endogenous ligands have raised questions on the physiological relevance of cannabinoids in the regulation of immune system. The immune system has been shown to be sensitive to the toxic effects of cannabinoids, although the mechanism remains unclear. Preliminary studies from our lab demonstrated that THC can induce apoptosis in activated T cells as well as in T cell lymphoma lines through cannabinoid receptors. Moreover, mice treated with THC were found to exhibit marked atrophy of the thymus and spleen. Based on these findings, we wish to test the hypothesis that ligation of cannabinoid receptors on lymphocytes with agonists leads to induction of apoptosis and dysregulation of immune functions. The following specific alms will test this hypothesis: 1) Role of CB1 and CB2 receptors in cannabinoid-induced apoptosis in lymphocytes will be investigated in vitro using a wide range of CB1 and CB2 receptor agonists and antagonists. We will test whether CB1 and CB2 receptors are modulated during lymphocyte activation and subsequent apoptosis. Lymphocytes from CB1 receptor knockout mice will be tested for apoptosis. 2) Whether cannabinoids can induce apoptosis in vivo and whether such a mechanism accounts for immunosuppression will be tested. In addition, we will use fetal thymus organ cultures to delineate whether cannabinoids directly act on T cells in the thymus to induce apoptosis or whether they also act on bone marrow stem cells to prevent lymphopoiesis. Superantigens such as Staphylococcal enterotoxin A will be used in mice to investigate whether cannabinoids induce apoptosis in antigen-specific Vbeta3+ and Vbeta1 1+ T cells. T cell replication in vivo during cannabinoid exposure will be monitored using CFSE and flow cytometry. 3) We will test whether cannabinoids induce apoptosis in lymphocytes through death-receptor pathway or mitochondrial pathway. Using DNA array we will screen a large pool of genes involved in cannabinoid-induced apoptosis. We will investigate whether caspase inhibitors can block cannabinoid-induced apoptosis in vivo and ameliorate immunotoxicity. The current study will provide a basis for future studies on pharmacologic and molecular manipulations of cannabinoid receptors, so as to regulate apoptosis in immune cells. This will provide new and exciting treatment modalities to prevent immune dysfunction resulting from drug abuse as well as facilitate the development of new approaches to treat wide range of immunologic disorders.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZDA1-TXL-Q (10))
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Sharp, Charles
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Virginia Commonwealth University
Schools of Medicine
United States
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Singh, Narendra P; Nagarkatti, Mitzi; Nagarkatti, Prakash (2008) Primary peripheral T cells become susceptible to 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated apoptosis in vitro upon activation and in the presence of dendritic cells. Mol Pharmacol 73:1722-35
Hegde, Venkatesh L; Hegde, Shweta; Cravatt, Benjamin F et al. (2008) Attenuation of experimental autoimmune hepatitis by exogenous and endogenous cannabinoids: involvement of regulatory T cells. Mol Pharmacol 74:20-33
Singh, Narendra P; Hegde, Venkatesh L; Hofseth, Lorne J et al. (2007) Resveratrol (trans-3,5,4'-trihydroxystilbene) ameliorates experimental allergic encephalomyelitis, primarily via induction of apoptosis in T cells involving activation of aryl hydrocarbon receptor and estrogen receptor. Mol Pharmacol 72:1508-21
Lombard, Catherine; Nagarkatti, Mitzi; Nagarkatti, Prakash (2007) CB2 cannabinoid receptor agonist, JWH-015, triggers apoptosis in immune cells: potential role for CB2-selective ligands as immunosuppressive agents. Clin Immunol 122:259-70
Singh, Narendra P; Nagarkatti, Mitzi; Nagarkatti, Prakash S (2007) Role of dioxin response element and nuclear factor-kappaB motifs in 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated regulation of Fas and Fas ligand expression. Mol Pharmacol 71:145-57
Jia, Wentao; Hegde, Venkatesh L; Singh, Narendra P et al. (2006) Delta9-tetrahydrocannabinol-induced apoptosis in Jurkat leukemia T cells is regulated by translocation of Bad to mitochondria. Mol Cancer Res 4:549-62
McKallip, Robert J; Jia, Wentao; Schlomer, Jerome et al. (2006) Cannabidiol-induced apoptosis in human leukemia cells: A novel role of cannabidiol in the regulation of p22phox and Nox4 expression. Mol Pharmacol 70:897-908
McKallip, Robert J; Fisher, Michael; Gunthert, Ursula et al. (2005) Role of CD44 and its v7 isoform in staphylococcal enterotoxin B-induced toxic shock: CD44 deficiency on hepatic mononuclear cells leads to reduced activation-induced apoptosis that results in increased liver damage. Infect Immun 73:50-61
McKallip, Robert J; Nagarkatti, Mitzi; Nagarkatti, Prakash S (2005) Delta-9-tetrahydrocannabinol enhances breast cancer growth and metastasis by suppression of the antitumor immune response. J Immunol 174:3281-9
Camacho, Iris A; Singh, Narendra; Hegde, Venkatesh L et al. (2005) Treatment of mice with 2,3,7,8-tetrachlorodibenzo-p-dioxin leads to aryl hydrocarbon receptor-dependent nuclear translocation of NF-kappaB and expression of Fas ligand in thymic stromal cells and consequent apoptosis in T cells. J Immunol 175:90-103

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