Exposure to Δ9-Tetrahydrocannabinol Impairs the Differentiation of Human Monocyte-derived Dendritic Cells and their Capacity for T cell Activation
- 460 Downloads
The capacity for human monocytes to differentiate into antigen-presenting dendritic cells (DC) can be influenced by a number of immune modulating signals. Monocytes express intracellular cannabinoid type 1 (CB1) and 2 (CB2) receptors and we demonstrate that exposure to Δ9-tetrahydrocannabinol (THC) inhibits the forskolin-induced generation of cyclic adenosine monophosphate in a CB2-specific manner. In order to examine the potential impact of cannabinoids on the generation of monocyte-derived DC, monocytes were cultured in vitro with differentiation medium alone [containing granulocyte/macrophage-colony stimulating factor (GM-CSF) and Interleukin-4 (IL-4)] or in combination with THC. The presence of THC (0.25–1.0 μg/ml) altered key features of DC differentiation, producing a concentration-dependent decrease in surface expression of CD11c, HLA-DR and costimulatory molecules (CD40 and CD86), less effective antigen uptake, and signs of functional skewing with decreased production of IL-12 but normal levels of IL-10. When examined in a mixed leukocyte reaction, DC that had been generated in the presence of THC were poor T cell activators as evidenced by their inability to generate effector/memory T cells or to stimulate robust IFN-γ responses. Some of these effects were partially restored by exposure to exogenous IL-7 and bacterial superantigen (S. aureus Cowans strain). These studies demonstrate that human monocytes express functional cannabinoid receptors and suggest that exposure to THC can alter their differentiation into functional antigen presenting cells; an effect that may be counter-balanced by the presence of other immunoregulatory factors. The impact of cannabinoids on adaptive immune responses in individuals with frequent drug exposure remains to be determined.
KeywordsΔ9-tetrahydrocannabinol Cannabinoid receptor Monocyte Dendritic cell T cell activation Cytokines
Research reported in this publication was supported by the National Institute on Drug Abuse, National Institutes of Health, under award numbers 5-R01-DA003018 and 1-R01-DA037102. JT Castaneda was supported by a Ruth L. Kirschstein National Research Service Award (NRSA) Individual Predoctoral Fellowship to Promote Diversity in Health-Related Research from the National Institute on Drug Abuse, National Institutes of Health, under award numbers 1 F31 DA036293. Flow cytometry was performed in the UCLA Jonsson Comprehensive Cancer Center (JCCC) and Center for AIDS Research (CFAR) Flow Cytometry Core Facility that is supported by National Institutes of Health awards CA-16042 and AI-28697, and by the JCCC, the UCLA AIDS Institute, and the David Geffen School of Medicine at UCLA.
Conflicts of Interest
The authors declare that they have no conflict of interest.
Statement of Human Rights
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
- Alonso MN, Wong MT, Zhang AL, Winer D, Suhoski MM, Tolentino LL, Gaitan J, Davidson MG, Kung TH, Galel DM, Nadeau KC, Kim J, Utz PJ, Söderström K, Engleman EG (2011) TH1, TH2, and TH17 cells instruct monocytes to differentiate into specialized dendritic cell subsets. Blood 118(12):3311–3320. doi: 10.1182/blood-2011-03-341065 PubMedCentralPubMedCrossRefGoogle Scholar
- Castaneda JT, Harui A, Kiertscher SM, Roth JD, Roth MD (2013) Differential expression of intracellular and extracellular CB(2) cannabinoid receptor protein by human peripheral blood leukocytes. J Neuroimmune Pharmacol 8(1):323–332. doi: 10.1007/s11481-012-9430-8 PubMedCentralPubMedCrossRefGoogle Scholar
- Desrosiers NA, Himes SK, Scheidweiler KB, Concheiro-Guisan M, Gorelick DA, Huestis MA (2014) Phase I and II cannabinoid disposition in blood and plasma of occasional and frequent smokers following controlled smoked cannabis. Clin Chem 60(4):631–643. doi: 10.1373/clinchem.2013.216507 PubMedCrossRefGoogle Scholar
- Do Y, McKallip RJ, Nagarkatti M, Nagarkatti PS (2004) Activation through cannabinoid receptors 1 and 2 on dendritic cells triggers NF-kappaB-dependent apoptosis: novel role for endogenous and exogenous cannabinoids in immunoregulation. J Immunol 173(4):2373–2382. doi: 10.4049/jimmunol.173.4.2373 PubMedCrossRefGoogle Scholar
- Galiègue S, Mary S, Marchand J, Dussossoy D, Carrière D, Carayon P, Bouaboula M, Shire D, Le Fur G, Casellas P (1995) Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem 232(1):54–61. doi: 10.1111/j.1432-1033.1995.tb20780.x PubMedCrossRefGoogle Scholar
- Karmaus PW, Chen W, Crawford RB, Harkema JR, Kaplan BL, Kaminski NE (2011) Deletion of cannabinoid receptors 1 and 2 exacerbates APC function to increase inflammation and cellular immunity during influenza infection. J Leukoc Biol 90(5):983–995. doi: 10.1189/jlb.0511219 PubMedCentralPubMedCrossRefGoogle Scholar
- Karmaus PWF, Chen W, Crawford R, Kaplan BLF, Kaminski NE (2013) Δ9-Tetrahydrocannabinol impairs the inflammatory response to influenza infection: role of antigen-presenting cells and the cannabinoid receptors 1 and 2. Toxicol Sci 131(2):419–433. doi: 10.1093/toxsci/kfs315 PubMedCentralPubMedCrossRefGoogle Scholar
- Lu T, Newton C, Perkins I, Friedman H, Klein TW (2006b) Role of cannabinoid receptors in Delta-9-tetrahydrocannabinol suppression of IL-12p40 in mouse bone marrow-derived dendritic cells infected with Legionella pneumophila. Eur J Pharmacol 532(1–2):170–177. doi: 10.1016/j.ejphar.2005.12.040 PubMedCrossRefGoogle Scholar
- Rajkovic I, Dragicevic A, Vasilijic S, Bozic B, Dzopalic T, Tomic S, Majstorovic I, Vucevic D, Djokic J, Balint B, Colic M (2011) Differences in T-helper polarizing capability between human monocyte-derived dendritic cells and monocyte-derived Langerhans’-like cells. Immunology 132(2):217–25. doi: 10.1111/j.1365-2567.2010.03356.x PubMedCentralPubMedCrossRefGoogle Scholar
- Robinson RH, Meissler JJ, Breslow-Deckman JM, Gaughan J, Adler MW, Eisenstein TK (2013) Cannabinoids inhibit T-cells via cannabinoid receptor 2 in an in vitro assay for graft rejection, the mixed lymphocyte reaction. J Neuroimmune Pharmacol 8(5):1239–1250. doi: 10.1007/s11481-013-9485-1 PubMedCrossRefGoogle Scholar
- Roth MD, Gitlitz BJ, Kiertscher SM, Park AN, Mendenhall M, Moldawer N, Figlin RA (2000) Granulocyte/macrophage-colony stimulating factor and interleukin-4 enhance the number and antigen-presenting activity of circulating CD14+ and CD83+ cells in cancer patients. Cancer Res 60(7):1934–1941PubMedGoogle Scholar