Abstract
Cannabinoid receptors CB1 and CB2 are primarily expressed in cells of the nervous and immune systems, respectively. Recently, the synthetic CB1/CB2 agonist WIN55,212-2 was found to suppress replication of HIV-1 in microglial cell cultures. The present study was undertaken to test the hypothesis that WIN55,212-2’s antiviral effect is mediated via CB2 receptors. By reverse transcription-polymerase chain reaction, microglia were found to express both CB1 and CB2 receptors. Using additional CB1/CB2 receptor agonists and selective antagonists, we found that CB2 receptors are involved in WIN55,212-2’s antiviral activity and surprisingly that the CB1 receptor-selective antagonist SR141716A behaved as an agonist in these brain macrophages.
References
Baldwin GC, Roth MD (2005) Biological links between cannabinoids and HIV infection. In: Friedman H (ed) Infectious Diseases and Substance Abuse. Kluwer Academic/Plenum Publishers, New York, pp 13–32
Cabral GA, Dove Pettit DA (1998) Drugs and immunity: cannabinoids and their role in decreased resistance to infectious disease. J Neuroimmunol 83:116–123
Cabral GA, Marciano-Cabral F (2005) Cannabinoid receptors in microglia of the central nervous system: immune functional relevance. J Leukoc Biol 78:1192–1197
Carlisle SJ, Marciano-Cabral F, Staab A, Ludwick C, Cabral GA (2002) Differential expression of the CB2 cannabinoid receptor by rodent macrophages and macrophage-like cells in relation to cell activation. Int Immunopharmacol 2:69–82
Despres JP, Golay A, Sjostrom L (2005) Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med 353:2121–2134
Ehrhart J, Obregon D, Mori T, Hou H, Sun N, Bai Y, Klein T, Fernandez F, Tan J, Shytle RD (2005) Stimulation of cannabinoid receptor 2 (CB2) suppresses microglial activation. J Neuroinflammation 2:29
Facchinetti F, Del Giudice E, Furegato S, Passarotto M, Leon A (2003) Cannabinoids ablate release of TNF-alpha in rat microglial cells stimulated with lypopolysaccharide. Glia 41:161–168
Gross A, Terraza A, Marchant J, Bouaboula M, Ouahrani-Bettache S, Liautard JP, Casellas P, Dornand J (2000) A beneficial aspect of a CB1 cannabinoid receptor antagonist: SR141716A is a potent inhibitor of macrophage infection by the intracellular pathogen Brucella suis. J Leukoc Biol 67:335–344
Guo CJ, Li Y, Tian S, Wang X, Douglas SD, Ho WZ (2002) Morphine enhances HIV infection of human blood mononuclear phagocytes through modulation of beta-chemokines and CCR5 receptor. J Investig Med 50:435–442
Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG (2002) International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev 54:161–202
Klegeris A, Bissonnette CJ, McGeer PL (2003) Reduction of human monocytic cell neurotoxicity and cytokine secretion by ligands of the cannabinoid-type CB2 receptor. Br J Pharmacol 139:775–786
Klein TW, Newton C, Larsen K, Lu L, Perkins I, Nong L, Friedman H (2003) The cannabinoid system and immune modulation. J Leukoc Biol 74:486–496
Pertwee RG (1997) Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther 74:129–180
Pertwee RG (2006) Cannabinoid pharmacology: the first 66 years. Br J Pharmacol 147(Suppl 1):S163–S171
Peterson PK, Gekker G, Hu S, Cabral G, Lokensgard JR (2004) Cannabinoids and morphine differentially affect HIV-1 expression in CD4(+) lymphocyte and microglial cell cultures. J Neuroimmunol 147:123–126
Puffenbarger RA, Boothe AC, Cabral GA (2000) Cannabinoids inhibit LPS-inducible cytokine mRNA expression in rat microglial cells. Glia 29:58–69
Savinainen JR, Kokkola T, Salo OM, Poso A, Jarvinen T, Laitinen JT (2005) Identification of WIN55212-3 as a competitive neutral antagonist of the human cannabinoid CB2 receptor. Br J Pharmacol 145:636–645
Sinha D, Bonner TI, Bhat NR, Matsuda LA (1998) Expression of the CB1 cannabinoid receptor in macrophage-like cells from brain tissue: immunochemical characterization by fusion protein antibodies. J Neuroimmunol 82:13–21
Szabo I, Wetzel MA, Zhang N, Steele AD, Kaminsky DE, Chen C, Liu-Chen LY, Bednar F, Henderson EE, Howard OM, Oppenheim JJ, Rogers TJ (2003) Selective inactivation of CCR5 and decreased infectivity of R5 HIV-1 strains mediated by opioid-induced heterologous desensitization. J Leukoc Biol 74:1074–1082
Acknowledgements
This work was supported by grants from National Institute on Drug Abuse, DA-04381 and DA-09789, and was supported in part by U.S. Public Health Service grant DA-04381.
Author information
Authors and Affiliations
Corresponding author
Additional information
Human fetal brain tissue was obtained under the protocol approved by the Human Subjects Research Committee at our institution.
Rights and permissions
About this article
Cite this article
Rock, R.B., Gekker, G., Hu, S. et al. WIN55,212-2-Mediated Inhibition of HIV-1 Expression in Microglial Cells: Involvement of Cannabinoid Receptors. Jrnl Neuroimmune Pharm 2, 178–183 (2007). https://doi.org/10.1007/s11481-006-9040-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11481-006-9040-4