Cannabinoid-Induced Immune Suppression and Modulation of Antigen-Presenting Cells

  • Thomas W. KleinEmail author
  • Guy A. Cabral
Invited Review


The study of marijuana cannabinoid biology has led to many important discoveries in neuroscience and immunology. These studies have uncovered a new physiological system, the endocannabinoid system, which operates in the regulation of not only brain function but also the regulation of the immune system. Studies examining the effect of cannabinoid-based drugs on immunity have shown that many cellular and cytokine mechanisms are suppressed by these agents leading to the hypothesis that these drugs may be of value in the management of chronic inflammatory diseases. In this report, we review current information on cannabinoid ligand and receptor biology, mechanisms involved in immune suppression by cannabinoids with emphasis on antigen-presenting cells, and preclinical and clinical models analyzing the therapeutic potential of cannabinoid-based drugs.


Fatty Acid Amide Hydrolase Vanilloid Receptor Palmitoylethanolamide Ajulemic Acid Noladin Ether 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This study was supported in part by DA03646 (TWK) and DA05832 and DA15608 (GAC) from NIDA.


  1. Arevalo–Martin A, Vela JM, Molina–Holgado E, Borrell J, Guaza C (2003) Therapeutic action of cannabinoids in a murine model of multiple sclerosis. J Neurosci 23:2511–2516PubMedGoogle Scholar
  2. Baker D, Pryce G, Croxford JL, Brown P, Pertwee RG, Huffman JW, Layward L (2000) Cannabinoids control spasticity and tremor in a multiple sclerosis model. Nature 404:84–87CrossRefPubMedGoogle Scholar
  3. Baker D, Pryce G, Croxford JL, Brown P, Pertwee RG, Makriyannis A, Khanolkar A, Layward L, Fezza F, Bisogno T, Di Marzo V (2001) Endocannabinoids control spasticity in a multiple sclerosis model. FASEB J 15:300–302PubMedGoogle Scholar
  4. Baker D, Pryce G, Giovannoni G, Thompson AJ (2003) The therapeutic potential of cannabis. Lancet Neurol 2:291–298CrossRefPubMedGoogle Scholar
  5. Berdyshev EV, Boichot E, Germain N, Allain N, Anger JP, Lagente V (1997) Influence of fatty acid ethanolamides and Δ9–tetrahydrocannabinol on cytokine and arachidonate release by mononuclear cells. Eur J Pharmacol 330:231–240CrossRefPubMedGoogle Scholar
  6. Bisogno T, Hanus L, De Petrocellis L, Tchilibon S, Ponde DE, Brandi I, Moriello AS, Davis JB, Mechoulam R, Di Marzo V (2001) Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol 134:845–852CrossRefPubMedGoogle Scholar
  7. Bisogno T, Howell F, Williams G, Minassi A, Cascio MG, Ligresti A, Matias I, Schiano-Moriello A, Paul P, Williams EJ, Gangadharan U, Di Marzo V, Doherty P (2003) Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. J Cell Biol 163:463–468CrossRefGoogle Scholar
  8. Blanchard DK, Newton C, Klein TW, Stewart WE III, Friedman H (1986) In vitro and in vivo suppressive effects of delta–9–tetrahydrocannabinol on interferon production by murine spleen cells. Int J Immunopharmacol 8:819–824CrossRefPubMedGoogle Scholar
  9. Bouaboula M, Rinaldi M, Carayon P, Carillon C, Delpech B, Shire D, LeFur G, Casellas P (1993) Cannabinoid-receptor expression in human leukocytes. Eur J Biochem 214:173–180CrossRefPubMedGoogle Scholar
  10. Brady CM, DasGupta R, Dalton C, Wiseman OJ, Berkley KJ, Fowler CJ (2004) An open-label pilot study of cannabis-based extracts for bladder dysfunction in advanced multiple sclerosis. Mult Scler 10:425–433CrossRefPubMedGoogle Scholar
  11. Breivogel CS, Griffin G, Di Marzo V, Martin BR (2001) Evidence for a new G protein-coupled cannabinoid receptor in mouse brain. Mol Pharmacol 60:155–163PubMedGoogle Scholar
  12. Buckley NE, McCoy KL, Mezey E, Bonner T, Zimmer A, Felder CC, Glass M, Zimmer A (2000) Immunomodulation by cannabinoids is absent in mice deficient for the cannabinoid CB2 receptor. Eur J Pharmacol 396:141–149CrossRefPubMedGoogle Scholar
  13. Burnette–Curley D, Cabral GA (1995) Differential inhibition of RAW264.7 macrophage tumoricidal activity by Δ9–tetrahydrocannabinol. Proc Soc Exp Biol Med 210:64–76PubMedGoogle Scholar
  14. Burnette–Curley D, Marciano–Cabral F, Fischer–Stenger K, Cabral GA (1993) Delta–9–tetrahydrocannabinol inhibits cell contact-dependent cytotoxicity of Bacillus Calmette–Guerin–activated macrophages. Int J Immunopharmacol 15:371–382PubMedCrossRefGoogle Scholar
  15. Burstein SH, Audette CA, Breuer A, Devane WA, Colodner S, Doyle SA, Mechoulam R (1992) Synthetic nonpsychotropic cannabinoids with potent antiinflammatory, analgesic, and leukocyte antiadhesion activities. J Med Chem 35:3135–3141CrossRefPubMedGoogle Scholar
  16. Burstein SH, Karst M, Schneider U, Zurier RB (2004) Ajulemic acid: a novel cannabinoid produces analgesia without a “high.” Life Sci 75:1513–1522CrossRefPubMedGoogle Scholar
  17. Cabral GA, Mishkin EM (1989) Delta–9–tetrahydrocannabinol inhibits macrophage protein expression in response to bacterial immunomodulators. J Toxicol Environ Health 26:175–182PubMedGoogle Scholar
  18. Cabral GA, Vasquez R (1992) Δ9–Tetrahydrocannabinol suppresses macrophage extrinsic antiherpesvirus activity. Proc Soc Exp Biol Med 199:255–263PubMedGoogle Scholar
  19. Cabral G, Dove Pettit D (1998) Drugs and immunity: cannabinoids and their role in decreased resistance to infectious diseases. J Neuroimmunol 83:116–123CrossRefPubMedGoogle Scholar
  20. Cabral GA, Marciano–Cabral F (2004) Cannabinoid-mediated exacerbation of brain infection by opportunistic amebae. J Neuroimmunol 147:127–130CrossRefPubMedGoogle Scholar
  21. Cabral GA, Staab A (2005) Effects on the immune system. In: Pertwee R (ed) Handbook of Experimental Pharmacology, Springer–Verlag, Heidelberg, pp 385–423Google Scholar
  22. Cabral GA, Lockmuller JC, Mishkin EM (1986) Δ9–Tetrahydrocannabinol decreases alpha/beta interferon response to herpes simplex virus type 2 in the B6C3F1 mouse. Proc Soc Exp Biol Med 181:305–311PubMedGoogle Scholar
  23. Cabral GA, Toney DM, Fischer–Stenger K, Harrison MP, Marciano–Cabral F (1995) Anandamide inhibits macrophage-mediated killing of tumor necrosis factor-sensitive cells. Life Sci 56:2065–2072CrossRefPubMedGoogle Scholar
  24. Calignano A, La Rana G, Giuffrida A, Piomelli D (1998) Control of pain initiation by endogenous cannabinoids. Nature 394:277–281CrossRefPubMedGoogle Scholar
  25. Carayon P, Marchand J, Dussossoy D, Derocq JM, Jbilo O, Bord A, Bouaboula M, Galiegue S, Mondiere P, Penarier G, LeFur G, Defrance T, Casellas P (1998) Modulation and functional involvement of CB2 peripheral cannabinoid receptors during B–cell differentiation. Blood 92:3605–3615PubMedGoogle Scholar
  26. Carlisle S, Marciano–Cabral F, Staab A, Ludwick C, Cabral G (2002) Differential expression of the CB2 cannabinoid receptor by rodent macrophages and macrophage-like cells in relation to cell activation. Int Immunopharmacol 2:69–82CrossRefPubMedGoogle Scholar
  27. Carrier EJ, Kearn CS, Barkmeier AJ, Breese NM, Yang W, Nithipatikom K, Pfister SL, Campbell WB, Hillard CJ (2004) Cultured rat microglial cells synthesize the endocannabinoid 2–arachidonylglycerol, which increases proliferation via a CB2 receptor-dependent mechanism. Mol Pharmacol 65:999–1007CrossRefPubMedGoogle Scholar
  28. Chuchawankul S, Shima M, Buckley NE, Hartmann CB, McCoy KL (2004) Role of cannabinoid receptors in inhibiting macrophage costimulatory activity. Int Immunopharmacol 4:265–278CrossRefPubMedGoogle Scholar
  29. Coffey RG, Yamamoto Y, Snella E, Pross S (1996) Tetrahydrocannabinol inhibition of macrophage nitric oxide production. Biochem Pharmacol 52:743–751CrossRefPubMedGoogle Scholar
  30. Condie R, Herring A, Koh WS, Lee M, Kaminski NE (1996) Cannabinoid induction of adenylate cyclase-mediated signal transduction and interleukin 2 (IL–2) expression in the murine T–cell line, EL4.IL–2. J Biol Chem 271:13175–13183CrossRefPubMedGoogle Scholar
  31. Croxford JL, Miller SD (2003) Immunoregulation of a viral model of multiple sclerosis using the synthetic cannabinoid R+WIN55,212. J Clin Invest 111:1231–1240CrossRefPubMedGoogle Scholar
  32. Daaka Y, Zhu W, Friedman H, Klein TW (1997) Induction of IL–2 receptor a gene by Δ9–tetrahydrocannabinol is mediated by nuclear factor kB and CB1 cannabinoid receptor. DNA Cell Biol 16:301–309PubMedGoogle Scholar
  33. Dajani EZ, Larsen KR, Taylor J, Dajani NE, Shahwan TG, Neeleman SD, Taylor MS, Dayton MT, Mir GN (1999) 1′,1′–Dimethylheptyl–delta–8–tetrahydrocannabinol–11–oic acid: a novel, orally effective cannabinoid with analgesic and anti-inflammatory properties. J Pharmacol Exp Ther 291:31–38PubMedGoogle Scholar
  34. Derocq J, Segui M, Marchand J, LeFur G, Casellas P (1995) Cannabinoids enhance human B–cell growth at low nanomolar concentrations. FEBS Lett 369:177–182CrossRefPubMedGoogle Scholar
  35. Deutsch DG, Ueda N, Yamamoto S (2002) The fatty acid amide hydrolase (FAAH). Prostaglandins Leukot Essent Fat Acids 66:201–210CrossRefGoogle Scholar
  36. Devane WA, Dysarz FA III, Johnson MR, Melvin LS, Howlett AC (1988) Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol 34:605–613PubMedGoogle Scholar
  37. Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A, Mechoulam R (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258:1946–1949PubMedGoogle Scholar
  38. Di Filippo C, Rossi F, Rossi S, D'Amico M (2004) Cannabinoid CB2 receptor activation reduces mouse myocardial ischemia–reperfusion injury: involvement of cytokine/chemokines and PMN. J Leukoc Biol 75:453–459CrossRefPubMedGoogle Scholar
  39. Di Marzo V, Bifulco M, De Petrocellis L (2004) The endocannabinoid system and its therapeutic exploitation. Nat Rev Drug Discov 3:771–784CrossRefPubMedGoogle Scholar
  40. Fischer–Stenger K, Updegrove AW, Cabral GA (1992) Δ9–tetrahydrocannabinol decreases cytotoxic T lymphocyte activity to herpes simplex virus type 1–infected cells. Proc Soc Exp Biol Med 200:422–430PubMedGoogle Scholar
  41. Fowler CJ, Holt S, Nilsson O, Jonsson KO, Tiger G, Jacobsson SO (2005) The endocannabinoid signaling system: pharmacological and therapeutic aspects. Pharmacol Biochem Behav 81:248–262CrossRefPubMedGoogle Scholar
  42. Friedman H, Klein T, Specter S (1991) Immunosuppression by marijuana components. In: Ader R, Felten DL, Cohen N (eds) Psychoneuroimmunology, Academic, San Diego pp 931–953Google Scholar
  43. Galieque S, Mary S, Marchand J, Dussossoy D, Carriere 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 232:54–61CrossRefPubMedGoogle Scholar
  44. Gallily R, Yamin A, Waksmann Y, Ovadia H, Weidenfeld J, Bar–Joseph A, Biegon A, Mechoulam R, Shohami E (1997) Protection against septic shock and suppression of tumor necrosis factor alpha and nitric oxide production by dexanabinol (HU–211), a nonpsychotropic cannabinoid. J Pharmacol Exp Ther 283:918–924PubMedGoogle Scholar
  45. Gaoni Y, Mechoulam R (1964) Isolation, structure, and partial synthesis of an active constituent of hashish. J Am Chem Soc 86:1646–1647CrossRefGoogle Scholar
  46. Gerard CM, Mollereau C, Vassart G, Parmentier M (1991) Molecular cloning of a human cannabinoid receptor which is also expressed in testis. Biochem J 279:129–134PubMedGoogle Scholar
  47. Glass M, Felder CC (1997) Concurrent stimulation of cannabinoid CB1 and dopamine D2 receptors augments cAMP accumulation in striatal neurons: evidence for a Gs linkage to the CB1 receptor. J Neurosci 17:5327–5333PubMedGoogle Scholar
  48. Hanus L, Abu–Lafi S, Fride E, Breuer A, Vogel Z, Shalev DE, Kustanovich I, Mechoulam R (2001) 2–Arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor. Proc Natl Acad Sci U S A 98:3662–3665PubMedGoogle Scholar
  49. Ho WS, Hiley CR (2004) Vasorelaxant activities of the putative endocannabinoid virodhamine in rat isolated small mesenteric artery. J Pharm Pharmacol 56:869–875CrossRefPubMedGoogle Scholar
  50. Howlett AC, Johnson MR, Melvin LS, Milne GM (1988) Nonclassical cannabinoid analgetics inhibit adenylate cyclase: development of a cannabinoid receptor model. Mol Pharmacol 33:297–302PubMedGoogle Scholar
  51. 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 54:161–202CrossRefPubMedGoogle Scholar
  52. Howlett AC, Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Porrino LJ (2004) Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology 47:345–358CrossRefPubMedGoogle Scholar
  53. Ibrahim MM, Deng H, Zvonok A, Cockayne DA, Kwan J, Mata HP, Vanderah TW, Lai J, Porreca F, Makriyannis A, Malan TP Jr (2003) Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: pain inhibition by receptors not present in the CNS. Proc Natl Acad Sci U S A 100:10529–10533PubMedGoogle Scholar
  54. Jarai Z, Wagner JA, Varga K, Lake KD, Compton DR, Martin BR, Zimmer AM, Bonner TI, Buckley NE, Mezey E, Razdan RK, Zimmer A, Kunos G (1999) Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors. Proc Natl Acad Sci U S A 96:14136–14141PubMedGoogle Scholar
  55. Jeon YJ, Yang K, Pulaski JT, Kaminski NE (1996) Attenuation of inducible nitric oxide synthase gene expression by D9–tetrahydrocannabinol is mediated through the inhibition of nuclear factor–kB/Rel activation. Mol Pharmacol 50:334–341PubMedGoogle Scholar
  56. Jorda MA, Verbakel SE, Valk PJ, Vankan–Berkhoudt YV, Maccarrone M, Finazzi–Agro A, Lowenberg B, Delwel R (2002) Hematopoietic cells expressing the peripheral cannabinoid receptor migrate in response to the endocannabinoid 2–arachidonoylglycerol. Blood 99:2786–2793CrossRefPubMedGoogle Scholar
  57. Joseph J, Niggemann B, Zaenker KS, Entschladen F (2004) Anandamide is an endogenous inhibitor for the migration of tumor cells and T lymphocytes. Cancer Immunol Immunother 53:723–728CrossRefPubMedGoogle Scholar
  58. Kaminski NE, Abood ME, Kessler FK, Martin BR, Schatz AR (1992) Identification of a functionally relevant cannabinoid receptor on mouse spleen cells that is involved in cannabinoid-mediated immune modulation. Mol Pharmacol 42:736–742PubMedGoogle Scholar
  59. Kaminski N, Koh WS, Yang KH, Lee M, Kessler FK (1994) Suppression of the humoral immune response by cannabinoids is partially mediated through inhibition of adenylate cyclase by a pertussis toxin-sensitive G–protein coupled mechanism. Biochem Pharmacol 48:1899–1908CrossRefPubMedGoogle Scholar
  60. Kaplan BL, Rockwell CE, Kaminski NE (2003) Evidence for cannabinoid receptor-dependent and –independent mechanisms of action in leukocytes. J Pharmacol Exp Ther 306:1077–1085PubMedGoogle Scholar
  61. Kawakami Y, Klein TW, Newton C, McCarthy CA, Djeu J, Dennert G, Specter S, Friedman H (1988) Suppression by cannabinoids of a cloned cell line with natural killer cell activity. Proc Soc Exp Biol Med 187:355–359PubMedGoogle Scholar
  62. Kishimoto S, Gokoh M, Oka S, Muramatsu M, Kajiwara T, Waku K, Sugiura T (2003) 2–Arachidonoylglycerol induces the migration of HL–60 cells differentiated into macrophage-like cells and human peripheral blood monocytes through the cannabinoid CB2 receptor-dependent mechanism. J Biol Chem 278:24469–24475CrossRefPubMedGoogle Scholar
  63. Kishimoto S, Kobayashi Y, Oka S, Gokoh M, Waku K, Sugiura T (2004) 2–Arachidonoylglycerol, an endogenous cannabinoid receptor ligand, induces accelerated production of chemokines in HL–60 cells. J Biochem (Tokyo) 135:517–524Google Scholar
  64. Klein TW (2005) Cannabinoid-based drugs as anti-inflammatory therapeutics. Nat Rev Immunol 5:400–411CrossRefPubMedGoogle Scholar
  65. Klein TW, Friedman H (1990) Modulation of murine immune cell function by marijuana components. In: R Watson (ed) Drugs of Abuse and Immune Function, Boca Raton, FL, CRC Press, pp 87–111Google Scholar
  66. Klein TW, Newton CA, Widen R, Friedman H (1985) The effect of delta–9–tetrahydrocannabinol and 11–hydroxy–delta–9–tetrahydrocannabinol on T lymphocyte and B lymphocyte mitogen responses. J Immunopharmacol 7:451–466PubMedGoogle Scholar
  67. Klein TW, Kawakami Y, Newton C, Friedman H (1991) Marijuana components suppress induction and cytolytic function of murine cytotoxic T cells in vitro and in vivo. J Toxicol Environ Health 32:465–477PubMedCrossRefGoogle Scholar
  68. Klein TW, Newton C, Friedman H (1994) Resistance to Legionella pneumophila suppressed by the marijuana component, tetrahydrocannabinol. J Infect Dis 169:1177–1179PubMedGoogle Scholar
  69. Klein TW, Newton CA, Nakachi N, Friedman H (2000) D9–tetrahydrocannabinol treatment suppresses immunity and early IFNγ, IL–12, and IL–12 receptor β2 responses to Legionella pneumophila infection. J Immunol 164:6461–6466PubMedGoogle Scholar
  70. Klein T, Newton C, Friedman H (1998a) Cannabinoid receptors and immunity. Immunol Today 19:373–381CrossRefPubMedGoogle Scholar
  71. Klein T, Friedman H, Specter S (1998b) Marijuana, immunity and infection. J Neuroimmunol 83:102–115CrossRefPubMedGoogle Scholar
  72. Klein TW, Newton C, Larsen K, Lu L, Perkins I, Nong L, Friedman H (2003) The cannabinoid system and immune modulation. J Leukoc Biol 74:486–496CrossRefPubMedGoogle Scholar
  73. Knoller N, Levi L, Shoshan I, Reichenthal E, Razon N, Rappaport ZH, Biegon A (2002) Dexanabinol (HU–211) in the treatment of severe closed head injury: a randomized, placebo-controlled, phase II clinical trial. Crit Care Med 30:548–554CrossRefPubMedGoogle Scholar
  74. Ligresti A, Morera E, Van Der Stelt M, Monory K, Lutz B, Ortar G, Di Marzo V (2004) Further evidence for the existence of a specific process for the membrane transport of anandamide. Biochem J 380:265–272CrossRefPubMedGoogle Scholar
  75. Liu J, Li H, Burstein SH, Zurier RB, Chen JD (2003) Activation and binding of peroxisome proliferator-activated receptor gamma by synthetic cannabinoid ajulemic acid. Mol Pharmacol 63:983–992CrossRefPubMedGoogle Scholar
  76. Lyman WD, Sonett JR, Brosnan CF, Elkin R, Bornstein MB (1989) Δ9–tetrahydrocannabinol: a novel treatment for experimental autoimmune encephalomyelitis. J Neuroimmunol 23:73–81CrossRefPubMedGoogle Scholar
  77. Maccarrone M, Valensise H, Bari M, Lazzarin N, Romanini C, Finazzi–Agro A (2001) Progesterone up-regulates anandamide hydrolase in human lymphocytes: role of cytokines and implications for fertility. J Immunol 166:7183–7189PubMedGoogle Scholar
  78. Malfait AM, Gallily R, Sumariwalla PF, Malik AS, Andreakos E, Mechoulam R, Feldmann M (2000) The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis [see comments]. Proc Natl Acad Sci U S A 97:9561–9566PubMedGoogle Scholar
  79. Marciano–Cabral F (1988) Biology of Naegleria spp. Microbiol Rev 52:114–133PubMedGoogle Scholar
  80. Massi P, Fuzio D, Vigano D, Sacerdote P, Parolaro D (2000) Relative involvement of cannabinoid CB(1) and CB(2) receptors in the Delta(9)–tetrahydrocannabinol–induced inhibition of natural killer activity. Eur J Pharmacol 387:343–347CrossRefPubMedGoogle Scholar
  81. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI (1990) Structure of cannabinoid receptor and functional expression of the cloned cDNA. Nature 346:561–564PubMedGoogle Scholar
  82. McCoy KL, Gainey D, Cabral GA (1995) Δ9–Tetrahydrocannabinol modulates antigen processing by macrophages. J Pharmacol Exp Ther 273:1216–1223PubMedGoogle Scholar
  83. McCoy KL, Matveyeva M, Carlisle SJ, Cabral GA (1999) Cannabinoid inhibition of the processing of intact lysozyme by macrophages: evidence for CB2 receptor participation. J Pharmacol Exp Ther 289:1620–1625PubMedGoogle Scholar
  84. Mechoulam R, Ben–Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, Gopher A, Almog S, Martin BR, Compton DR, Pertwee RG, Griffin G, Bayewitch M, Barg J, Vogel Z (1995) Identification of an endogenous 2–monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol 50:83–90PubMedGoogle Scholar
  85. Mechoulam R, Panikashvili D, Shohami E (2002) Cannabinoids and brain injury: therapeutic implications. Trends Mol Med 8:58–61CrossRefPubMedGoogle Scholar
  86. Mishkin EM, Cabral GA (1985) Delta–9–tetrahydrocannabinol decreases host resistance to herpes simplex virus type 2 vaginal infection in the B6C3F1 mouse. J Gen Virol 66:2539–2549PubMedGoogle Scholar
  87. Mitchell VA, Aslan S, Safaei R, Vaughan CW (2005) Effect of the cannabinoid ajulemic acid on rat models of neuropathic and inflammatory pain. Neurosci Lett 382:231–235CrossRefPubMedGoogle Scholar
  88. Molina–Holgado F, Molina–Holgado E, Guaza C (1998) The endogenous cannabinoid anandamide potentiates interleukin–6 production by astrocytes infected with Theiler's murine encephalomyelitis virus by a receptor-mediated pathway. FEBS Lett 433:139–142CrossRefPubMedGoogle Scholar
  89. Molina–Holgado F, Pinteaux E, Moore JD, Molina–Holgado E, Guaza C, Gibson RM, Rothwell NJ (2003) Endogenous interleukin–1 receptor antagonist mediates anti–inflammatory and neuroprotective actions of cannabinoids in neurons and glia. J Neurosci 23:6470–6474PubMedGoogle Scholar
  90. Morahan PS, Klykken PC, Smith SH, Harris LS, Munson AE (1979) Effects of cannabinoids on host resistance to Listeria monocytogenes and herpes simplex virus. Infect Immun 23:670–674PubMedGoogle Scholar
  91. Munro S, Thomas KL, Abu–Shaar M (1993) Molecular characterization of a peripheral receptor for cannabinoids. Nature 365:61–65PubMedGoogle Scholar
  92. Nakano Y, Pross SH, Friedman H (1992) Modulation of interleukin 2 activity by Δ9–tetrahydrocannabinol after stimulation with concanavalin A, phytohemagglutinin, or anti-CD3 antibody. Proc Soc Exp Biol Med 201:165–168PubMedGoogle Scholar
  93. Offertaler L, Mo FM, Batkai S, Liu J, Begg M, Razdan RK, Martin BR, Bukoski RD, Kunos G (2003) Selective ligands and cellular effectors of a G protein-coupled endothelial cannabinoid receptor. Mol Pharmacol 63:699–705CrossRefPubMedGoogle Scholar
  94. Okamoto Y, Morishita J, Tsuboi K, Tonai T, Ueda N (2004) Molecular characterization of a phospholipase D generating anandamide and its congeners. J Biol Chem 279:5298–5305CrossRefPubMedGoogle Scholar
  95. Panikashvili D, Simeonidou C, Ben–Shabat S, Hanus L, Breuer A, Mechoulam R, Shohami E (2001) An endogenous cannabinoid (2–AG) is neuroprotective after brain injury. Nature 413:527–531CrossRefPubMedGoogle Scholar
  96. Pertwee RG (2002) Cannabinoids and multiple sclerosis. Pharmacol Ther 95:165–174CrossRefPubMedGoogle Scholar
  97. Porter AC, Sauer JM, Knierman MD, Becker GW, Berna MJ, Bao J, Nomikos GG, Carter P, Bymaster FP, Leese AB, Felder CC (2002) Characterization of a novel endocannabinoid, virodhamine, with antagonist activity at the CB1 receptor. J Pharmacol Exp Ther 301:1020–1024PubMedGoogle Scholar
  98. Puffenbarger RA, Boothe AC, Cabral GA (2000) Cannabinoids inhibit LPS–inducible cytokine mRNA expression in rat microglial cells. Glia 29:58–69CrossRefPubMedGoogle Scholar
  99. Ramirez BG, Blazquez C, Gomez del Pulgar T, Guzman M, de Ceballos ML (2005) Prevention of Alzheimer's disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. J Neurosci 25:1904–1913CrossRefPubMedGoogle Scholar
  100. Rayman N, Lam KH, Laman JD, Simons PJ, Lowenberg B, Sonneveld P, Delwel R (2004) Distinct expression profiles of the peripheral cannabinoid receptor in lymphoid tissues depending on receptor activation status. J Immunol 172:2111–2117PubMedGoogle Scholar
  101. Rhee MH, Vogel Z, Barg J, Bayewitch M, Levy R, Hanus L, Breuer A, Mechoulam R (1997) Cannabinol derivatives: binding to cannabinoid receptors and inhibition of adenylylcyclase. J Med Chem 40:3228–3233CrossRefPubMedGoogle Scholar
  102. Rog DJ, Nurmikko TJ, Friede T, Young CA (2005) Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology 65:812–819PubMedGoogle Scholar
  103. Saario SM, Savinainen JR, Laitinen JT, Jarvinen T, Niemi R (2004) Monoglyceride lipase-like enzymatic activity is responsible for hydrolysis of 2–arachidonoylglycerol in rat cerebellar membranes. Biochem Pharmacol 67:1381–1387CrossRefPubMedGoogle Scholar
  104. Sacerdote P, Massi P, Panerai AE, Parolaro D (2000) In vivo and in vitro treatment with the synthetic cannabinoid CP55, 940 decreases the in vitro migration of macrophages in the rat: involvement of both CB1 and CB2 receptors. J Neuroimmunol 109:155–163CrossRefPubMedGoogle Scholar
  105. Schwarz H, Blanco FJ, Lotz M (1994) Anandamide, an endogenous cannabinoid receptor agonist inhibits lymphocyte proliferation and induces apoptosis. J Neuroimmunol 55:107–115CrossRefPubMedGoogle Scholar
  106. Shohami E, Gallily R, Mechoulam R, Bass R, Ben–Hur T (1997) Cytokine production in the brain following closed head injury: dexanabinol (HU–211) is a novel TNF–alpha inhibitor and an effective neuroprotectant. J Neuroimmunol 72:169–177CrossRefPubMedGoogle Scholar
  107. Smith SR, Terminelli C, Denhardt G (2000) Effects of cannabinoid receptor agonist and antagonist ligands on production of inflammatory cytokines and anti-inflammatory interleukin–10 in endotoxemic mice. J Pharmacol Exp Ther 293:136–150PubMedGoogle Scholar
  108. Srivastava MD, Srivastava BIS, Brouhard B (1998) Δ9 Tetrahydrocannabinol and cannabidiol alter cytokine production by human immune cells. Immunopharmacology 40:179–185CrossRefPubMedGoogle Scholar
  109. Stefano GB, Bilfinger TV, Rialas CM, Deutsch DG (2000) 2–Arachidonyl–glycerol stimulates nitric oxide release from human immune and vascular tissues and invertebrate immunocytes by cannabinoid receptor 1. Pharmacol Res 42:317–322CrossRefPubMedGoogle Scholar
  110. Sugiura T, Kondo S, Sukagawa A, Tonegawa T, Nakane S, Yamashita A, Waku K (1996) Enzymatic synthesis of anandamide, an endogenous cannabinoid receptor ligand, through N–acylphosphatidylethanolamine pathway in testis: involvement of Ca(2+)–dependent transacylase and phosphodiesterase activities. Biochem Biophys Res Commun 218:113–117CrossRefPubMedGoogle Scholar
  111. Sugiura T, Kobayashi Y, Oka S, Waku K (2002) Biosynthesis and degradation of anandamide and 2–arachidonoylglycerol and their possible physiological significance. Prostaglandins Leukot Essent Fat Acids 66:173–192CrossRefGoogle Scholar
  112. Svendsen KB, Jensen TS, Bach FW (2004) Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial. BMJ 329:253CrossRefPubMedGoogle Scholar
  113. Tomida I, Pertwee RG, Azuara–Blanco A (2004) Cannabinoids and glaucoma. Br J Ophthalmol 88:708–713CrossRefPubMedGoogle Scholar
  114. Valk P, Verbakel S, Vankan Y, Hol S, Mancham S, Ploemacher R, Mayen A, Lowenberg B, Delwel R (1997) Anandamide, a natural ligand for the peripheral cannabinoid receptor is a novel synergistic growth factor for hematopoietic cells. Blood 90:1448–1457PubMedGoogle Scholar
  115. Vaney C, Heinzel–Gutenbrunner M, Jobin P, Tschopp F, Gattlen B, Hagen U, Schnelle M, Reif M (2004) Efficacy, safety and tolerability of an orally administered cannabis extract in the treatment of spasticity in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled, crossover study. Mult Scler 10:417–424CrossRefPubMedGoogle Scholar
  116. Varga K, Wagner JA, Bridgen DT, Kunos G (1998) Platelet– and macrophage-derived endogenous cannabinoids are involved in endotoxin-induced hypotension. FASEB J 12:1035–1044PubMedGoogle Scholar
  117. Veldhuis WB, van der Stelt M, Wadman MW, van Zadelhoff G, Maccarrone M, Fezza F, Veldink GA, Vliegenthart JF, Bar PR, Nicolay K, Di Marzo V (2003) Neuroprotection by the endogenous cannabinoid anandamide and arvanil against in vivo excitotoxicity in the rat: role of vanilloid receptors and lipoxygenases. J Neurosci 23:4127–4133PubMedGoogle Scholar
  118. Wade DT, Makela P, Robson P, House H, Bateman C (2004) Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients. Mult Scler 10:434–441CrossRefPubMedGoogle Scholar
  119. Wagner JA, Varga K, Kunos G, Bridgen DT (1998) Cardiovascular actions of cannabinoids and their generation during shock platelet– and macrophage–derived endogenous cannabinoids are involved in endotoxin–induced hypotension. J Mol Med 76:824–836CrossRefPubMedGoogle Scholar
  120. Wagner JA, Jarai Z, Batkai S, Kunos G (2001) Hemodynamic effects of cannabinoids: coronary and cerebral vasodilation mediated by cannabinoid CB(1) receptors. Eur J Pharmacol 423:203–210CrossRefPubMedGoogle Scholar
  121. Waksman Y, Olson JM, Carlisle SJ, Cabral GA (1999) The central cannabinoid receptor (CB1) mediates inhibition of nitric oxide production by rat microglial cells. J Pharmacol Exp Ther 288:1357–1366PubMedGoogle Scholar
  122. Wang Y, Liu Y, Ito Y, Hashiguchi T, Kitajima I, Yamakuchi M, Shimizu H, Matsuo S, Imaizumi H, Maruyama I (2001) Simultaneous measurement of anandamide and 2–arachidonoylglycerol by polymyxin B–selective adsorption and subsequent high-performance liquid chromatography analysis: increase in endogenous cannabinoids in the sera of patients with endotoxic shock. Anal Biochem 294:73–82CrossRefPubMedGoogle Scholar
  123. Watzl B, Scuderi P, Watson RR (1991) Influence of marijuana components (THC and CBD) on human mononuclear cell cytokine secretion in vitro. In: H Friedman, S Specter, TW Klein (eds) Advances in Experimental Medicine and Biology, Plenum, New York, pp 63–70Google Scholar
  124. Welch SP, Huffman JW, Lowe J (1998) Differential blockade of the antinociceptive effects of centrally administered cannabinoids by SR141716A. J Pharmacol Exp Ther 286:1301–1308PubMedGoogle Scholar
  125. Wirguin I, Mechoulam R, Breuer A, Schezen E, Weidenfeld J, Brenner T (1994) Suppression of experimental autoimmune encephalomyelitis by cannabinoids. Immunopharmacology 28:209–214CrossRefPubMedGoogle Scholar
  126. Yebra M, Klein TW, Friedman H (1992) Δ9–Tetrahydrocannabinol suppresses concanavalin A induced increase in cytoplasmic free calcium in mouse thymocytes. Life Sci 51:151–160CrossRefPubMedGoogle Scholar
  127. Zhu W, Igarashi T, Friedman H, Klein TW (1995) Δ9–Tetrahydrocannabinol (THC) causes the variable expression of IL2 receptor subunits. J Pharmacol Exp Ther 274:1001–1007PubMedGoogle Scholar
  128. Zhu LX, Sharma S, Stolina M, Gardner B, Roth MD, Tashkin DP, Dubinett SM (2000) Δ–9–tetrahydrocannabinol inhibits antitumor immunity by a CB2 receptor-mediated, cytokine-dependent pathway. J Immunol 165:373–380PubMedGoogle Scholar
  129. Zurier RB, Rossetti RG, Lane JH, Goldberg JM, Hunter SA, Burstein SH (1998) Dimethylheptyl–THC–11 oic acid. A nonpsychoactive antiinflammatory agent with a cannabinoid template structure. Arthritis Rheum 41:163–170CrossRefPubMedGoogle Scholar
  130. Zurier RB, Rossetti RG, Burstein SH, Bidinger B (2003) Suppression of human monocyte interleukin–1beta production by ajulemic acid, a nonpsychoactive cannabinoid. Biochem Pharmacol 65:649–655CrossRefPubMedGoogle Scholar
  131. Zygmunt PM, Petersson J, Andersson DA, Chuang H, Sorgard M, Di Marzo V, Julius D, Hogestatt ED (1999) Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400:452–457CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media 2006

Authors and Affiliations

  1. 1.Department of Medical Microbiology and ImmunologyUniversity of South Florida College of MedicineTampaUSA
  2. 2.Department of Microbiology and ImmunologyVirginia Commonwealth University, School of MedicineRichmondUSA

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